expert opinion

It is time to establish a dietary reference intake for omega-3 fatty acids

December 15, 2013

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Penny M. Kris-Etherton, Ph.D., Department of Nutritional Sciences of Pennsylvania State University, USA

“Considerable progress has been made over the past decade to better understand the biological effects of dietary fatty acids. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), modulate both metabolic and immune processes and confer health benefits in areas of cardiovascular disease (CVD) and neurodevelopment. The shortest n-3 PUFA is alpha-linolenic acid (ALA), an 18-carbon fatty acid found in a variety of plant-based foods. In contrast, EPA and DHA (comprised of 20 and 22 carbons, respectively) are considered highly unsaturated fatty acids and are found in marine sources (mainly fish and especially oily fish); DHA is also found in algae. Clinical trials, animal studies, and observational studies have demonstrated that increased intakes of fish and fish oil improve different in- flammatory pathologies (1). Numerous mechanistic details as to how EPA and DHA modulate chronic disease have been reported (2). Accumulating evidence indicates that increasing EPA and DHA intake reduces the risk of CVD (3); however, the optimal dose of n-3 PUFAs remains to be resolved. Given the substantial new evidence published since the last Institute of Medicine (IOM) report in 2002, it is time for the IOM to address the question of establishing a DRI for n-3 PUFAs again. A DRI for EPA and DHA will help inform nutrition policy decisions and will reduce consumer uncertainty about target n-3 PUFA intakes.

There has been a transition in the DRI model from a “nutrient adequacy” approach to one that also focuses on “disease prevention.” A DRI review is no longer based only on whether a nutrient is essential, but also on whether a certain level of intake can reduce the risk of what they define as a chronic disease. This perspec- tive is captured in the acceptable macronutrient distribution range (AMDR) with a lower and upper boundary. This is an intake range for macronutrients, expressed as a percentage of the total energy that is associated with the reduced risk of chronic disease while providing adequate intake of essential nutrients. If an indivi- dual consumes below or above this range, there is a potential for increasing the risk of chronic diseases shown to affect long-term health, as well as increasing the risk of insufficient intakes of essential nutrients. This new perspective on chronic disease risk was evident in the 2010 IOM report on DRIs for vitamin D and calcium, which used bone health as well as non-skeletal chronic disease outcomes as indicators (4). Although chronic disease is often addressed, DRIs are intended to meet the needs of healthy people, not individuals with disease. Another challenge is to define the word “healthy.” Importantly, the aim is to offer dietary guid- ance for the promotion of health and the prevention of chronic diseases, particularly since the latter are rampant in the United States.

For omega-3 fatty acids there is currently no estimated average requirement (EAR) – the average daily nut- rient intake level estimated to meet the requirement of half of the healthy individuals in a particular life stage and gender group –, which is the basis for recommended daily allowance (RDA) – the average daily dietary nutrient intake level sufficient to meet the nutrient requirement of nearly all (97–98%) healthy individuals in a particular life stage and gender group. There is, however, an adequate intake (AI) – i.e. the recommended average daily intake level based on observed or experimentally determined approximations or estimates of nutrient intake by a group of apparently healthy people that are assumed to be adequate – for ALA (1.6 g/ day for adult men and 1.1 g/day for adult women). This is based on the observed median intake in the Unit- ed States at which no nutrient deficiency is present. In addition, the AMDR for ALA is defined as 0.6–1.2% of energy, between 6% and 10% of which can be consumed as EPA and/or DHA. In humans, endogenous syn- thesis of EPA and DHA from ALA is minimal, with between 0.01% and 8% of ALA being converted to EPA and less to DHA; thus, omega-3 fatty acid plasma and tissue levels are determined largely by direct consump- tion. Since EPA and DHA have various metabolic functions not duplicated by other fatty acids, they could be viewed as conditionally essential fatty acids.

Many organizations and expert committees acknowledge the important role of EPA and DHA in human nutri- tion. The Dietary Guidelines for Americans recommend consuming about 8 oz/week (i.e. two 4-oz servings) of a variety of seafood to reduce cardiac deaths among individuals with or without preexisting CVD (5). This would provide about 250 mg/day of EPA and DHA, which is sufficient to obtain cardioprotective effects for primary prevention of CVD. The American Heart Association (AHA) recommends that adults without coronary heart disease (CHD) eat fish (particularly fatty fish) at least twice a week (6), which provides about 500 mg/ day of EPA and DHA. Individuals with CHD are advised to consume 1 g/day of EPA and DHA for secondary prevention of CVD, preferably from seafood and in consultation with a physician. Those who need to lower triglyceride levels are recommended to take 2 to 4 g/day of EPA and DHA as capsules under a physician’s care. In terms of their effects on blood levels of EPA and DHA, fish oil supplements provide benefits similar to those of seafood (7). Inadequate intake of DHA by pregnant women may impair neural development in the neonate. Sufficient DHA intake during pregnancy and lactation is crucial for proper brain development of infants. Thus, recommendations have been made for pregnant and lactating women. The International So- ciety for the Study of Fatty Acids and Lipids recommends that pregnant and/or lactating women consume at least 300 mg/day of DHA (8); the European Food Safety Agency recommends women consume at least 250 mg/day of EPA and DHA plus an additional 100 to 200 mg/day of DHA (9). Children, pregnant women, and women who may become pregnant are advised to avoid eating fish with higher levels of mercury. In addition, EPA and DHA have been shown to beneficially affect cognitive function. There is increasing evidence linking deficiency in EPA and DHA to mental and neurological disorders (10). More intervention trials are necessary to better understand the role of n-3 PUFAs in ameliorating neurodegeneration. The current data is not suffi- cient to support an intake level different from that needed to achieve CVD risk reduction.

The available data for cardiac mortality provides a basis for establishing a DRI for EPA and DHA. Current intakes (approximately 100 mg/day) are not sufficient; setting a DRI for EPA and DHA is important for reali- zing health benefits, specifically CVD prevention. In a data analysis, 566 mg/day of EPA and DHA was the average intake associated with the greatest reduction (37%) in risk of CHD mortality (11). Based on these data, an AI of 566 mg/day could be considered for EPA and DHA intake. However, if 566 mg/day is assumed as the median requirement, i.e. if it reduces the risk of CHD mortality in 50% of the population, then 566 mg /day would be considered as an EAR. The RDA could then be calculated using the standard deviation (224 mg/day). Two standard deviations above the EAR would be approximately 1 g/day, which would be the am- ount of EPA and DHA expected to meet the needs of nearly all healthy individuals. Of course, such requirem- ents are speculative; the convening of a DRI committee is necessary to thoroughly examine the body of evidence and determine whether an RDA can even be established. Recommendations calling for more than 1 g/day of EPA and DHA are typically aimed at secondary prevention of CVD. To date, no tolerable upper intake level (UL) – the highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population – for EPA and DHA has been set by any authoritative body. The US Food and Drug Administration (FDA) has stated that levels up to 3 g/day are generally recognized as safe (12), although other authorities have reported no adverse effects at intake levels up to between 5 and 6 g/day (13).

Much research remains to be done to establish a DRI for EPA and DHA. We need to improve our understand- ing of the requirements for the individual long-chain n-3 fatty acids and the factors that affect their conver- sion and biological function. In addition, we need to identify the appropriate endpoints to use for establishing a DRI for n-3 fatty acids and to improve understanding of differences between the individual n-3 PUFAs with respect to health outcomes, conversion efficiency and metabolism. Clearly, establishing a DRI for EPA and DHA is a large undertaking that will require input from many experts across multiple fields. Nonetheless, there is overwhelming evidence that justifies the public health importance of establishing a DRI for EPA and DHA.”

Based on: Flock M. R. et al. Long-chain omega-3 fatty acids: time to establish a dietary reference intake. Nutrition Reviews. October 2013.

References

1. Zhang M. J. and Spite M. Resolvins: anti-inflammatory and proresolving mediators derived from omega-3 polyunsaturated fatty acids. Annu Rev Nutr. 2012; 33:203–227.

2. Adkins Y. and Kelley D. S. Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids. J Nutr Biochem. 2010;21:781–792.

3. Trikalinos T. A. et al. Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-Analysis of Randomized Trials and Prospective Cohorts: Nutritional Research Series, Vol. 4. 2012.

4. Ross A. C. et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011; 96:53–58.

5. US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 2010. 7th ed. Washington, DC: US Government Printing Office; 2010.

6. Kris-Etherton P. M. et al. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol. 2003; 23:151–152.

7. Harris W. S. et al. Comparison of the effects of fish and fish-oil capsules on the n–3 fatty acid content of blood cells and plasma phospholipids. Am J Clin Nutr. 2007; 86:1621–1625.

8. Simopoulos A. P. et al. Workshop statement on the essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2000; 63:119–121.

9. European Food Safety Authority Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion of the Panel on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol. EFSA J. 2010; 8:1461.

10. Zhang W. et al. Omega-3 polyunsaturated fatty acids in the brain: metabolism and neuroprotection. Front Biosci. 2011; 16:2653–2670.

11. Harris W. S. et al. Intakes of long-chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in healthy adults. Curr Atheroscler Rep. 2008; 10:503–509.

12. US Food and Drug Administration. Letter regarding dietary supplement health claim for omega-3 fatty acids and coronary heart disease. October 31, 2000.

13. European Food Safety Authority. Scientific Opinion on the Tolerable Upper Intake Level of eicosap- entaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA J. 2012; 10:2815–2882.