Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver a scientific opinion on the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA).
Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) contain one of the double bonds located at three carbon atoms from the methyl end. The main n-3 PUFAs in the diet are a-linoleic acid (ALA; 18:3Δ9c,12c,15c), eicosapentaenoic acid (EPA; 20:5Δ5c,8c,11c,14c,17c), docosahexaenoic acid (DHA; 22:6Δ4c,7c,10c,13c,16c,19c ) and docosapentaenoic acid (DPA; 22:5Δ7c,10c,13c,16c,19c). EPA, DHA and DPA are n-3 long-chain PUFAs (n-3 LCPUFA), i.e. n-3 PUFA with 20 or more carbon atoms. The n-3 LCPUFAs are important structural components of cell membranes and contribute to various membrane functions such as fluidity, permeability, activity of membrane-bound enzymes and receptors, and signal transduction.
Fish is a uniquely rich source of n-3 LCPUFAs. Other natural sources are human milk, cultivated marine algae, marine mammals and krill. EPA, DHA and DPA may also be provided by foods and supplements enriched with n-3 LCPUFAs (e.g. fish oils, single cell oils, krill oils added to foods or consumed as food supplements). The ratios of EPA:DHA:DPA differ between the various sources of n-3 LCPUFAs, although DPA is generally a minor quantitative component compared to EPA and DHA. Food supplements containing mainly EPA, or mainly DHA (isolated from microalgae), are also available. Pure DPA is not commercialised for human consumption.
Adverse effects, which have been described in humans in association with high intakes of EPA and DHA, include bleeding episodes, impaired immune function, increased lipid peroxidation, and impaired lipid and glucose metabolism. However, no tolerable upper intake level (UL) for EPA, DHA or DPA has been set by any authoritative body.
Previous assessments on the safety of n-LCPUFAs referred to mixtures of EPA and DHA (DPA was not explicitly mentioned), and were primarily based on a large number of human studies. The Panel considers that the evaluation of the safety of n-3 LCPUFA intakes should be based on the human studies available.
The majority of human intervention studies which have investigated the effects of n-3 LCPUFAs on different health outcomes have used fish oils containing known amounts of EPA and DHA and generally unknown (but relatively low) amounts of DPA; EPA and DHA in combination as ethyl esters; or more rarely mostly EPA or mostly DHA. Very few studies are available using krill oil as a source of EPA and DHA, and no studies have been conducted with sources containing mainly DPA, or with DPA alone.
Long-term human intervention studies which have investigated the effects of supplemental intakes of EPA and DHA, either alone or in combination, at doses up to about 1 g/day on a variety of health outcomes (e.g., cardiovascular, neurological, immunological), have generally reported no adverse effects in relation to the consumption of EPA or DHA at these doses.
Long-term supplemental intakes of EPA and DHA combined up to about 5 g/day do not increase the risk of spontaneous bleeding episodes or bleeding complications even in subjects at high risk of bleeding (e.g. taking acetylsalicylic acid or anti-coagulants).
Supplemental intakes of EPA and DHA combined at doses up to 5 g/day consumed for up to 12 weeks do not significantly affect glucose homeostasis in healthy or diabetic subjects, nor do they induce changes in immune functions which might raise concern in relation to the risk of infections or inappropriate activation of inflammatory responses. The data available are insufficient to conclude on whether the same doses administered mostly as EPA or mostly as DHA would have different effects on these outcomes.
Supplemental intakes of EPA and DHA consumed either alone or in combination at doses up to about 5 g/day for up to 16 weeks do not induce changes in lipid peroxidation which might raise concern in relation to cardiovascular disease (CVD) risk as long as the oxidative stability of these n-3 LCPUFA is guaranteed.
Supplemental intakes of EPA and DHA combined of 2-6 g/day, and supplemental intakes of mostly DHA of 2-4 g/day, increase blood concentrations of LDL cholesterol by about 3 %. Such increase is accompanied by a decrease in triglycerides with no changes in total (or non-HDL) cholesterol concentrations. Supplemental intakes of mostly EPA at doses up to 4 g/day have no significant effect on LDL-cholesterol concentrations. The Panel considers that the small increase in LDL-cholesterol concentrations associated with combined EPA and DHA supplementation or with DHA supplementation alone at the doses mentioned above may not have an adverse effect on CVD risk.
The Panel concludes that the available data are not sufficient to establish a tolerable upper intake level for n-3 LCPUFA (DHA, EPA, and DPA, individually or combined) for any population group.
At observed intake levels, consumption of n-3 LCPUFA has not been associated with adverse effects in healthy children or adults.
The Panel considers that supplemental intakes of EPA and DHA combined at doses up to 5 g/day, and supplemental intakes of EPA alone up to 1.8 g/day, do not raise safety concerns for the adult population. Limited data are available on the effects of long-term supplementation with these n-3 LCPUFAs at higher doses. The Panel also notes that observed intakes of EPA and DHA from food and food supplements in European populations are generally below these amounts. Dietary recommendations for EPA and DHA based on CVD risk considerations for European adults are between 250 and 500 mg/day. There are no specific recommendations for EPA.
The Panel also considers that supplemental intakes of DHA alone up to about 1 g/day do not raise safety concerns for the general population. Limited data are available on the effects of long-term supplementation with DHA alone at higher doses. The Panel notes that specific dietary recommendations for DHA for European adults and children are well below this amount.
No data are available for DPA when consumed alone. The Panel notes that in the majority of the human studies considered, fish oils, which also contained DPA in generally unknown (but relatively low) amounts, were the source of EPA and DHA. No dietary recommendations have been made specifically for DPA.