An overview of international reference values for vitamin E intake – similarities and differences in derivation

Abstract

Purpose

The scientific knowledge for the essential fat-soluble vitamin E (VitE) remains inconclusive. There is still a lack of valid status parameters and deficiency symptoms for insufficient intake. Therefore, the derivation of a dietary reference value (DRV) for VitE is challenging and differs between the different organizations and countries. The aim of the current paper is to provide an overview of selected international DRVs and discuss the different derivation procedures.

Methods

DRVs from sixteen countries and international organizations were retrieved, compared and evaluated.

Results

The DRVs are inconsistent in the absolute value as well as the employed concept of derivation. Due to the uncertainty of the available data some organizations did not specify a DRV. Others used plasma cut off levels or the required amount for the protection of polyunsaturated fatty acids against oxidation. Many DRVs are based on population intake data and given as adequate intake. But this approach may overestimate the VitE needs.

Conclusion

In conclusion, due to missing symptoms and markers of insufficient supply, the compensation of daily losses with the consideration of the bioavailability appears to be a good basis for deriving a DRV for VitE intake. A balanced and plant-based diet (without supplements) appears to be sufficient for an adequate VitE supply.

Introduction

Vitamin E (VitE) belongs to the group of fat-soluble vitamins and comprises a family of eight plant-derived compounds (α-, β-, γ-, δ-tocopherols and α-, β-, γ-, δ-tocotrienols) [1]. In addition to these eight VitE congeners other less-known tocochromanols such as tocomonoenols and tocodienols have been suggested as potential VitE congeners [2]. In the diet, α- and γ-tocopherol are the main congeners and in Europe mainly α-tocopherol is consumed [3, 4]. VitE occurs dominantly in lipid-containing parts of plants such as nuts and seeds; consequently, vegetable oils obtained from nuts and seeds are good sources for VitE. Almonds, hazelnuts, germ oil, canola and sunflower oil contain high amounts of α-tocopherol, while γ-tocopherol is the predominant form in walnuts, palm oil and soybeans [5, 6]. The most biologically active and retained form of VitE in the body is α-tocopherol, due to the selection by the hepatic α-tocopherol transfer protein (α-TTP). It preferentially binds α-tocopherol in the liver and transfers it to lipoproteins for further circulation in the blood. Hepatic VitE catabolism serves to release excessive amounts of α-tocopherol and to promote the excretion of non-α-tocopherol congeners, in turn decreasing blood concentrations of non-α-tocopherol relative to the blood concentrations of α-tocopherol [7].

To consider the different dietary forms of VitE and their differences in bioactivity compared to α-tocopherol (based on animal experiments), sometimes α-tocopherol equivalents (α-TE) are used e.g. 1 mg of RRR-α-tocopherol equivalent corresponds to 1 mg of RRR-α-tocopherol or 4 mg RRR-γ-tocopherol (D-γ-tocopherol) [8]. Although the term “vitamin E” is often used to refer to the various forms, so far only for α-tocopherol has been demonstrated to have a vitamin property, i.e. a protective effect against human deficiency disease [2]. Therefore, there is an ongoing discussion that the name “vitamin E” should only be used for α-tocopherol [9].

α-Tocopherol is a powerful antioxidant molecule located primarily within the phospholipid bilayer of cell membranes. The major biological roles are to protect (poly)unsaturated fatty acids (PUFA) and other components of cell membranes as well as low-density lipoproteins (LDL) from oxidation by free radicals, like reactive oxygen species. VitE (especially α- and γ-tocopherol) is particularly effective in preventing lipid peroxidation, a series of chemical reactions involving the oxidative degradation of PUFAs [8]. Therefore, α-tocopherol is considered to be essential for membrane stability, especially for the stabilization of erythrocytes and nerve conductivity of the central as well as peripheral nervous system [10]. VitE, especially α-tocopherol, also seems to have non-antioxidant activities, such as the modulation of gene expression, the inhibition of cell proliferation, and the regulation of bone mass. In addition, it influences the activity of enzymes such as protein kinase C (PKC), protein phosphatase 2 A (PPA2), cyclooxygenase 2 (COX-2), and 5-lipoxygenase (5-LOX), thereby affecting the eicosanoid synthesis and the immune system [11, 12]. There is also evidence from in vitro and in vivo studies that suggest a regulatory potential of vitamin E metabolites, especially in inflammatory processes [13].

The metabolism of VitE is tightly regulated, and unlike other fat-soluble vitamins there is no toxic accumulation in the liver. Excessive amounts of α-tocopherol as well as all other tocopherol congeners and all tocotrienols are initially catabolized in the liver by cytochrome P450 enzymes, namely CYP4F2 or CYP3A4, resulting in the formation of side-chain-carboxylated metabolites which are subsequently β-oxidised in peroxisomes and mitochondria into water-soluble catabolic metabolites that are excreted in urine and faeces [14, 15].

Absorption and bioavailability of VitE are influenced by many exogenous and endogenous factors, exhibit high inter-individual variability, and are associated to lipoprotein metabolism. Efficient absorption of VitE requires the presence of dietary fat. As VitE is naturally occurring with fat in foods, good absorption is usually given in a balanced diet. The average absorption rate in a normal mixed diet is around 75%, but varies from about 10% to 80% for different fat intakes [6, 16]. This average amount is based on the results of two balance studies and a kinetic study using a multi-compartmental model of α-tocopherol metabolism and is also consistent with the high efficiency of lipid absorption from the diet [6].

So far, no valid biomarkers for VitE status and intake have been identified [6, 17]. The concentration of α-tocopherol in plasma or serum is often used to determine the supply of VitE. But there are several factors affecting plasma α-tocopherol concentrations such as gender, lifestyle, genetic predisposition, obesity, blood lipid concentrations, metabolic syndrome or high levels of oxidative stress, that cause variations in the absorption, metabolism and excretion of α-tocopherol [15, 18, 19]. Even if α-tocopherol concentrations in plasma or serum alone are not valid markers for estimating VitE status in humans, studies indicate that α-tocopherol concentrations of < 12 µmol/L can be classified as insufficient, due to a higher risk of erythrocyte haemolysis [20].

According to studies in humans, so far only α-tocopherol meets VitE requirements for humans. This is based on the observation that α-tocopherol reverses deficiency symptoms, most notably neurological impairments, in patients with Ataxia with Vitamin E Deficiency (AVED) [9, 21]. However, several studies in cell and animal models as well as humans indicate that other non-α-tocopherols and tocotrienols, especially γ-tocopherol and α-tocotrienol, as well as their metabolites also have bioactive properties [3, 4, 22]. In general, deficiency symptoms of VitE are rare and mainly occur due to genetic or other disorders affecting absorption and/or metabolism of VitE, rather than a low dietary intake [17].

More than 100 years after its discovery as a vitamin in rats, it is still challenging to define human requirements for VitE. Thanks to intensive basic research on VitE e.g. with use of stable isotopes and to improved analytical methods, recent studies throw new light on the metabolism and functions of the different VitE forms and their metabolites [10].

However, there is still a lack of data from human studies to define valid biomarkers and to assess adequate intake and derive reference values. The variety of dietary intake recommendations for VitE in values, gender and type of VitE congener demonstrate that there is still uncertainty about how the VitE requirements should be determined. Furthermore, current research shows that there is a constant need to review, define, and assess the dietary requirements for VitE or only for α-tocopherol in different populations, life stages or other conditions [18, 19].

The aim of the current review is to provide an overview on the current dietary reference values provided in recent dietary recommendations from sixteen countries and major international organizations and the different procedures used for the derivation of VitE (or α-tocopherol) requirements.

Methods

The literature search was conducted as part of the revision of the DRV for Germany and Austria. Therefore, the official dietary reference values from western industrialised countries (i.e. Australia, France, Germany and Austria, Ireland, Italy, Japan, New Zealand, Spain, Switzerland, the United Kingdom, and the United States of America) were collected by screening the official websites of the representative national nutrition societies or health ministries. In addition, values from major international organizations, including the Nordic Nutrition Recommendations, the European Food Safety Authority, the World Health Organization, and the Food and Agriculture Organization of the United Nations, were gathered. An additional literature search was conducted in PubMed database and Google Scholar. The inclusion criteria were: published official dietary reference values for VitE or its derivatives for adults in western industrialised countries in the following languages: German, English, French, Spanish and Italian. The search was performed by one author in June 2024 with an update in March 2025. These reference values and their scientific derivations were then evaluated and compared.

International dietary reference values for vitamin E intake

Overview of current dietary reference values for vitamin E intake

Derivation based on the intake of polyunsaturated fatty acids

The latest updated dietary reference values for VitE are found in the Nordic Nutrition Recommendations (NNR), which were revised in 2023 based on a systematic literature screening and quality control of all articles published in PubMed by using an NNR-adjusted AMSTAR2 checklist. The NNR 2023 report constitutes scientific advice to the national authorities in Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway, and Sweden [23]. In the derivation process, no new studies could be identified that are relevant for a reassessment of the derivation for VitE from the previous NNR in 2012.

Nevertheless, the scientific board working on the derivation decided to make changes of the dietary reference values. The dietary reference values for VitE of the NNR 2023 are no longer a recommended intake based on the estimated average requirement. The values have been replaced by an adequate intake and a provisional average requirement. The provisional average requirement is a newly developed parameter which has a larger uncertainty than an estimated average requirement. It is calculated by multiplying adequate intake by a factor of 0.8 and is used when an average requirement cannot be determined [23].

The basic principles of derivation and the calculated values have remained more or less the same since 2004 [24] and are based on dietary PUFA intake. To estimate the adequate intake for VitE the NNR Committee 2023 considered a basal VitE requirement plus a factor based on the dietary intake of PUFA. The recommended intake of PUFA is 5–10% of energy intake and, the lower value of this range (5%) was used to set the adequate intake for VitE. The estimated optimal VitE/PUFA ratio (mainly based on linoleic acid intake) to prevent PUFA oxidation ranges from 0.4 to 0.6 mg α-tocopherol per gram PUFA in the diet [25]. It was considered reasonable to use a mean ratio of 0.5 mg α-TE per gram of PUFA [26, 27]. In adults, a basal requirement of 4 mg of α-tocopherol equivalents per day has been estimated to support adequate plasma levels (> 12 µmol/L) [20]. Therefore, the average intake is set to 10 mg α-TE per day in females and 11 mg α α-TE per day in males. The provisional average requirement is set to 8 mg α-TE per day for females and 9 mg α-TE per day for males [23]. It should be noted that in the case of the NNR 2023 an α-TE corresponds only to RRR-α-tocopherol in foods (Table 1) [28].

Table 1.

Overview of the different dietary reference values for adults by country respectively organization

Organization/Country	Publication year	Type of dietary reference value	DRV for adults	Derivation	References
Derivation based on the intake of polyunsaturated fatty acids
Nordic and Balticcountries (Nordic Council of Ministers NNR)	2023	AI Provisional AR (pAR)	> 11 y: AI: 11 mg α-TE/da(m) 10 mg α-TE/d (f) pAR: 9 mg α-TE/d (m) 8 mg α-TE/d (f)	While NNR2012 defined a RI for VitE, NNR2023 define an AI. The AI is based on a basal VitE requirement (4 mg) plus a factor based on the dietary intake of 5 E% PUFA. The provisional AR is calculated from the AI To estimate the AI for VitE the NNR Committee considered a basal VitE requirement (4 mg) plus a factor based on the dietary intake of PUFA. The recommended intake of PUFA is 5–10 E%. For calculating the AI, the lower value of this range is used (i.e., 5 E %). The estimated optimal VitE:PUFA ratio, which ranges from 0.4 to 0.6 mg RRR-α-tocopherol/g of PUFA in the diet, suggests that a ratio of 0.5 mg α-TE/g of PUFA can reasonably be used Factorial approach: Basal requirement [4 mg TE/d] + 0,5 × PUFA in grams (at 5 E%) NNR2023: VitE activity is confined only to the naturally α-tocopherol in food, since α-tocopherol is the only form that is recognized to meet human requirements	[23]
	2012	Recommended intake/average requirement/lower intake level	> 14 y: RI: 10 mg α-TE/db (m) 8 mg α-TE/d (f) AR: 6 mg α-TE/d (m) 5 mg α-TE/d (f) LIL: 4 mg α-TE/d (m) 3 mg α-TE/d (f)	The Nordic Council''s is derived based on two criteria used for establishing the average requirements and the recommended VitE intakes: 1) plasma concentration of α-T (> 12 µmol/L) and 2) the relationship to PUFA intake. Based on a suggested requirement of 0.6 α-TE/g PUFA and an average PUFA level of 5% of energy intake, an intake of 7 and 9 mg α-T/d for women and men, respectively, would be sufficient. The Scientific Committee on Food considered a ratio of 0.4 α-TE/g total PUFA to be adequate for adults provided vitamin E does not fall below 4 mg/d for adult men and 3 mg/d for adult women (set as LIL). Based on this ratio, the estimated average requirement would thus be 5 and 6 mg α-Tl/d for women and men, respectively. These values are used as average requirements (ARs) in NNR 2012 In the absence of signs of VitE inadequacy in the general Nordic population and since no new data supporting changes have emerged, the recommended intake (RI) from 2004 is maintained in NNR 2012. The RI of VitE is set to 8 α-TE/d for women and 10 α-TE/d for men α-TE corresponds only to α-tocopherol in foods and 2R-α-tocopherols in VitE preparations	[28]
	2004	Recommended intake (RI) EAR Minimum requirement	> 14 y: 10 mg α-TEb (m) 8 mg α-TE (f) 6 mg α-TE/d (m) 5 mg α-TE/d (f) 4 mg α-TE/d (m) 3 mg α-TE/d (f)	In the absence of signs of VitE inadequacy in the general Nordic population, the recommended intake of VitE is set to 8 mg/d a-TE/d for women and 10 mg/d a-TE/d for men The EAR would thus be 5 and 6 mg α-TE/d for women and men, respectively. Using a ratio of 0.6 mg α-TE/g PUFA and an average PUFA level of 5 E%, an intake of 7 and 9 mg α-TE/d for women and men, respectively, would be sufficient. The Scientific Committee on Food considered a ratio of 0.4 α-TE/g total PUFA to be adequate both for adults and infants. As no human data are available on the biopotency, apart from antioxidative activity, of tocopherols and tocotrienols other than the 2R-isomers of a-tocopherol, the reference values (α-TE) only apply to the 2R-isomers	[24]
Germany and Austria (German Nutrition Society, DGE and Austrian Nutrition Society, ÖGE)	2000	Estimated value	15—< 51y.: 15 mg α-TE/dc (m) 12 mg α-TE/d (f) 51—< 65 y: 13 mg α-TE/d (m) 12 mg α-TE/d (f)	4 mg α-TE/da basal requirement plus the requirement to protect the double bonds of the fatty acids calculated on the percental distribution of fatty acids, i.e. monoene, diene and triene fatty acids	[29, 30]
	1991	ND	13 mg/d mg α-TE/c	4–6 mg α-TE/d basal requirement if intake of linoleic acid is around 7 g/d, additional requirements for higher polyunsaturated fatty acid intake: 0,4–0,6 mg/g PUFA	[31]
	1963	ND	5–30 mg/d	First DRV: depends on the intake of unsaturated fatty acids	[32]
Derivation based on intake data
EFSA (European Food Safety Authority)	2015	AI	>19 y: 13 mg/d α-T (m) 11 mg/d α-T (f)	Estimated from observed dietary intakes of healthy populations without apparent α-T deficiency based on approximate midpoints of surveys	[6]
Netherlands (Health Council of the Netherlands)	2018	AI	>19 y: 13 mg/d α-T (m) 11 mg/d α-T (f)	Adapted values from the EFSA	[33]
Switzerland	2021	AI	>19 y: 13 mg/d α-T (m) 11 mg/d α-T (f)	Adopted from EFSA	[34]
Spain(Agencia Española de Seguridad Alimentaria y Nutrición [AESAN])	2019	AI	>19 y: 13 mg/d α-T (m) 11 mg/d α-T (f)	Adopted from EFSA	[35]
France (French Agency for Food, Environmental and Occupational Health & Safety; ANSES)	2021	AI	>19 y: 10 VitE mg/d (m) 9 VitE mg/d (f)	Following the EFSA approach: AI examined as the average intake of the French population, excluding fortified products and supplements (Data from the INCA3 –study, 2014–15), VitE refers to the tocopherols and tocotrienols form without conversion factor	[36]
	2016	AI	>19 y: 10.5 VitE mg/d (m) 9.9 VitE mg/d (f)	VitE intake data from the INCA-2-Study (2006–2007)	[37]
	2001	AI	>19 y: 12 VitE mg/d	From intake data, no EAR could be set	[38]
Italy (Società italiana di nutrizione umana)	2014	AI	13 mg/d α-TE (m) 12 mg/d α-TE (f)	Based on dietary intake data from Italian population	[39]
Poland	2021	AI	>19 y: 10 mg aT (m) 8 mg aT (f)	Standards for VitE have been set at the level of sufficient intake	[40]
	2010	RDA	15 mg/d	Adopted from United States
Codex Alimentarius (WHO/FAO)	2019	AI	9 mg/d α-T	Average of the DRV of EFSA, NHMRC/MOH (Aus+NZ), NIHN (Japan), WHO/FAO: AI (12 + 8.5 + 6.8 + 8.8)/4 = 9 mg/d The DRVs for VitE given as INL98 (IoM) were officially advised as set too high or were older theoretically derived values. All other DRVs including from WHO/FAO (2004) were AIs based on dietary intakes in the range 7–12 mg/d	[41]
Australia and New Zealand (National Health and Medical Research Council)	2006	AI	≥ 19 y: 10 mg α-TE/dd (m), 7 mg α-TE/d (f)	As there are not sufficient data on which to base an EAR for adults, an AI was set based on the median intakes in Australia and New Zealand from the National Nutrition Surveys with rounding up to the nearest milligram. The values set for men and women were the highest median intake for any respective adult age band DRV is expressed as α-TE with conversion factors given for several forms of α-tocopherol, plus β-tocopherol and γ-tocopherol	[42]
Derivation based on erythrocyte membrane protection
United States of America (Food Nutrition Board by National Academics of Medicine)	2000	EAR and RDA	≥ 19 y: EAR: 12 mg α T/db RDA: 15 mg α T/d	The EAR was based on data on induced deficiency in men. Therefore, a plasma concentration of > 12 μmol α-T/L was considered as normal and an intake of at least 12 mg α-T/d (EAR) In addition, the amount of α-T required daily, based on the ratio of at least 0.4 mg α-T/g of PUFAs for adults and mean PUFA intakes from National Health and Nutrition Examination Survey (NHANES) II was considered to be covered by the EAR of 12 mg α-T/d As no information was available on the standard deviation of the requirement, the RDA of 15 mg α-T/d was derived from the EAR by assuming a CV of 10%	[5]
	1989	RDA	10 mg/d α-TEe (m) 8 mg/d α-TE (f)	The EAR was based on data on induced deficiency in men. Therefore, a plasma concentration of > 12 μmol α-T/L was considered as normal. RDA committee concluded that the requirement for men should 10 mg/d α-TE, although it was known that millions of persons have lived long lives while consuming much less	[43]
Japan (Ministry of Health, Labour and Welfare)	2020	AI	18–49 y: 6 mg/d α-T (m) 50 − 74 y: 7 mg/d α-T (m) 18–29 y: 5.0 mg/d α-T (f) 30–49 y: 5.5 mg/d α-T 50–64 y: 6.0 mg/d α-T 65–74 y: 6.5 mg/d α-T	Based on median dietary intakes reported in National Health and Nutrition Survey 2016 that are expected to yield blood α-tocopherol levels exceeding 12 μmol/L	[44]
	2015	AI	> 18 y: 6.5 mg/d α-T (m) 6.0 mg/d α-T (f)	Based on median dietary intakes reported in National Health and Nutrition Survey 2010 and 2011 that are expected to yield blood α-tocopherol levels exceeding 12 μmol/L
	2010	AI	> 18 y: 7.0 mg/d α-T (m) 6.5 mg/d α-T (f)	Based on median dietary intakes reported in National Health and Nutrition Survey 2005/6. These intakes are expected to yield blood α-tocopherol level >12 μmol/L. Median values for those aged 18–29 years stratified by sex and age group (α-tocopherol) Japan (NIHN) also rejected the evidence of Horwitt (1960) and instead used studies that simultaneously reported VitE intake and average serum α-tocopherol levels to set AI values of 7.0 mg/d for men and 6.5 mg/d for women that are expected to yield blood α-tocopherol levels exceeding 12 μmol/L	[45]
Other approaches of derivation
WHO/FAO	2004	Best estimate of requirements	>10 y 10 mg α-TE/de (m) 7,5 mg α-TE/d (f)	At present, data are not sufficient to formulate recommendations for VitE intake for different age groups Data were not strong enough to formulate recommendations. Therefore, the figures represent the best estimate of requirements	[8]
United Kingdom (Department of Health)	1991	Safe intake levels	> 4 mg α-TE/dc (m) > 3 mg α-TE /d (f)	PUFA intake varies widely and so the Panel concluded that it was not possible to set DRVs for VitE. But safe intakes have been set at more than 4 mg α-TE /d for men and more than 3 mg α-TE /d for women	[46]
Ireland (Food Safety Authority of Ireland)	1999	ND	ND	Since foods rich in PUFA are also rich in vitamin E this Working Group concluded that requirements would be met even though a recommendation has not been set. There should be no DRV recommendation for VitE	[47]

α-T: α-tocopherol, α-TE: α-tocopherol equivalents, AI: adequate intake; DRV: dietary reference values, E%: energy%, EAR: estimated average requirement, LIL: low intake level, PUFA: polyunsaturated fatty acids, RDA: recommended dietary allowances, VitE: vitamin E

^aα-TE = RRR-tocopherol

^bα-TE = RRR-tocopherol in foods and 2R-α-tocopherols in VitE preparations

^c1 mg α-tocopherol equivalents (TE) = 1 mg RRR-α-tocopherol = 1,1 mg RRR-α-tocopherylacetat = 2 mg RRR-β-tocopherol = 4 mg RRR-γ-tocopherol = 100 mg RRR-δ-tocopherol = 3,3 mg RRR-α-tocotrienol = 1,49 mg all-rac-α-tocopherylacetat [31]

^d1 mg α-TE = 1 mg RRR-tocopherol = 0.91 mg RRR-α-tocopherol acetate; 0.81 mg RRR-α-tocopherol acid succinate; 0.74 mg all-rac-α-tocopherol; 0.67 mg all-rac-α-tocopherol acetate, 0.25–0.40 mg RRR-β-tocopherol, 0.10 mg RRR-γ-tocopherol; 0.25–0.30 mg α-tocotrienol [39]

^e1 mg α-TE = 1 mg RRR-tocopherol = 2 mg β-tocopherol = 10 mg γ-tocopherol= 3 mg γ-tocotrienol [5, 8]

The dietary reference values for VitE for Germany and Austria published by the German Nutrition Society (DGE) and the Austrian Nutrition Society (ÖGE) have been also calculated based on the intake of unsaturated fatty acids. But, in contrast to the NNR 2023, the estimation was not only performed on overall PUFA intake, respectively the intake of linoleic acid. Instead, the calculation is based on the guiding values for fat intake and the percental distribution of fatty acids, i.e. monoene, diene and triene fatty acids included. This considers the different numbers of double bonds of the fatty acids to be protected from oxidation by VitE. For the protection of the double bonds in monoene, diene, triene, etc. fatty acids, different VitE quantities in specific ratio are required, which correspond to 0.06; 0.4; 0.6; 0.8; 1.0; 1.2 mg α-TE per g of monoene fatty acids, diene fatty acids, etc. This calculation is based on 0.4 mg of α-TE, which are regarded as an adequate amount of VitE to protect 1 g of linoleic acid (diene fatty acid). In addition, the basal need of 4 mg α-TE per day for the protection of the unsaturated fatty acid in the body is considered.

Using this approach, the estimated dietary reference values for Germany and Austria are 15 mg α-TE per day for men and 12 mg α-TE per day for women. Thus, these estimated dietary reference values take all tocopherols and tocotrienols into account (Table 1) [29–31].

Derivation based on intake data

The dietary reference values of the European Food Safety Authority (EFSA) are based on observed dietary intakes in healthy populations with no apparent VitE deficiency and is solely for α-tocopherol. The argumentation behind the DRVs of the EFSA is that the data on markers of α-tocopherol intake/status/function (e.g. plasma/serum α-tocopherol concentrations, hydrogen peroxide-induced haemolysis, urinary α-carboxyethyl hydroxychroman (CHEC) excretion, markers of oxidative damage), on α-tocopherol kinetics/metabolism and body pools (distribution and storage) or on the relationship between PUFA intake and required α-tocopherol intake are insufficient; thus, average requirements and population reference intakes cannot be set for α-tocopherol. Moreover, VitE is defined by the EFSA only as α-tocopherol, whereby both the natural as well as the synthetic 2R-stereoisomer forms are considered [6]. The dietary intakes of VitE were estimated using the EFSA Comprehensive European Food Consumption Database and the EFSA Food Composition Database. The intake assessment considered 13 dietary surveys in nine countries of the European Union: (Finland, France, Germany, Ireland, Italy, Latvia, the Netherlands, Sweden and the United Kingdom). Most food composition databases used in the countries of the European Union contain values of VitE as α-tocopherol equivalents and only two countries (Finland and Sweden) have VitE values in their food composition databases as α-tocopherol values. Dietary intakes of both α-tocopherol and α-tocopherol equivalents were estimated by EFSA for males and females for all considered countries, and combined the approximate mid-points of both ranges of average EFSA intake estimates to set adequate intakes for α-tocopherol for adults after rounding. For adults, an adequate intake for α-tocopherol was derived as 13 mg/d for men and 11 mg/d for women [6].

For harmonization in Europe the dietary reference values of the EFSA were adopted by some European countries, e.g. Netherlands, Spain and Switzerland (Table 1) [33–35]. Others (France, Italy and Poland as well as the Codex Alimentarius) followed the procedure of the derivation based on the intake data but used country-specific intake data as reference. As a consequence, the adequate intake values of these countries differ from that derived by the EFSA [36, 39–41].

As an example, the French reference values, which have been derived since 2001 based on the intake data of the French population are presented. The French dietary reference values changed from 12 mg/d α-tocopherol for both sexes in 2001 to an adequate intake of 10 mg/d α-tocopherol for males and 9 mg/d α-tocopherol for females based on data obtained from the Third French Individual and National Food Consumption (INCA3) survey conducted 2014–2015. Of note this survey specifically excludes fortified products and supplements. Consequently, the adequate intake values are therefore slightly lower than those set by EFSA (Table 1). Although the French Agency for Food, Environment and Occupational Safety (ANSES) adopts the EFSA approach for deriving reference values, it is unclear whether these values are based solely on α-tocopherol, as done by EFSA, or include all forms of VitE, since they are expressed in mg of VitE per day [36].

Italy also uses country-specific intake data for the derivation of an adequate intake (13 mg/d α-TE for men and 12 mg/d α-TE for females), which is expressed as α-tocopherol equivalents (Table 1) [39].

In 2006, the National Health and Medical Research Council of Australia and New Zealand evaluated that there is not sufficient data to derive an estimated average requirement for VitE for adults. Similar to the other countries discussed above, an adequate intake value was set based on the median intakes in Australia and New Zealand based on data obtained from the National Nutrition Surveys. The values set for men and women were the highest median intake for any respective adult age range and were set at 10 mg α-TE/d for men and 7 mg α-TE/d for females respectively. In contrast to the EFSA, the adequate intake value for VitE intake is indicated as α-tocopherol equivalents and therefore considers that other tocopherols such as γ-tocopherol also have VitE activity [42].

Derivation based on erythrocyte membrane protection

The current recommended dietary allowance of the Food and Nutrition Board of the US National Academy of Sciences (previously Institute of Medicine) is 15 mg α-tocopherol for adult men and women, respectively [5]. The recommended dietary allowance (RDA) was set in 2000 based on the concept that α-tocopherol is an antioxidant that protects membranes. The calculation of the estimate average requirement (12 mg/d) is largely based on data on induced deficiency in men during the Elgin Project in the 1960’s. During this project in vitro peroxide-induced erythrocyte haemolysis was used as a biomarker for vitamin E status [20, 48–52].

Based on the results of the Elgin study it was concluded that adequate circulating α-tocopherol concentrations in humans are > 12 µmol/L, corresponding to a Vit E intake of at least 12 mg α-tocopherol per day. Furthermore, the estimated average requirement of 12 mg/d α-tocopherol covers the required daily amount for the protection of unsaturated fatty acids, which is the ratio of at least 0.4 mg α-tocopherol per gram of PUFAs for adults and the average PUFA intake from the National Health and Nutrition Examination Health and Nutrition Examination Survey (NHANES) II. The RDA is based on the naturally occurring RRR-form and the synthetic 2R-stereoisomers (RSR, RRS and RSS) of α-tocopherol, because the other naturally occurring tocopherols and tocotrienols cannot be converted to α-tocopherol in humans and are recognized poorly by α-TTP in the liver [5].

The prevention of haemolysis of the erythrocyte membrane is also the basis of the Japanese dietary reference values. Serum values of more than 12 µmol/L α-tocopherol are also considered adequate here. However, in contrast to the American approach, no EAR and RDA were derived due to the lack of deficiency symptoms. Instead, the intake data collected at regular intervals in national surveys is also used to derive the dietary reference values as an adequate intake. The rationale is that studies which have measured both intake and serum values of α-tocopherol demonstrated that mean serum concentrations of more than 22 µmol/L are reached, so that adequate serum values of more than 12 µmol/L are achieved with a normal diet [45, 46].

Other approaches of derivation

The WHO and FAO do not provide a dietary reference value for VitE with the rationale that the assessment of the VitE requirement for humans is confounded by the very rare occurrence of clinical signs of deficiency. Therefore, the suggestion is that normal diets contain sufficient VitE to satisfy nutritional needs. Moreover, the WHO and FAO assessed the data regarding the primary role of VitE as a lipid antioxidant and deemed it insufficient to derive a recommended nutrient intake based on the additional health benefits associated with higher nutrient intakes than typically observed [8].

Despite its important biological antioxidant properties, there is no consistent evidence that supplementation with amounts of VitE above those consumed in the usual diet prevents chronic diseases. Consequently, WHO and FAO use a value of the best estimate of requirements (acceptable intakes) of 10 mg α-TE per day for males and 7 mg α-TE per day for females instead of a dietary reference value. These values are based on data on VitE intakes in the US and UK and their recommendations for VitE intake, because these countries have a high dietary intake of PUFAs. The hypothesis behind this approach is that diets high in PUFAs are usually also high in VitE. Therefore, a dietary recommendation for VitE based on data from a population with a very high PUFA intake would differ from the average VitE intake in most Western populations, where PUFA intake is usually lower, and would ensure adequate VitE intake [8].

The Department of Health United Kingdom also derives VitE requirement based on PUFA intake. Because intake of PUFAs is highly variable, it is impossible to set dietary reference values and only a safe value of more than 4 mg/d for men and 3 mg/d for women have been set. Furthermore, because foods rich in PUFA also tend to contain large amounts of VitE, high intakes of PUFA are usually accompanied by corresponding amounts of the VitE. For instance, the average ratio of α-tocopherol equivalent (mg)/PUFA (g) in the UK was over 0.6, which is above what would be appropriate. However, there is an extra advice, that if supplements of PUFA are taken, that they should contain adequate amounts of VitE [46].

Discussion

The comparison of the various dietary reference values and methods used for their derivation shows that there are significant differences between the organizations and countries, both in the procedure and basic principles for derivation as well as in the reported values themselves. The values range from no value or a low safe intake of 4 mg/d for men and 3 mg/d for women [46] to recommended dietary allowances of 15 mg/d for both sexes [5].

On the other hand, there is a broad consensus that currently only α-tocopherol meets the requirements to be used for the derivation of recommendations for an intake (value), as it is the only form for which a vitamin function, i.e. the prevention of the deficiency disease in humans termed AVED, has been confirmed in humans so far [2, 9]. For the other VitE congeners the evidence in humans so far is insufficient to take them into account for the derivation of a DRV.

Only the older reference values of the WHO/FAO [8] and DGE/ÖGE [29, 30] still use α-tocopherol equivalents to take differences in the conversion factors of the other tocopherol forms into account. Another reason why only α-tocopherol should be considered is that the conversion factors are derived solely from animal studies, making a direct application to humans questionable. Therefore, these factors should no longer be used in the derivation of dietary reference values or intake recommendations until valid data from human studies are available.

It should be noted, however, that there is evidence that other forms of VitE, e.g. γ-tocopherol and α-tocotrienols as well as the metabolites derived from different VitE congeners may also have biological functions and beneficial health effects [2, 13, 53]. Although the evidence is insufficient to give numerical recommendations for all VitE forms, the recommendation of a diet that includes a variety of VitE-rich foods ensures that other forms are likely consumed in adequate amounts.

All scientific societies agree that VitE deficiency in general is very rare and is not caused by an inadequate intake, but rather by genetic defects or disorders of lipid metabolism. The lack of deficiency symptoms and valid biomarkers are the main reasons why a standardized procedure for deriving a dietary reference value is difficult. As a result, the dietary reference values for VitE are often derived from country-specific intake data obtained from national surveys and stated as adequate intake. The EFSA also used this approach by using the average intake from several observed intake data from healthy populations from national surveys. Therefore, for harmonization purposes, other (European) countries have adopted the EFSA dietary reference values for VitE intake. In some cases, such as France, only the approach was adopted and country-specific intake data was used.

Dietary intake surveys are a widely used method to assess the nutrient status of populations, although the disadvantages of this approach must be considered. Limitations of such methods are the possible misreporting of food intake, and differences in the quality and actuality of the data of the food composition database used. Especially for VitE there are significant uncertainties in the available food composition and interpretation of consumption data. Most European food composition databases contain values for VitE only expressed as α-tocopherol equivalents and not as α-tocopherol, which is a problem for the derivation of dietary reference values based on dietary intake data from national surveys, like the adequate intake of the EFSA, which depends only on α-tocopherol [6, 23]. In addition, the frequent fortification of foods with VitE for technological purposes aimed at enhancing shelf life can lead to misinterpretations of intake data. Fortification is highly diverse and often not sufficiently included in the nutrient databases, and thus it is not recorded in the nutritional surveys.

Another limitation of the survey-based approach is that changes in dietary habits can lead to changes in the intake data, resulting in changed dietary reference values without any biological plausibility. This is illustrated, for example, by the slightly fluctuating dietary reference values in Japan, which are regularly adjusted to the result obtained from national surveys (Table 1). Due to missing VitE deficiency symptoms in the general population, the approach of derivation on intake data seems to overestimate the VitE needs, and reference values are probably too high.

The derivation of some dietary reference values takes into account the amount of VitE required to prevent dietary PUFAs from oxidation. To quantify the required amount of VitE a basal VitE requirement plus an additional requirement of VitE for the prevention of oxidation of dietary PUFAs is considered. Evidence from preclinical and human studies indicates that a minimal basal requirement of 4–5 mg/day of α-tocopherol is necessary even when the diet is very low in PUFAs [25]. But there is no consensus on the exact ratio of VitE and PUFA that determine the required amount of VitE since a precise VitE/PUFA ratio may not be applicable to all types of diet, age groups and genders as well as health status. However, the required amount of VitE seems to rise with an increasing consumption of PUFA and with the number of double bonds of the PUFA in the diet. Thus, published data from human studies indicate that the additional required amount of VitE ranges from 0.4 to 0.6 mg α-tocopherol per gram of PUFA in the diet, for a diet with an average content of PUFAs and in which linoleic acid is the main dietary PUFA [25].

Assessing of PUFA intake is often limited to linoleic acid, although the protection of monounsaturated fatty acids should also be considered, as these represent a much higher proportion of the dietary fat intake (10–15% of Energy intake). Additionally, other unsaturated fatty acid, especially the recommended omega-3 fatty acids α-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid should also be considered. Moreover, animal studies show that for fatty acids with a higher degree of unsaturation, the VitE requirement seems to increase almost linearly with the number of double bonds in the molecule, a finding which is considered in the derivation of the DGE and ÖGE [29]. But even this complex calculation of the VitE requirement based on the proportion of the various unsaturated fatty acids provides only a misleading accuracy, as the proportion of fatty acids is highly inter-individually variable in both tissues and foods. Nevertheless, the estimated VitE requirement in relation to the typical ranges of unsaturated fatty acid intake in the Western diet, including a basic requirement of 4 mg per day, would be in the range of 12 to 20 mg/day [54].

As mentioned above, the content of unsaturated fatty acids in the diet is highly variable which makes it difficult to set valid dietary reference values for VitE intake due to the unknown number of double bonds which have to be protected by VitE. A good example for this is shown in the derivation of the dietary reference values of the UK. Data from nutrition surveys estimated an intake of n-6 PUFA ranging from 5.1 to 29 g/d (2.5 and 97.5 percentile) which would result in a wide range for an adequate intake of VitE of approximate 3 to 18 mg/d. Therefore, the Panel on Dietary Reference Values of the Committee from the Department of Health in UK has considered that recommending these would be undesirable, as it could suggest that groups with much lower, but adequate PUFA intakes should increase their intake of VitE. Another reason is e.g. the fact of missing deficiency symptoms as well as that surveys showed that the population with median VitE intake of 9.3 mg/d had serum tocopherol/cholesterol ratio levels above 2.25 µmol/mmol (which has been indicated as adequate). So, the panel decided to recommend no dietary reference value for VitE, only safe daily VitE intakes of more than 4 mg/ for men and 3 mg/d for women, respectively [46].

Approaches that calculate the adequate intake of VitE for the protection of PUFAs from oxidation also neglect the fact that α-tocopherol is not depleted or degraded in this process but regenerated by other antioxidants such as vitamin C, selenium, and ubiquinols [55, 56]. This raises the legitimate question whether it is necessary to consider an additional requirement in relation to the consumption of PUFA. The compensation of the estimated losses of 4–5 mg α-tocopherol per day appears to be sufficient, especially as food rich in PUFAs is also rich in VitE.

The recommendations on VitE intake by the US National Academy of Sciences is based on the prevention of deficiency symptoms, using the sensitivity of erythrocytes to haemolysis as a marker of VitE deficiency. The basic data have been derived from the ELGIN-project in which VitE depletion and repletion in men has been estimated using erythrocyte haemolysis as a biomarker. The authors concluded that individuals with plasma concentrations of at least 12 µmol/L of α-tocopherol have a low percentage of erythrocyte haemolysis and that a plasma α-tocopherol concentration of 12 µmol/L corresponds to a VitE intake of about 12 mg/d. Based on this, the estimated average requirement for VitE in humans was set 12 mg/d and the recommended dietary allowances of 15 mg/d α-tocopherol for both sexes was extrapolated from that value [5]. There is some criticism concerning, as the same data had been used in deriving earlier US recommended daily intake, which were 10 mg/d, but were interpreted differently in the revision in 2000, leading to considerably 50% higher recommendations [57]. Due to a lack in the original data in plasma α-tocopherol concentrations between 5 and 12 µmol/L, the interpretation of the data is problematic in relation to the level of plasma α-tocopherol at which adverse effects e.g. erythrocyte haemolysis was observed. However, changing the cut-off point makes this large difference to the estimated requirement. In addition, the authors of the key paper themselves expressed concern about the validity of their method for assessing VitE requirements [42, 57]. Moreover, since this reference value is not reached by a large part of the population and there is nevertheless no deficiency, this value seems to be set too high.

Many dietary reference values of VitE are different for women and men. This is due to the higher intake of VitE, PUFA and total energy in men. But there are no known physiological needs for gender-specific recommendations. As mentioned before, α-tocopherol is recycled in its function as an antioxidant and a higher intake of PUFA is normally also accompanied by a higher VitE intake. According to our current knowledge, there are no significant gender-specific differences in metabolism and excretion [5].

The used procedure on how data is evaluated is especially important for the derivation of dietary reference values. For example, the revised NNR published in 2023 demonstrates that the well-established method of evidence-based assessment of the literature using Grade and/or AMSTAR with a focus on systematic reviews and meta-analyses is only applicable to a limited extent for the derivation of dietary reference values. Using this approach, data from basic research on biomarkers, metabolism, excretion, etc. are only inadequately considered. But VitE is a good example of how the data availability in these areas has improved in recent years, e.g. through better analysis and studies with stable isotopes, etc. In addition, there has also been an increased focus on other forms of VitE such as γ-tocopherol as well as the metabolites of VitE. These aspects cannot yet be considered by systematic reviews of human studies which is the basis of the NNR 2023 [23].

There is also consensus between different scientific societies and respective organizations on the basal minimum amount of 4 mg VitE per day. This originates from the aforementioned ELGIN project conducted in the 1960s, in which this amount was determined to maintain a minimum concentration of 12 µmol/L α-tocopherol in plasma [20, 50, 51]. The basal requirement of 4 mg/d VitE determined in this manner corresponds approximately to the daily losses of α-tocopherol observed in kinetic studies in healthy adults. These were about 4 to 5 mg/d in subjects with mean α-tocopherol plasma concentrations of approx. 20 to 23 µmol/L, regardless of gender [58, 59]. Since there is insufficient evidence that the α-tocopherol concentrations in plasma from the studies can be regarded as a reference value for an adequate VitE supply, these values are not suitable as a basis for determining an average requirement [6]. Nevertheless, the data support a daily loss of α-tocopherol of 4 to 5 mg/day, which must be compensated by dietary intake.

Therefore, it seems to be reasonable to focus on the recommendation of consuming VitE-rich foods such as nuts and seeds and plant oils, especially as foods rich in PUFA are usually also rich in VitE for their preservation. These food groups are also an integral part of food-based dietary guidelines and medical guidelines for their health benefits, such as reducing cardiovascular risk factors and improving the fatty acid profile [60–62]. It has to be highlighted that supplementation of VitE/α-tocopherol does not seem necessary, as the primary preventive properties for various nutrition-related diseases have yet to be proven conclusively [63].

Perspective: a novel approach for establishing vitamin E status and assessing dietary adequacy

In summary, due to the insufficient data from human studies to determine an average VitE requirement due to the lack of valid biomarkers of VitE status, the absence of deficiency symptoms and insufficient data on the relationship between PUFA intake or the protection of unsaturated fatty acids and VitE status, only estimated values for an adequate VitE intake can be derived.

Therefore, the following procedure is proposed for future derivations of an estimated value for an adequate VitE intake: Based on the described daily losses of approx. 5 mg/d α-tocopherol and considering an average absorption rate of α-tocopherol with a usual balanced diet of about 75% provided by the EFSA [6], an intake of about 6.5 mg/d α-tocopherol seems to be sufficient to compensate for daily losses. Taking the inter-individual variations into account, a coefficient of variation of 10% (which corresponds to an addition of 20%) should be considered. Due to missing deficiency symptoms in healthy adults without fat malabsorption this amount seems to be sufficient. This results in an estimated value of 8 mg/d α-tocopherol for adults 19 years and older for both sexes [64]. For this amount of VitE, potential beneficial effects have already been reported for dietary intake, because protective effects have been observed already at low doses ranging from approximately 2–15 mg/day [26, 65].

Conclusion

Adequate VitE intake without using supplements is possible with a balanced and plant-based diet containing nuts, seeds and unsaturated plant oils, like it is recommended by the German Nutrition Society [66] or the Planetary Health Diet [67] as foods with high amounts of PUFA usually also contain VitE (all different forms) in respective amounts. In addition, there are no deficiency symptoms for VitE observed in the general population, even when VitE intake is low. Taking into account daily losses and bioavailability appears to be a solid base for deriving reference value for VitE intake. The recommendation of a regular/daily consumption of foods rich in VitE appears to be sufficient for an adequate supply of VitE for healthy people without medical issues on fat metabolism like fat malabsorption as the preventive effect of higher doses remain to be conclusively proven.

Author contributions

Conceptualization, C.B. and S.L.; writing—original draft preparation, C.B.; writing—review and editing, V.B., I.E., S.L., M.P and K.H.W. All authors have read and agreed to the published version of the manuscript.

Funding

The German Nutrition Society is partly funded by the German Federal Ministry of Agriculture, Food and Regional Identity. The funder had no role in the decisions about data collection, analyses, interpretation of data, in writing of the report nor in the decision to submit the article for publication.

Declarations

Conflict of interest

CB, VB, IE, MP and KHW declare no conflicts of interest. SL has received research grants from DSM-Firmenich AG (Kaiseraugst, Switzerland), but the research grant had no relation to the derivation of nutrient reference values and DSM-Firmenich; the sponsor had no influence on the content of this publication and is not aware of its content.