EFSA Issues Advice on DRVs for Zinc, Selenium and Chromium

14 Oct 2014 --- The European Food Safety Authority (EFSA) has published scientific opinions on dietary reference values (DRVs) for zinc, selenium and chromium. The opinions were all made available for public consultation before being finalised. They are part of EFSA’s ongoing review of existing advice on DRVs for energy, macronutrients and micronutrients.

Zinc has a wide array of vital physiological functions. It has a catalytic role in each of the six classes of enzymes. The human transcriptome has 2,500 zinc finger proteins, which have a broad intracellular distribution and the activities of which include binding of RNA molecules and involvement in protein–protein interactions. Thus, their biological roles include transcriptional and translational control/modulation and signal transduction.

The majority of dietary zinc is absorbed in the upper small intestine. The luminal contents of the duodenum and jejunum, notably phytate, can have a major impact on the percentage of zinc that is available for absorption. Absorption of zinc by the enterocyte is regulated in response to the quantity of bioavailable zinc ingested. Albumin is the major transporter of zinc in both portal and systemic circulation. Virtually no zinc circulates in a free ionised form, and the majority of total body zinc is in muscle and bone; zinc does not have an identified major storage site. The quantity of zinc secreted into and excreted from the intestinal tract depends on body zinc concentrations, and the quantities of endogenous zinc in the faeces and exogenous zinc absorbed in normal adults are related. The kidneys and integument are minor routes of loss of endogenous zinc.

Plasma/serum zinc concentration and other putative biomarkers of zinc adequacy, deficiency and excess are not useful for estimating DRVs for zinc. Zinc requirements have been estimated by the factorial approach involving two stages. The first is the estimation of physiological requirements, defined as the minimum quantity of absorbed zinc needed to match losses of endogenous zinc and to meet any additional requirements for absorbed zinc that may be necessary for growth in healthy well-nourished infants and children, and in pregnancy and lactation. The second stage is the determination of the quantity of dietary zinc available for absorption that is needed to meet these physiological requirements. From the published literature, 15 studies were identified that included data on endogenous faecal zinc and total absorbed zinc that enabled an estimation to be made of the physiological zinc requirements of adults. Individual’s data from these studies were supplied by the authors. Data were assessed for physiological plausibility and, after careful evaluation, some data were excluded from further calculations. The final numbers of subjects contributing data to the estimate of physiological zinc requirements were 31 males and 54 females, from a total of 10 studies. Dietary phytate intakes were available for some of the included studies, either as mean study values or as individual’s data. The range of dietary phytate intakes in the available data was 0–2 080 mg/day. Multiple regression analysis was used to evaluate the possible relationships between physiological requirements and sex, zinc balance (difference between absorbed zinc and total losses of endogenous zinc) and body size. The coefficient of determination (R2) values for the models with body weight, height, body mass index and body surface area variables were 0.46, 0.42, 0.37 and 0.47, respectively. It was decided to use the equation relating physiological requirement to body weight in further analyses, for reasons of convenience and accuracy of measurement. The equation for physiological requirement was calculated on the basis that physiological requirement is equivalent to total absorbed zinc when absorbed zinc minus total endogenous zinc losses equals zero at a given body weight. For deriving the dietary zinc requirement, a trivariate saturation response model of the relationship between zinc absorption, and dietary zinc and phytate was established using 72 mean datasets (reflecting 650 individual measurements) reported in 18 publications. The R2 of the fit of this model was 0.81. From this model, the Average Requirement (AR) was determined as the intercept of the total absorbed zinc needed to meet physiological requirements. Estimated ARs and Population Reference Intakes (PRIs) for zinc are provided for phytate intake levels of 300, 600, 900 and 1 200 mg/day, which cover the range of mean/median phytate intakes observed in European populations. ARs range from 6.2 to 10.2 mg/day for women with a reference body weight of 58.5 kg and from 7.5 to 12.7 mg/day for men with a reference body weight of 68.1 kg. PRIs for adults were estimated as the zinc requirement of individuals with a body weight at the 97.5th percentile for reference body weights for men and women, respectively, and range from 7.5 to 12.7 mg/day for women and from 9.4 to 16.3 mg/day for men.

For infants from seven months of age and children, DRVs for zinc were derived using the factorial approach, taking into account endogenous zinc losses via urine, sweat and integument, faeces and, in adolescent boys and girls, semen and menses, respectively, as well as zinc required for synthesis of new tissue for growth. Urinary and integumental losses were extrapolated based on estimates of adult losses, whereas endogenous faecal zinc losses were estimated by linear regression analysis of endogenous faecal zinc losses versus body weight for the subjects contributing data to the adult estimates, and for infants and young children from two studies from China and the USA. Zinc requirements for growth were taken into account based on the zinc content of new tissue, and by estimating daily weight gains for each age group. Absorption efficiency of zinc from mixed diets was assumed to be 30 %. Estimated ARs range from 2.4 mg/day in infants aged 7–11 months to 11.8 mg/day in adolescent boys. Owing to the absence of reference body weights for infants and children at the 97.5th percentile, and in the absence of knowledge about the variation in requirements, PRIs for infants and children were estimated based on a coefficient of variation (CV) of 10 %, and range from 2.9 to 14.2 mg/day.

The physiological requirements for pregnancy and lactation can be calculated by adding the increases in physiological requirements that are predicted to meet the demands for new tissue primarily of the conceptus, and the replacement of zinc that is secreted in breast milk. For pregnancy, an additional requirement for zinc for the four quarters of pregnancy of about 0.4 mg/day was assumed because of zinc accumulation in the fetus; placental, uterine and mammary tissue; amniotic fluid and maternal blood. The Panel decided not to use the trivariate model to estimate the dietary zinc intake required to meet the additional physiological requirement. Instead, the Panel applied a mean fractional absorption of zinc of 0.3 that has been observed in healthy adults to the physiological requirement of 0.4 mg/day. The additional requirement for pregnant women was calculated to be 1.3 mg/day and the additional PRI for pregnancy was estimated based on a CV of 10 % and was 1.6 mg/day.

For lactation, taking into account breast milk zinc concentration, the breast milk volume transferred and the postnatal redistribution of zinc owing to involution of the uterus and reduction of maternal blood volume, the additional physiological requirement calculated over six months of lactation was estimated to be 1.1 mg/day. Assuming that fractional absorption of zinc is increased 1.5-fold in lactation, and applying a fractional absorption of zinc of 0.45 to the additional physiological requirement of 1.1 mg/day, resulted in an additional dietary requirement for lactating women of 2.4 mg/day. The additional PRI for lactation, based on a CV of 10 %, was 2.9 mg/day.

Meat, legumes, eggs, fish, and grains and grain-based products are rich dietary zinc sources. On the basis of data from 12 dietary surveys in nine European Union (EU) countries, zinc intake was assessed using food consumption data from the EFSA Comprehensive Food Consumption Database and zinc composition data from the EFSA nutrient composition database. Average zinc intake ranged from 4.6 to 6.2 mg/day in children aged one to less than three years, from 5.5 to 9.3 mg/day in children aged 3 to < 10 years, from 6.8 to 14.5 mg/day in adolescents (10 to < 18 years) and from 8.0 and 14.0 mg/day in adults. The main food groups contributing to zinc intake were meat and meat products, grains and grain-based products, and milk and dairy products. Published data on phytate intake in the EU are limited and indicate a wide range of dietary phytate intakes.

In the diet, selenium is mainly present in organic compounds, as l-selenomethionine and l-selenocysteine, with lower amounts in inorganic compounds, as selenate and selenite. Because quantification and speciation of selenium in foods is complex and because there is considerable variation in the selenium content of foods, food composition tables are often inaccurate, resulting in imprecise estimates of selenium intake.

A total of 25 selenoproteins with a variety of functions, including antioxidant effects, T-cell immunity, thyroid hormone metabolism, selenium homeostasis and transport, and skeletal and cardiac muscle metabolism, have been identified in humans. Selenoprotein P (SEPP1) plays a central role in selenium supply to tissues and participates in the regulation of selenium metabolism in the organism.

Selenium in its various forms appears to be well absorbed from the diet. Upon absorption, selenocysteine, selenate and selenite are available for the synthesis of selenoproteins. Selenomethionine is non-specifically integrated into the methionine pool and can substitute for methionine in proteins. Selenomethionine may also be converted to selenocysteine and enter the functional selenium body pool. The production of methylated selenium compounds in the liver, which are excreted predominantly in the urine, participates in the regulation of selenium metabolism in the organism.

Selenium deficiency affects the expression and function of selenoproteins and has been involved in the degeneration of organs and tissues leading to the manifestation of Keshan and Kashin-Beck diseases.

Plasma selenium includes selenium in selenoproteins (the functional pool of selenium), and other plasma proteins in which selenomethionine non-specifically substitutes for methionine. Thus, plasma selenium is not a direct marker of the functional selenium body pool. Measures of glutathione peroxidases (GPxs) activity can be used as a biomarker of selenium function. However, the activity of GPxs reaches a steady state with levels of selenium intake that are lower than those required for the levelling off of SEPP1. The latter is considered the most informative biomarker of selenium function on the basis of its role in selenium transport and metabolism and its response to different forms of selenium intake. Intervention studies using different levels of selenium intake showed that plasma SEPP1 concentration levels off in response to increasing doses of selenium. The levelling off of plasma SEPP1 was considered to be indicative of an adequate supply of selenium to all tissues and to reflect saturation of the functional selenium body pool, ensuring that selenium requirement is met. This criterion was used for establishing DRVs for selenium in adults.

Evidence from human studies on the relationship between selenium intake and plasma SEPP1 concentration was reviewed. The Panel noted uncertainties with respect to estimates of background selenium intake in most studies. Habitual selenium intakes of 50–60 µg/day were not sufficient for SEPP1 concentration to reach a plateau in Finnish individuals, while selenium intakes of 100 µg/day and above were consistently associated with plasma SEPP1 concentration at a plateau in population groups from Finland, the UK and the USA. In a study in healthy individuals from New Zealand, selenium intakes of around 60–70 µg/day were required for SEPP1 concentration to level off. Although this was the only study that quantified background selenium intake from the analysed selenium content of consumed foods, the Panel noted the large variability in the results of this study. In another study among Chinese subjects, a selenium intake of 0.85 µg/kg body weight per day led to the levelling off of plasma SEPP1 concentration. The Panel noted, however, that there were uncertainties related to the intake estimates and to the extrapolation of results from Chinese individuals to the European population.The Panel also noted uncertainties in extrapolating values derived from studies that administered selenium as l-selenomethionine to dietary selenium including other forms of selenium.

Given the uncertainties in available data on the relationship between total selenium intake and SEPP1 concentration, they were considered insufficient to derive an Average Requirement for selenium in adults. Instead, an Adequate Intake (AI) of 70 µg/day for adult men and women was set. A review of observational studies and randomised controlled trials that investigated the relationship between selenium and health outcomes did not provide evidence for additional benefits associated with selenium intake beyond that required for the levelling off of SEPP1.

No specific indicators of selenium requirements were available for infants, children or adolescents.

For infants aged 7–11 months, an AI of 15 µg/day was derived by extrapolating upwards from the estimated selenium intake with breast milk of younger exclusively breast-fed infants and taking into account differences in reference body weights. For children and adolescents, the AIs for selenium were extrapolated from the AI for adults by isometric scaling and application of a growth factor. The AIs range from 15 µg/day for children aged one to three years to 70 µg/day for adolescents aged 15–17 years.

There is evidence suggesting adaptive changes in the metabolism of selenium during pregnancy, and it was considered that these changes cover the additional selenium needs during this period. The Panel proposes that the AI set for adult women also applies to pregnancy. Based on an average amount of selenium secreted in breast milk of 12 μg/day and an absorption efficiency of 70 % from usual diets, an additional selenium intake of 15 µg/day was considered to replace these losses. Thus, an AI of 85 μg/day is proposed for lactating women.

In 1993, the Scientific Committee for Food was unable to define a specific physiological requirement of chromium and did not propose DRVs for chromium, but other authorities have subsequently proposed DRVs for chromium.

Trivalent chromium (Cr(III)) has been reported as an essential trace element in that it has been postulated to be necessary for the efficacy of insulin in regulating the metabolism of carbohydrates, lipids and proteins. However, at present, the mechanism(s) for these roles and the essential function of chromium in metabolism have not been substantiated. The postulation of chromium’s essentiality for humans was almost entirely based on case reports of patients on long-term total parenteral nutrition (TPN) who developed metabolic and neurological defects, which were reported to respond to supplementation with Cr(III). The Panel noted that the chromium concentrations in the TPN solutions that induced the presumed deficiency symptoms were not reported in all the patients studied. In the three studies in which the concentration of chromium in the TPN solution was reported, the daily chromium supply was between 5 and 10 µg; at an absorption efficiency of 5 % this amount of infused chromium is equivalent to an oral intake of 100–200 µg/day. The Panel notes that this intake is well above the estimated mean daily intakes in the 17 European countries for which data were available to perform an assessment of chronic dietary chromium intake. On the basis of these case reports, the Panel concludes that it is unclear whether deficiency of chromium has occurred in these patients and whether chromium deficiency occurs in healthy populations.

The Panel considered the criteria for the essentiality of a trace element and noted that attempts to create chromium deficiency in animal models have not produced consistent results, that there is no evidence of essentiality of Cr(III) as a trace element in animal nutrition and that Cr(III) requirements could not be established for animal feed. The Panel considered that there is a possibility that Cr(III) is an essential trace element for humans, but that there is, as yet, no convincing evidence of this. The evidence from reported improvements associated with chromium supplementation in patients on TPN is arguably the most convincing, but overall these data do not provide sufficient information on the reversibility of the possible deficiencies and on the nature of any dose–response curve in order to identify a dietary requirement for humans. The existence and functional characterisation of a chromium–oligopeptide complex (chromodulin) is still unclear.

The Panel concludes that no Average Requirement and no Population Reference Intake for chromium for the performance of physiological functions can be defined.

Nevertheless, as for fluoride, DRVs might be derived if a consistent dose–response relationship could be established between dietary chromium intake and a beneficial health outcome. A comprehensive search of the literature published between January 1990 and October 2011 was performed to identify relevant health outcomes upon which DRVs for chromium may potentially be based. Several studies that assessed the effect of chromium supplementation on glucose and/or lipid metabolism were retrieved in the literature search. In most studies, chromium intake from the diet was not assessed, and information on total chromium intake is therefore not available. In one cross-over study for which total chromium intake was available, there was no significant difference in the parameters of glucose metabolism between the placebo and chromium-supplemented periods in normoglycaemic subjects. The Panel considered that there is no evidence of beneficial effects associated with chromium intake in healthy subjects. The Panel concludes that the setting of an Adequate Intake for chromium is also not appropriate.

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