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Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 99–104

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Prostaglandins, Leukotrienes andEssential Fatty Acids

0952-32

doi:10.1

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journal homepage: www.elsevier.com/locate/plefa

Dietary reference intakes for DHA and EPA

Penny M. Kris-Etherton a,�, Jessica A. Grieger a, Terry D. Etherton b

a Departments of Nutritional Sciences, The Pennsylvania State University, 319 Chandlee Laboratory, University Park, PA 16802, USAb Dairy and Animal Science, The Pennsylvania State University, University Park, PA 16802, USA

78/$ - see front matter & 2009 Published by

016/j.plefa.2009.05.011

esponding author. Tel.: +1814 863 2923; fax:

ail address: pmk3@psu.edu (P.M. Kris-Etherto

a b s t r a c t

Various organizations worldwide have made dietary recommendations for eicosapentaenoic acid (EPA),

docosahexaenoic acid (DHA), and fish intake that are primarily for coronary disease risk reduction and

triglyceride (TG) lowering. Recommendations also have been made for DHA intake for pregnant women,

infants, and vegetarians/vegans. A Dietary Reference Intake (DRI), specifically, an Adequate Intake (AI),

has been set for a-linolenic acid (ALA) by the Institute of Medicine (IOM) of The National Academies.

This amount is based on an intake that supports normal growth and neural development and results in

no nutrient deficiency. Although there is no DRI for EPA and DHA, the National Academies have

recommended that approximately 10% of the Acceptable Macronutrient Distribution Range (AMDR) for

ALA can be consumed as EPA and/or DHA. This recommendation represents current mean intake for EPA

and DHA in the United States (E100 mg/day), which is much lower than what many groups worldwide

are currently recommending. Global recommendations for long-chain omega-3 fatty acids underscore

the pressing need to establish DRIs for DHA and EPA because DRIs are recognized as the ‘‘official’’

standard by which federal agencies issue dietary guidance or policy directives for the health and well-

being of individuals in the United States and Canada. Because of the many health benefits of DHA and

EPA, it is important and timely that the National Academies establish DRIs for the individual long-chain

(20 carbons or greater) omega-3 fatty acids.

& 2009 Published by Elsevier Ltd.

1. Introduction

There has been a long-standing interest in understandingnutrient needs that can be translated to food-based recommenda-tions for healthful diets. Early interest focused on understandingdietary adequacy and the prevention of dietary deficiency diseasesand under-nutrition [1]. The first set of Recommended DietaryAllowances (RDAs) was published in 1941 by the Institute ofMedicine. This was preceded by the release of RecommendedNutrient Intakes (RNIs) by Health and Welfare, Canada in 1938 [1].The RDAs and RNIs quickly became positioned as the benchmarkfor dietary reference standards that were used for diet assessmentand planning purposes, and, consequently, became the basis fornutrition and health policy [2]. From 1941 until the 1990s, RDAswere the ‘‘gold standard’’ used for establishing nutrient recom-mendations that had as the primary focus, nutrient adequacy. TheRDA model for determining nutrient requirements remainedessentially unchanged for over 50 years.

With the growing recognition of the role of over-nutrition inchronic diseases, a new model for setting nutrient recommendationsemerged. In part, this model was based on the recognition that asingle RDA or RNI value did not meet the changing needs for nutrient

Elsevier Ltd.

+1814 863 6103.

n).

reference values [2]. With the introduction of the DRI concept in 1994[3], there was a paradigm shift in setting nutrient-based referencevalues, which was formalized with the release of the first DRIs in1997 for calcium, phosphorus, magnesium, vitamin D and fluoride[4]. Subsequently, six DRI reports were issued between 1997 and2005, and in 2002, DRIs were reported for energy and macronutrients[5]. Notable by absence was that there was no DRI set for EPA andDHA, which reflected the modest evidence base that existed at thetime. Since then, the ‘‘floodgate’’ has opened and an impressivedatabase has been built demonstrating many health benefits of theselong-chain omega-3 (n-3) fatty acids. As a result, numerous groups,globally and including the United States, have issued recommenda-tions for EPA and DHA, as well as for fish which is the predominantfood source of EPA and DHA, for different population groups.

The purpose of this paper is to describe the process andevidence required for making specific nutrient recommendationsand to present the case for convening an expert panel to makeofficial recommendations in the United States for DHA and EPAand possibly other long-chain omega-3 fatty acids.

2. Dietary reference intakes

Dietary reference intakes (DRI) are a set of five nutrient-basedreference values issued by the Institute of Medicine of theNational Academies [5]. The DRIs are used in the United States

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and Canada by the general public and health professionals forapplications that include: food labels; composition of diets forschools, prisons, hospitals or nursing homes; industries develop-ing new food products; and healthcare policy makers and publichealth officials. DRI components include:

Estimated Average Requirements (EAR): The average dailynutrient intake level estimated to meet the requirement ofhalf of the healthy individuals in a particular life stage andgender group. The EAR reflects the estimated median require-ment and is particularly appropriate for applications related toplanning and assessing intakes for groups of persons.Recommended Daily Allowance (RDA): The average daily dietarynutrient intake level sufficient to meet the nutrient require-ment of nearly all (97–98%) healthy individuals in a particularlife stage and gender group. The RDA is derived from the EARand the corresponding population variability in requirements.Adequate Intake (AI): The recommended average daily intakelevel based on observed or experimentally determined approx-imations or estimates of nutrient intake by a group (or groups)of apparently healthy people that are assumed to be adequate– used when an RDA cannot be determined.Tolerable Upper Intake Level (UL): The highest average dailynutrient intake level that is likely to pose no risk of adversehealth effects to almost all individuals in the general popula-tion. As intake increases above the UL, the potential risk ofadverse effects may increase.Acceptable Macronutrient Distribution Range (AMDR): An intakerange for an energy source associated with reduced risk ofchronic disease.

Conceptually, the EAR, RDA, and UL are presented in Fig. 1 in thecontext of nutrient adequacy/inadequacy/risk of excess, as well aschronic disease risk, the latter of which is a new approach forestablishing DRIs. Of note is that there are several importantconcepts that typically guide the process of setting DRIs. Withrespect to the EAR, a normal or symmetrical distribution (meanand median are similar) is typically assumed. Inherent to thedefinition of the EAR is that it presupposes that an individualrandomly selected from the population would have a 50% chanceof having their requirement met for a specific nutrient. Importantto note is that the EAR’s usefulness as a predictor of an individual’snutrient requirement is a function of the nutritional indicator/criterion used to set the EAR, as well as the robustness of theevidence basis. Thus, for a given nutrient, different nutritional

0.5

Observed leve

EAR RDA

Increase

Ris

k of

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equa

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isea

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Fig. 1. Dietary reference intakes: risk relationship

indicators and/or criteria can be used to set the EAR for differentpopulation groups. As is evident, the model that is used to setEAR’s results in a range of nutrient requirement values that reflectdifferent nutritional indicators that have been set for specifiedpopulation groups. By virtue of the definition of the RDA, the riskof inadequacy for randomly chosen individuals from thepopulation would be very small (i.e., 2–3%). Implicit to themodel is that at intakes between the RDA and the UL the risk foreither inadequacy or excess is close to zero.

As noted by Dr. John Suttie at a workshop on the developmentof the DRIs, 1994–2004 [2], the DRIs as reference values nowinclude chronic disease endpoints within the array of endpointsused to establish DRIs and address concepts of probability and riskto define a DRI. The ‘‘endpoint’’ concept is the foundation for DRIsbecause these are the criteria used to frame nutrient needs. Forexample, one level of a nutrient might be sufficient to prevent anovert deficiency disease, however, a higher level of the samenutrient is necessary to reduce risk of chronic disease. Thus, weare evolving our perspectives about nutrient needs and how todefine them in terms of health and well-being. The ongoingtransition marks a shift from a nutrient adequacy model to onethat encompasses disease prevention. This comes with inherentcomplexities in that defining the endpoint (i.e., benchmark for theDRI) takes on multiple possibilities.

3. Dietary recommendations for omega-3 fatty acids and fish

The current AI for ALA (issued by the Institute of Medicine ofthe National Academies) is 1.6 g/day for men 19–470 years, and1.1 g/day for women 19–470 years [5]. The AMDR for ALA is0.6–1.2% of energy. The lower boundary of the range meets the AIfor ALA. The upper boundary corresponds to the highest ALAintake from foods consumed by individuals in the United Statesand Canada. Approximately 10% of the AMDR for ALA can beconsumed as EPA and/or DHA. The DRI Report for Macronutrients[5] recognized that research suggests that higher intakes of ALA,EPA and DHA may afford some protection against CHD. However,since the physiological potency of EPA and DHA is greater thanALA, it was not possible to estimate an AMDR for each omega-3fatty acid.

The Dietary Guidelines for Americans, 2005, support therecommendations made by the IOM for omega-3 fatty acids andalso note: ‘‘Limited evidence suggests an association betweenconsumption of fatty acids in fish and reduced risks of mortalityfrom cardiovascular disease for the general population. Other

0.5

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UL

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s-nutrient adequacy and disease indicators.

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Table 2Amount of EPA and DHA in selected commercial supplements (per softgel).

Supplement Calories EPA, mg DHA, mg EPA:DHA

ABC Vitamin Life 10 360 240 1.5

Max EPA 10 180 120 1.5

Herbal Remedies 5 200 150 1.3

Omega Max 10 360 240 1.5

Nordic Naturals 10 325 225 1.4

(Ultimate Omega)

NutraOrigin 10 420 240 1.75

Epecta Lipila 5 – 200 –

Life’sDHA 5 – 200 –

Cardiostat 11 540 170 3.2

VitalOils 1000 11 250 750 0.33

a Expecta LIPIL DHA Supplement is for pregnant and breastfeeding mothers.

P.M. Kris-Etherton et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 99–104 101

sources of EPA and DHA may provide similar benefits; however,more research is needed’’ [5]. The Dietary Guidelines also note:‘‘There is evidence that suggests that consumption of approxi-mately two servings of fish per week (approximately 8 oz (224 g)total) may reduce the risk of mortality from coronary heartdisease and that consuming EPA and DHA may reduce the risk ofmortality from cardiovascular disease in people who have alreadyexperienced a cardiac event’’ [5]. It is important to emphasize thatsince the release of the Dietary Guidelines for Americans 2005there has been a substantive increase in the evidence base aboutthe health benefits of omega-3 fatty acids [6,7]. Because of thehealth benefits associated with EPA and DHA, numerous agenciesand organizations worldwide, including the American DieteticAssociation (ADA), have issued recommendations for EPA andDHA, as well as for fish consumption, for health promotion anddecreased risk of many chronic diseases. Generally, nutritionistsrecommend a food-based approach for achieving nutrient ade-quacy and preventing and treating diseases [8]. However, forsome, nutritional supplements are needed to meet nutrient needs.With respect to EPA and DHA, a supplement (or fortified food)would be advised for vegans, individuals who are allergic orcannot eat fish, who do not like fish, or who elect to not include itin their diet. In addition, some individuals cannot meet the levelsof EPA and DHA recommended by diet. Thus, there are manystrategies for achieving the recommendations presented belowthat include: food (specifically fatty fish), fortified foods (with fishoil, ‘‘designer’’ oils high in EPA, and algae supplements) orsupplements (i.e., fish oil, algae). Tables 1 and 2 present theDHA and EPA content of various fatty fish and supplements. Inreviewing the data in these tables, it is apparent that fish providesproportionally more DHA than EPA compared with mostsupplements (excluding DHA supplements). Thus, individualswho try to meet current recommendations (i.e., 500 mg/day ofEPA+DHA) with fish versus supplements will consumeproportionately different quantities of EPA and DHA. Forexample, consumption of fish to meet the 500 mg/dayrecommendation will provide more DHA versus a supplement(with both EPA and DHA) that will provide more EPA.

3.1. United States and Canadian dietary recommendations for long-

chain omega-3 fatty acids and fish for primary prevention of coronary

diseases

Many recommendations for EPA and DHA and fish have beenissued by organizations in the United States and Canada: Theseinclude:

The American Dietetic Association/Dietitians of Canada: 500mg/day of EPA+DHA provided by two servings (one serving is4 oz (112 g) cooked) of fatty fish/week [9].

Table 1Quantity of EPA and DHA in selected fish (100 g, raw) [48].

Fish EPA, g DHA, g EPA:DHA

Blue fish 0.25 0.52 0.48

Atlantic cod 0.06 0.12 0.50

Pacific cod 0.08 0.14 0.57

Mackerel, Atlantic 0.90 1.40 0.64

Salmon, Atlantic

Wild 0.32 1.11 0.29

Farmed 0.86 1.10 0.48

Salmon, Coho

Wild 0.43 0.66 0.65

Farmed 0.36 0.82 0.44

American Diabetes Association: two or more servings of fish perweek (with the exception of commercially fried fish filets)provide omega-3 polyunsaturated fatty acids are recom-mended [10].American Heart Association: two servings of fish (preferablyfatty) per week [11,12].2005 Dietary Guidelines Advisory Committee Report: twoservings of fish (preferably high omega-3 fish) per day [7].The Dietary Guidelines for Americans 2005 Report: ‘‘Evidencesuggests that consuming two servings of fish per week(approximately 8 oz total) may reduce the risk of mortalityfrom CHD, and that consuming EPA and DHA may reduce therisk of mortality from CVD in people who have alreadyexperienced a cardiac event.’’ [7].National Cholesterol Education Program: fish is recommended asa food item for people to choose more often [13].National Academies: seafood is part of a healthy diet and can besubstituted for other protein sources that are higher insaturated fat [14].

3.2. Global recommendations for long-chain omega-3 fatty acids and

fish for primary prevention of coronary diseases

Australia and New Zealand National Health and Medical Research

Council: a suggested dietary target for men and women 19–470years of age – 610 and 430 mg/day of DHA/EPA/DPA (Docosapen-taenoic acid), respectively [15].

European Society for Cardiology: oily fish and n-3 fatty acidshave particular protective properties for primary CVD prevention[16].

France: AFFSA, CNERNA & CNRS – 500 mg/day of EPA+DHA;DHA 120 mg/day minimum [17].

Dutch Health Council: fish twice per week, one of which shouldbe oily to achieve the dietary reference intake of 450 mg/day ofomega-3 fatty acids from fish [18].

Superior Health Council of Belgium: minimum of 0.3% energyfrom EPA+DHA for adults (approximately 667 mg/day) [19].

International Society for the Study of Fatty Acids and Lipids: aminimum intake of EPA+DHA combined of 500 mg/day isrecommended for cardiovascular health [20].

National Heart Foundation of Australia: at least two fish(preferably oily fish) meals per week [21].

United Kingdom Scientific Advisory Committee on Nutrition:consume at least two portions of fish per week, of which oneshould be oily, and provide 450 mg/day of EPA+DHA [22].

World Health Organization: regular fish consumption (one totwo servings per week; each serving should provide theequivalent of 200–500 mg of EPA+DHA) [23].

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3.3. Recommendations for long-chain polyunsaturated fatty acids in

pregnancy, lactation and infancy

It is widely accepted that long-chain polyunsaturated fattyacids (PUFAs) are important for the growth and development ofinfants [24,25]. Sufficient DHA during pregnancy and after birth isessential because it is the predominant structural fatty acid in thecentral nervous system and retina, and its availability is crucial forbrain development. Metabolic studies have indicated that inyoung non-pregnant women compared with men, ALA isconverted to EPA more efficiently [26]. An important context isthat human milk is relatively low in EPA (0–0.12 wt%) and ishigher in ALA (0.08–1.1 wt%) as well as DHA (0.01–0.56 wt%) [27].Current thinking is that since ALA is converted to EPA, consump-tion of recommended amounts of ALA will provide adequateamounts of EPA during pregnancy, lactation and infancy [28].Pregnant and lactating women who attempt to meet the DHArecommendation from fish are advised to follow advisories aboutconsumption of certain fish high in mercury because of potentialharmful effects to the fetus or infant. Below are recommendationsfor long-chain PUFAs according to the World Association ofPerinatal Medicine, the Early Nutrition Academy, and the ChildHealth Foundation [29]:

�

Pregnant and lactating women should achieve an average dailyintake of least 200 mg of DHA. � Infant formula should provide DHA at levels between 0.2 and

0.5 wt% of total fat, and with minimum amounts of arachidonicacid equivalent to the amount of DHA. Dietary long-chain PUFAshould continue after the first 6 months of life, but quantitativerecommendations are not made due to insufficient evidence.

� Pregnant women should consume 200–300 mg/day of DHA

[30,31].

� The American Dietetic Association/Dietitians of Canada – In

infant formula, DHA should be at least 0.2% of total fatty acidsand the level of arachidonic acid should not be lower than DHA[9].

� Levels of DHA to arachidonic acid (1.4:1–2:1) are beneficial for

visual and cognitive development of low-birth-weight infants,and possibly normal birth weight infants, as well [32].

3.4. Other recommendations for long-chain omega-3 fatty acids and

fish

�

For primary prevention of CVD – 500 mg/day of EPA+DHA (2servings/week of oily fish would provide 400–500 mg/day ofEPA+DHA) [33]. � For primary prevention of CVD – 250 mg/day of EPA+DHA [6]. � For primary prevention of CHD death and after a coronary

event – 250 mg/day of EPA+DHA. Given the uncertainty of thisestimate and no evidence of harm at higher intakes,250–500 mg/day of EPA+DHA [34].

� For women of childbearing age and nursing mothers –

consume 2 seafood servings/week, limiting intake of selectedspecies (high in methyl mercury) [6].

� For vegans, 2–4 g of ALA per day, and 100–300 mg/day of DHA

[35].

� Some preliminary recommendations advise 2–3 servings/week

of fish to lower risk of Alzheimer’s disease, and cognitivedecline with aging [36–39].

� Omega-3 fatty acids may improve psychotic, depressive, and

aggressive symptoms in severe patients [40].

� For postpartum depression and bipolar depression – 0.15% of

energy from EPA+DHA shows major benefits [40].

�

For homicide mortality – 0.075% of energy from EPA+DHAshows major benefits [40]. � For major depression – 0.35–0.40% of energy from EPA+DHA

shows marked benefits [40].

� For rheumatoid arthritis – there is proven benefit of about

3.5 g/day (range 1.6–7.1 g/day) of EPA+DHA [41].

It is apparent from the many different recommendations thathave been set for different population groups and endpoints forEPA and/or DHA that different nutrient adequacy criteria wereused to establish them. Moreover, the majority recommend anamount of EPA+DHA without differentiating these quantitatively.A key question to consider, especially with respect to CVD, iswhether there is a need for a specific recommendation for EPA andone for DHA. Alternatively, should there be one recommendationfor a specific mass of the two fatty acids without consideration fordifferentiating them? The latter model would assume that the twofatty acids have equivalent biological effects, which for someendpoints we know is not the case (i.e., DHA requirement forneural development). It is insightful to use the CVD fish andomega-3 fatty acid supplement literature to illustrate thecomplexities in resolving the above questions.

4. Effects of fish and omega-3 fatty acid supplements on CVD risk

Several seminal clinical trials have shown benefits of both fishand omega-3 fatty acid supplements on CVD. In these studies,different amounts of the individual long-chain omega-3 fattyacids have been shown to be efficacious. The Diet and ReinfarctionTrial (DART) was the first randomized controlled clinical trial(RCT) to evaluate the effect of fish (or fish oil) consumption onCHD in men who had recovered from a myocardial infarct [42].One group of men was given advice to consume 200–400 g(7–14 oz) oily fish per week, or for those who chose not toconsume fish to take the equivalent EPA and DHA as fish oilcapsules (DHA: 120 mg; EPA: 180 mg; Maxepa). Over the 2 years,fish intake was approximately 300 g/week (43 g/day). In terms offatty acid intake, this would be as much as 360 mg EPA and540 mg DHA/day provided by Maxepa. Given that the ratio of DHAto EPA is different in fish versus fish oil supplements (Tables 1and 2), subjects would have consumed more DHA relative to EPA ifthey consumed fish versus the supplements. Those who ate fish orconsumed fish oil supplements had an approximate reduction incardiac death by 33% and all cause mortality by 29%.

In the Gruppo Italiano per la Sperimentazione della Strepto-chinasi nell’Infarto Miocardico (GISSI) trial with more than 11,000patients who had survived a myocardial infarct, the treatmentgroup who received 850–882 mg EPA and DHA (1:2 ratio or about289 mg of EPA and 578 mg of DHA) capsules daily, reduced theirrisk for CVD by 11–20% and had a 47% decrease in sudden cardiacdeath [43] versus those who received no EPA+DHA supplement[44].

Most recently, in the prospective, randomized open-label,Japan EPA Lipid Intervention Study (JELIS), patients who wererandomly assigned 1800 mg of EPA daily (with statin) had a 19%relative reduction in major coronary events (P ¼ 0.011) comparedwith those who received the statin only. Although only EPA wasused in this study, it appears that it has benefits in preventingmajor coronary events and especially non-fatal coronary events.This dose, however, is much greater than would typically beobtained by consuming fish.

While the DART, GISSI and JELIS studies have shown clearbenefits of long-chain omega-3 fatty acids, it is not clear whetherboth fatty acids confer comparable cardio-protective effects. TheJELIS Study shows clear benefits of EPA alone, and the GISSI and

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DART fish groups demonstrate that fish with a higher proportionof DHA to EPA also decreased CVD events in coronary patients.Thus, a combined target recommendation for EPA+DHA couldresult in not meeting the desired target for the biologically activelong-chain omega-3 fatty acid, yet still achieve the combinedEPA+DHA goal. This presupposes, however, that there arebiological potency differences between EPA and DHA for CVDrisk, which to date has not been demonstrated.

5. Intake of long-chain omega-3 fatty acids

Based on the National Health and Nutrition ExaminationSurvey, 1999–2000, for the US population (including all ages andboth genders), the mean intake of EPA and DHA is about 100 mg/day [45]. Intake of docosapentaenoic acid (DPA) is 10 mg/day.Current fish and shellfish consumption is 10 g/day (or about 2.5 oz(78 g) per week) for males and females of all ages (using1994–1996, USDA Continuing Survey of Food Intakes by Indivi-duals; n ¼ 16,103) [46]. According to NHANES 1999–2000 data,mean intake of fish is 2.9 oz (81 g) per week [7]. Much of theseafood consumed in the US is from fish low in omega-3 fattyacids (i.e., shrimp and other shellfish and whitefish) [14]. More-over, estimates are limited by the ‘‘all or none’’ phenomenon seenwith fish and shellfish consumption. The number of individualswho regularly eat fish and shellfish is small but consumptionwithin this group is high [47]. Thus, many in the population arenot meeting current recommendations for omega-3 fatty acidintake, which is consistent with US population intake data for EPAand DHA (E100 mg/day).

6. Conclusions

Numerous recommendations for long-chain omega-3 fatty acidintakes have been made globally by many federal agencies,professional groups, and scientists. The majority of recommenda-tions have been issued on the basis of amount of EPA+DHAtogether, without specific guidance for each fatty acid. Goingforward, it is clear, based on a robust evidence base, that there is apressing need to establish a DRI for the individual long-chainomega-3 fatty acids (20C or greater). It would seem that this wouldmake more ‘‘physiological sense’’ than current recommendationsfor total long-chain omega-3 fatty acids, which conveys themessage that all are the same biologically, and that implementa-tion of recommendations can be done in a myriad of ways (i.e.,varying proportions of EPA, DHA, as well as DPA). Given thatcurrent intake in the United States is low compared withrecommendations made to date, it is important to emphasizethat enormous health benefits are expected with new DRI(s) thatare based on the multiple biological effects ascribed to the long-chain omega-3 fatty acids.

Acknowledgments

The authors have no financial or personal interest in anycompany or organization involved in this review. P. Kris-Ethertonwas responsible for organizing and writing major sections of thereview. J. Grieger was responsible for the sections pertainingto fatty acid recommendations in pregnancy, lactation andinfancy; the effects of fish and fatty acids on CVD risk; as wellas in the overall preparation of the manuscript. T. Etherton wasresponsible for writing and reviewing major sections of thereview.

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