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Review of scientific and regulatory approaches in establishing a Codex NRV
values for -3-fatty acids based on eicosapentaenoic (EPA) and
docosahexaenoic acid (DHA) acids
by the Russian Federation1
This review has been done by the Russian Federation, part of the working schedule
of the CCNFSDU eWG on an NRV-NCD for omega-3 fatty acids.
Introduction
Biological role of omega-3 fatty acids cannot be overestimated. In humans,
endogenous synthesis of eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA) from alpha-linolenic acid (ALA) is minimal, with between 0.01% and 8%
of ALA being converted to EPA and less to DHA [5]; thus, omega-3 fatty acid
plasma and tissue levels are determined largely by direct consumption. Since
EPA and DHA have various metabolic functions not duplicated by other fatty
acids, they could be viewed as unconditionally essential fatty acids.
Omega-3 acids, also known as n-3 PUFA (polyunsaturated fatty acids), are
different by chemical structure and origin sources with key examples being ALA,
an 18-carbon fatty acid found in a variety of plant-based foods, EPA and DHA
(comprised of 20 and 22 carbons, respectively). The later are considered highly
unsaturated fatty acids and found in marine sources (mainly fish and especially
oily fish). DHA is also found in algae.
Accumulating evidence indicates that EPA and DHA modulate both metabolic
and immune processes and confer health benefits in areas of cardiovascular
disease (CVD), neurodevelopment and child’s health.
1
Professor VA Tutelyan, Russia’s Codex Contact Point, The Russian Institute of Nutrition,
Moscow
1
In particular, increasing EPA and DHA intake reduces the risk of CVD. A number
of clinical trials, animal studies, and observational studies have demonstrated
that increased intakes of fish and fish oil improve different inflammatory
pathologies. Numerous mechanistic details as to how EPA and DHA modulate
chronic disease have been reported [1,2,3,4]. However, the optimal dose of n-3
PUFAs has not yet been agreed upon. The analysis of approaches in defining
omega-3 fatty acids intakes shows, that over the recent years there has been a
transition from a model of “nutrient adequacy” to the “disease prevention”
approach.
The main objective of the “nutrient adequacy” model in the development of the
intake reference value was to establish a minimum level of micronutrient that is
necessary for the prevention of clinical deficiency for more than 97% of the
population of the corresponding sex and age group. .
In the other hand, the “disease prevention" approach suggests values which may
also have some positive effects on human health, including increase the overall
resistance to adverse environmental factors and reduction of the risk of some
nutrition-related diseases [5]. Essentially, the objective now is not just to provide
the human body with a minimum amount of a nutrient required but to supply
with an optimal amount required for the optimal health.
Thus, a daily reference intake (DRI) review is no longer based exclusively on
whether a nutrient is essential but also on whether a certain level of intake can
reduce the risk of what is defined as a chronic disease. This perspective is
captured for example in the concept of the acceptable macronutrient distribution
range (AMDR) with a lower and upper boundary.
This disease prevention approach was utilized in the 2010 IOM report [31] on
DRIs for vitamin D and calcium, which used bone health as well as non-skeletal
chronic disease outcomes as indicators. Although the chronic disease is the
motive of the preventive approach, the actual DRIs are intended to meet the
needs of healthy people, not individuals with disease.
One of the problems with defining optimal intake for nutrients is associated with
the fact that there is currently no uniform scientific terminology. The following
terminology examples are currently applied in different countries or by different
organizations:
1. According to WHO/FAO the Estimated Average Requirements (EAR) is the
average daily nutrient intake level estimated to meet the requirement of half
of the healthy individuals in a particular life stage and gender group.
 The EAR is used to define the Recommended Nutrient Intake (RNI) which
is the average daily dietary nutrient intake level sufficient to meet the
nutrient requirement of nearly all 97,5 % healthy individuals in a
particular life stage and gender group.
 The Upper tolerable nutrient intake (UL) is the level of nutrient that does
not adversely affect the health of the majority (97.5%) of people in the
respective age and gender group.
2

Daily reference intake (DRI) reflects reference values that are quantitative
estimates of nutrient intakes to be used for planning and assessing diets
for healthy people.
2. In the United States the Recommended Daily Allowance (RDA) is used as an
equivalent of the RNI. For the nutrients with no established RDA the
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, is used.
 USA’s Estimated Average Requirements (EAR) and Tolerable upper intake
(UL) are analogies of the WHO’s EAR and UL [32].
3. In the EU, Dietary Reference Values (DRV) are commonly used. Dietary
Reference Values (DRVs) are the complete set of nutrient
recommendations and reference values, such as population reference
intakes, the average requirement, adequate intake level and the lower
threshold intake. DRVs can be used, for instance, as a basis for reference
values in food labeling and for establishing Food-Based Dietary Guidelines
(FBDG).
The DRVs can be classified in three types:
• RNI - Reference Nutrient Intake (97.5% of the population's requirement is
met)
• EAR - Estimated Average Requirement (50% of the population's requirement
is met)
LRNI - Lower Recommended Nutritional Intake (2.5% of the population's
requirement is met)
4. In the countries of the Eurasian Economic Union the recommended
adequate intake, as defined in Russia’s "Norms of physiological needs of
energy and nutrients" as the average amount of an essential nutrient
required for optimal implementation of physiological and biochemical
processes enshrined in the human genotype. The numeric values and
norms of nutrients are the same for Russia and Belorussia. In Kazakhstan,
national requirements based on WHO/FAO (2004) norms and on US DRIs
[6].
5. The Codex Alimentarius Nutrient Reference Values (NRVs) are a set of
numerical values that are based on scientific data for purposes of
nutrition labeling and relevant claims. They comprise the following two
types of NRVs:
Nutrient Reference Values - Requirements (NRVs-R) refer to NRVs that are
based on levels of nutrients associated with nutrient requirements.
Nutrient Reference Values - Noncommunicable Disease (NRVs-NCD) refer to
NRVs that are based on levels of nutrients associated with the reduction in
the risk of alimentary noncommunicable diseases excluding nutrient
deficiency diseases or disorders [7].
In this review, we have evaluated the most common scientific approaches to the
assessment of the intakes for omega-3 fatty acids with an aim to offer dietary
guidance for the promotion of the human health and the prevention of chronic
diseases.
3
4
Approaches in the assessment of the NRV of omega-3 fatty acids
1. The omega-3 index
The omega-3 index is a measure of the proportion of fatty acids in red blood cell
membranes that are made up of EPA and DHA omega-3s. Studies have shown
the omega-3 index was a powerful risk factor for chronic diseases. One research
demonstrated that the omega-3 index was a stronger risk factor for sudden
cardiac death than traditional risk factors like cholesterol, triglycerides and Creactive protein [8].
The omega-3 index was defined in 2004 as the percentage of EPA+DHA in red cell
lipids. The level of the omega-3 index is directly influenced by the intake of EPA and
DHA: every 4 g of EPA and DHA ingested during a month increased the Omega-3
Index by 0.24 per cent. The Omega-3 Index is also influenced by age (+0.50% per
decade), diabetes (−1.13% t), body mass index (−0.30% per three units), gender,
physical activity, and a number of other factors such as social status or alcohol intake
[9].
A target range of omega-3 index was suggested between 8 and 11%. Values
below predispose to cardiovascular events, especially sudden cardiac death, as
well as to suboptimal brain function, like prolonged reaction times or even
depression [10,11].
In Serbian randomized, crossover clinical study participants during over an 8week period and separated by a 6-month washout period received an oily fish
(salmon) providing 274 mg of EPA and 671 mg of DHA daily, or a commercial
fish oil supplement, providing 396 mg EPA and 250 mg DHA per day.
The result of the intakes was rated by the count of the sum of EPA + DHA in the
red blood cell membranes. The sum of EPA + DHA significantly increased in both
groups following dietary recommendations for oily fish and fish oil supplements
intake in middle-aged healthy subjects with low baseline long-chain n-3 PUFA
status though targeted values with optimal cardioprotective omega-3 index of
more than 8% were still not achieved [12].
In Russia, cardiologists have used omega-3 index to reflect the content of
polyunsaturated fatty acids in red blood cell and cardiomyocites of patients with
coronary heart disease treated with 1g supplement with EPA ethyl ester (46%)
and DHA (38%). The total amount of ethyl esters of omega-3 PUFAs was over 90
per cent. After 6 months of treatment a statistically significant increase of
omega-3 index (by 21.1% from initial level, p<0.0001) was observed in the red
blood cell membranes.
For one patient the index has exceeded 8 per cent (low risk), for the remaining 9
patients omega-3-index medium was in the range of 4.3 to 6.2 per cent.
5
The study demonstrated that the omega-3 index served as a reliable marker that
reflected the content of omega-3 PUFAs in the myocardium of patients with
ischemic heart disease. In addition, it can also be used as a modifiable risk factor
for the likelihood of cardiovascular complications.
Another study also drew a conclusion that omega-3 index reflected the content
of omega-3 polyunsaturated fatty acids in cardiomyocyte membranes in patients
with CHD which can be used to evaluate the efficacy of treatment with omega-3
polyunsaturated fatty acids [13].
The following table summarizes intake levels used in studies with the direct
determination of EPA and DHA in red blood cell membranes.
Source
Serbian
study
[12]
Russian
study
[13]
Dosage of omega-3 intake and
Results
Daily intake 945 mg omega-y fatty
acids an oily fish or 646 mg of
commercial fish oil during 8-week
period and separated by a 6-month
washout period.
Daily intake 1 g of omega-3 fatty
acids (840 mg of EPA ethyl ester
(46%) and DHA (38%)) during 6
months demonstrated that the ratio
of omega-3 -reliability marker that
reflects the content of omega-3
PUFAs, in the myocardium of
patients with ischemic heart
disease.
Notes
Targeted values with optimal
cardioprotective effect of more
than 8% of omega-3 index
were not achieved
Targeted values with optimal
cardioprotective effect of 8% of
omega-3 index has exceeded
only for one patient, for the
remaining 9 patients omega-3index medium was from 4.3 to
6.2%.
2. Epidemiological studies based on dietary assessment and long-term
investigation of diseases risk reduction
Values etsablished by this approach have been generally based on the inverse
relationship observed between the consumption of n-3 long chain PUFA
(primarily from fish and fish oils) on different health outcomes in particular a
lower risk of coronary artery disease. For infants and young children (6 to 24
months of age) specific recommendations have also been made for DHA ranging
from 70-100 mg/day based on its accumulation in the central nervous system
and its effects on visual function during the complementary feeding period and
for additional DHA (100-200 mg/day) for pregnant and lactating women to
compensate for oxidative losses of maternal dietary DHA and accumulation of
DHA in body fat of the fetus/infant.
6
Using this approach, in Australia the highest dietary recommendations for EPA
and DHA (mostly as EPA and DHA or as DHA alone) for different population
subgroups have been set at 610 mg/day.
In the EU, the highest recommendations for EPA and DHA combined for adults
and children (250-500 mg/day) have been set based on the reduction of CVD
risk.
In other countries/territories, dietary recommendations from national and
international bodies for n-3 long-chain PUFA (mostly as EPA and DHA) range
from 200 mg to >600 mg/day for adults, and from 40 mg to 250 mg/day for
infants older than six months and for children and adolescents [14, 15, 16,17,18].
The results of the worldwide meta-analysis (1990-2010) [19] of dietary surveys
from 187 countries on omega-3 PUFAs revealed dramatic diversity across
nations. Country-specific omega-3 consumption ranged from 5 to 3,886 mg/day
(163 mg/day) for seafood omega-3; and <100 to 5,542 mg/day (1,371 mg/day)
for plant omega-3.
Global mean intake of seafood omega-3 fats was 163 mg/day, with tremendous
regional variation (from <50 to >700 mg/day) and national variation (from 5 to
3886 mg/day). Highest intakes were identified in island nations including
Maldives, Barbados, The Seychelles, and Iceland as well as in Malaysia, Thailand,
Denmark, South Korea and Japan.
The lowest Intakes were in Zimbabwe, Lebanon, the Occupied Palestinian
Territory, Botswana, And Guinea-Bissau. In 45 of 187 countries mean intakes
were ≥250 mg/day. Notably, 100 nations had very low mean consumption (<100
mg/day), generally in Sub-Saharan African And Asian regions as well as in the
North Africa/Middle East, representing over three billion people.
The mean plant-origin omega-3 consumption was 1371 mg/day, with a 10-fold
range (302 to 3205 mg/day) across regions. By country, intake ranged from
<100 to >3000 mg/day. The highest consumption was seen in Jamaica, China, the
UK, Tunisia, Angola, Senegal, Algeria, Canada, and the US. Several of these nations
have substantial linseed production, such as Canada (which also has high canola
production), China, and the US. Several South American nations (Brazil, Uruguay,
Paraguay and Argentina) also had higher plant omega 3 consumption, potentially
due to availability of chia seeds high in α-linolenic acid, or intakes of nuts and
other seeds. Lowest intakes were found in Israel, the Solomon Islands, Sri
Lanka,Comoros, Saint Lucia, and the Philippines [19].
Authors of the meta analysis did not evaluate the consequences of receiving
omega-3 and did not identify sufficient evidence to set a specific optimal intake
level for preventing chronic diseases. In comparison to the World Health
Organization Guidelines which suggest the mean population plant omega-3
consumption of ≥0.5% of energy intake, or ≥1100 mg for a 2000 kcal/day diet,
52 of 187 countries were in the WHO range. Among the 135 countries with lower
consumption, 61 had intakes <500 mg/day, substantially below current
7
recommendations, representing 800 million adults or 17.8 per cent of the global
adult population.
The following table summarizes intake levels recommended based on
epidemiological studies.
Source
Dosage of omega-3 intake and Notes
Results
EFSA, 2012 [18] For infants and young children These recommendations have
(6 to 24 months of age) for been generally based on the
DHA ranging from 70-100 inverse relationship observed
mg/day
between the consumption of
For pregnant and lactating these n-3 LCPUFA (primarily
women additional DHA (100- from fish and fish oils) on
200 mg/day)
different health outcomes in
The
highest
dietary particular a lower risk of
recommendations for EPA and coronary artery disease.
DHA (mostly as EPA and DHA
or as DHA alone) for different
population subgroups are 610
mg/day(Australia).
The highest recommendations
for EPA and DHA combined
for European adults and
children (250-500 mg/day).
Global,
Global mean intake of seafood In comparison with World
regional, and omega 3 fats was 163 mg/day, Health
Organization
national
with tremendous regional Guidelines suggest mean
consumption
variation (from <50 to >700 population plant omega 3
levels of dietary mg/day)
and
national consumption of ≥0.5%E, or
fats and oils in variation (from 5 to 3886 ≥1100 mg for a 2000
1990 and 2010 mg/day).
kcal/day diet, 52 of 187
[19]
In 45 of 187 countries mean countries met this intake.
intakes were ≥250 mg/day, in Among the 135 countries
line with current guidelines.
with lower consumption, 61
100 nations had very low had intakes <500 mg/day,
mean consumption (<100 substantially below current
mg/day), generally in Sub- recommendations,
Saharan African And Asian representing 800 million
Regions as well as North adults and 17.8% of the
Africa/Middle East. Mean global adult population
plant omega-3 consumption
was 1371 mg/day, with a 10fold range (302 to 3205
mg/day) across regions. By
country, intake ranged from
<100 to >3000 mg/day
3. Studies of risk of sudden cardiac death
8
Meta-analyses and systematic reviews of epidemiologic studies showed that
reductions in sudden cardiac death (SCD) by EPA+DHA were reported between
19% and 50% [20]. These figures are supported by reductions in total mortality
between 14-19% depending on the measuring approach and the time point of
the meta-analysis and/or systematic review. Most of the large intervention trials
were conducted with 850 mg ethyl esters of EPA+DHA/day. When factoring in
results of epidemiologic studies, some authors come to the conclusion that a
daily dose of 250 mg EPA+DHA/per day is effective in reducing death risks,
while others consider doses higher than 500 mg/day to be necessary [21,22].
The largest randomized intervention study to date, was JELIS, a five-year study
comparing 1.8 g EPA ethylester (9326 participants) with the control group
(9319 participants) of hyperlipidemic Japanese. Sudden cardiac death and
coronary death did not differ between groups. In patients with a history of
coronary artery disease who were given EPA treatment, major coronary events
were reduced by 19% (secondary prevention subgroup: 158 [8.7%] in the EPA
group vs 197 [10.7%] in the control group; p=0.048).
In patients with no history of coronary artery disease, EPA treatment reduced
major coronary events by 18 per cent but this finding was not statistically
significant (104 [1.4%] in the EPA group vs 127 [1.7%] in the control group;
p=0.132). This was most likely due to the high levels of EPA and DHA
traditionally consumed in Japan and found in red cells of Japanese. Therefore, the
results of JELIS rather argue for a protective effect of high levels of EPA+DHA in
red cells than against it [23].
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
and setting a higher DRI for EPA and DHA is important for realizing health
benefits, specifically the CVD prevention. In the data analysis, 566 mg/day of EPA
and DHA was the average intake associated with the greatest reduction (37%) in
risk of CVD mortality. 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 CVD mortality in 50 per cent 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 amount of EPA and DHA expected to meet the needs of nearly all
healthy individuals [5].
The following table summarizes intake levels recommended based on studies of
SCD.
Source
Dosage of omega-3 intake and
Results
US
Most of the large intervention
study,
trials conducted with 850 mg
2009
EPA+DHA/day as an ethyl ester.
[21, 22] When factoring in results of
Notes
Meta-analyses and systematic
reviews of epidemiologic studies
show reductions in sudden
cardiac deaths by EPA+DHA were
9
JELIS
study
2007
[23]
US
study,
2013
[5]
epidemiologic
studies,
some
authors come to the conclusion
that a daily dose of 250 mg
EPA+DHA/per day is effective,
while others consider doses
higher than 500 mg/day to be
necessary
The
largest
randomized
intervention study to date, was
JELIS, a five-year study comparing
1.8 g EPA ethyl ester (9326
participants) to no intervention
(9319
participants)
in
hyperlipidemic Japanese.
reported between 19% and 50%
The combined primary endpoint
(SCD,
fatal
and
non-fatal
myocardial infarction, and other
nonfatal events including unstable
angina
pectoris, angioplasty,
stenting, or coronary artery
bypass grafting) was reduced by
19 rel. per cent.
In a data analysis, 566 mg/day of The greatest reduction (37%) in
EPA and DHA was the average risk of CVD mortality in 50% of
intake associated with the the population.
greatest reduction (37%) in risk
of CHD mortality in 50% of the
population.
Two
standard
deviations above the EAR would
be approximately 1 g/day, which
would be the amount of EPA and
DHA expected to meet the needs
of nearly all healthy individuals.
4. Strength of the body of evidence
The dietary intake recommendation from some authorities is based on the
approach of "the level of evidence" in analysis of clinical and epidemiological
studies of intake omega-3 fatty acids. The design of the study and the endpoints
measured affect the strength of the evidence.
The first time this approach was proposed by the National Cancer Institute and
defined levels of evidence as "a ranking system used to describe the strength of
the results measured in a clinical trial or research study. The design of the study
[...] and the endpoints measured [...] affect the strength of the evidence".
The term was first used in a 1979 report by the "Canadian Task Force on the
Periodic Health Examination" and came out with its guidelines at United States
Preventive Services Task Force (USPSTF) in 1988 [24].
This approach was used by expert consultation from the Joint FAO/WHO Expert
Consultation on Fats and Fatty Acids in Human Nutrition [25]. Experts agreed on
the criteria to be used to judge the levels and strength of evidence required to
conclude that total fat and fatty acids which affect major health and disease
outcomes. It was decided to follow the same criteria employed in the report Diet,
10
Nutrition, and the Prevention of Chronic Diseases; Report of a Joint WHO/FAO
Expert Consultation (WHO TRS 916, Geneva, 2003), which had based its criteria
on a modified version of that used by the World Cancer Research Fund. Four
levels of judgment were identified:
• Convincing
• Probable
• Possible
• Insufficient
Convincing evidence
Evidence based on epidemiological studies showing consistent associations
between exposure and disease, with little or no evidence to the contrary. The
available evidence is based on a substantial number of studies including
prospective observational studies and where relevant, randomized controlled
trials of sufficient size, duration and quality showing consistent effects. The
association should be biologically plausible.
Probable evidence.
Evidence based on epidemiological studies showing fairly consistent associations
between exposure and disease, but where there are perceived shortcomings in
the available evidence or some evidence to the contrary, which precludes a more
definite judgment. Shortcomings in the evidence may be any of the following:
insufficient duration of trials (or studies); insufficient trials (or studies)
available; inadequate sample sizes; incomplete follow-up. Laboratory evidence is
usually supportive. Again, the association should be biologically plausible.
Possible evidence.
Evidence based mainly on findings from case-control and cross-sectional studies.
Insufficient randomized controlled trials, observational studies or nonrandomized controlled trials are available. Evidence based on nonepidemiological studies, such as clinical and laboratory investigations, is
supportive. More trials are required to support the tentative associations, which
should also be biologically plausible.
Insufficient evidence.
Evidence based on findings of a few studies which are suggestive, but are
insufficient to establish an association between exposure and disease. Limited or
no evidence is available from randomized controlled trials. More well-designed
research is required to support the tentative associations.
Given the limited number of randomized controlled trials of dietary fat and
chronic disease or death it was agreed that only evidence of sufficient strength to
be “convincing” or “probable” would allow a dietary recommendation to be
formulated. Based on this assumption, the WHO/FAO recommended dietary
intake for essential ALA: > 0.5%E and AMDR (EPA + DHA): 0. 250 – 2 g/day [25].
11
The National Health and Medical Research Council (NHMRC) in Australia has its
own forward-thinking approach to classifying levels of evidence for clinical
interventions (see table) [26].
The following table summarizes intake levels recommended based on evaluation
of evidence strength.
Source
Dosage of omega-3 intake and results
Notes
WHO/FAO
Essential (ALA):> 0.5%E
The limited number of
AMDR (EPA + DHA):0. 250 – 2 g/day.
randomized controlled
trials
and only
evidence of sufficient
strength
to
be
“convincing”
and
“probable”
National
Marine n-3 PUFA supplementation of I level of evidence i.e.
Heart
1000–4000 mg/day decreases serum evidence
obtained
Foundation of TG levels by 25–30% and increases from a systematic
Australia
high-density
lipoprotein
(HDL) review of all relevant
cholesterol levels by 1–3%. A dose randomised controlled
relationship exists between intake of trials.
marine n-3 PUFA and decreased serum
TG levels
In secondary prevention, ≥ 850 mg/day Evidence
obtained
marine n-3 PUFA supplementation from at least one
reduces the CVD risk
properly
designed
randomised controlled
CVD mortality and ≥1,800 mg/day trial.
reduces major coronary events
In secondary prevention, a diet with 2
g/day of ALA decreases the risk of CVD
5. Non-evidence based approach
The position of some national authorities in omega-3 intake has no specific
justification. For example in Russia the intake omega-3 fatty acids was
historically defined at 0.8-1.6 g / day or 5-8 per cent of daily dietary energy. This
level has been fixed in the food regulation of the Customs Union and national
methodological recommendations on rational nutrition (MR 2.3.1.2432-08).
For some countries recommentation of omega-3 intake have direct links to
other agencies. The recomendation of Cardiological Society of India for omega-3
intake EPA (460 mg)& DHA (380 mg) was based on providence by American
Heart Association(AHA), National Institute of Clinical Excellence (NICE) and
European Society of Cardiology (ESC), and recommendations of Australian &
New Zealand Health Authorities [27].
12
Chinese Nutrition Society has established official Dietary Reference Intakes for
EPA and DHA for adults varying from 250 mg to 2000 mg per day, that exactly
corresponds
to the WHO/FAO recommendations (Interim Summary of
Conclusions and Dietary Recommendations on Total Fat & Fatty Acids, WHO HQ,
Geneva, 2008) [14,28].
Brazilian guidelines have converged on consistent recommendations for the
general population to consume at least 250 mg/day of long-chain omega-3 fats
or at least two weekly servings of oily fish, that is not supported by a specific
evidence but copies EFSA (European Food Safety Authority) recommendations
[18, 29].
13
Assessment of upper intake level of omega-3 intake
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.
In 1997, the US Food and Drug Administration (FDA, 1997) [18] concluded that
total intakes (from diet and supplements) of EPA and DHA up to 3 g/day were
generally recognized as safe (GRAS). This figure was set on the basis of increased
bleeding times, increased fasting blood glucose concentrations in non-insulin
dependent, type 2 diabetic subjects, and increased LDL-cholesterol
concentrations, particularly in hypertriglyceridaemic or hypercholesterolaemic
subjects, at higher levels of intake.
In 2004, the FDA approved a mixture of EPA and DHA in the form of ethyl esters
as a registered drug for the treatment of hypertriglyceridaemia in adult patients
at doses of 4 g/day. No significant adverse effects were reported for the drug vs.
placebo in human intervention studies at this dose.
In 2005, the US Institute of Medicine (IoM, 2005) [18] also evaluated the safety
of n-3 LCPUFA and concluded that the available data were insufficient to set a UL
for EPA and DHA, although subjects with impaired glucose tolerance or type 2
diabetes and subjects with familial hypercholesterolemia using anticoagulants
were recommended to consume EPA and DHA supplements with caution. The
bases of this recommendation are not explicitly stated.
In May 2009, the German Federal Risk Assessment Agency (BfR, 2009)
recommended that 1.5 g/day of EPA and DHA from all sources should not be
exceeded and this recommendation was based on the increased risk of bleeding
reported in one study in children (Clarke et al., 1990).
Some authorities have reported no adverse effects at intake levels up to between
5 and 6 g/day [5].
In June 2011, the Norwegian Scientific Committee for Food Safety (VKM, 2011)
conducted a safety evaluation of n-3 LCPUFA from all sources. No clear adverse
effects were associated with EPA and DHA intakes up to 6.9 g/day and no UL
could be established [18].
The Panel on Dietetic Products, Nutrition and Allergies for the European
Commission delivered a scientific opinion on the Tolerable Upper Intake Level
(UL) of the n-3 LCPUFAs EPA, DHA and docosapentaenoic acid (DPA). Available
data were insufficient to establish an UL for n-3 LCPUFA (individually or
14
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. Long-term supplemental intakes of EPA and DHA combined up to about 5
g/day did not appear to increase the risk of spontaneous bleeding episodes or
bleeding complications, or affect glucose homeostasis immune function or lipid
peroxidation, provided the oxidative stability of the n-3 LCPUFA is guaranteed.
Supplemental intakes of EPA and DHA combined at doses of 2-6 g/day, and of
DHA at doses of 2-4 g/day were shown to induce an increase in LDL-cholesterol
concentrations of about 3 per cent, which may not have an adverse effect on
cardiovascular disease risk, whereas EPA at doses up to 4 g/day had no
significant effect on LDL cholesterol. 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, did not raise safety concerns for adults. Dietary recommendations for
EPA and DHA based on cardiovascular risk considerations for European adults
were between 250 and 500 mg/day.
Adverse effects which have been described in humans in association with high
intakes of n-3 LCPUFA 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 [30].
The table summarizes maximum intake levels studied for LCPUFA
Source
Upper
limits
of Notes
omega-3 intake and
Results
Food and Drug EPA and DHA up to 3 This figure was set on the basis of
Administration
g/day were generally increased bleeding times, increased
(FDA), 1997
recognized as safe
fasting blood glucose concentrations
in non-insulin dependent, type 2
diabetic subjects, and increased LDL
cholesterol
concentrations,
particularly
in
hypertriglyceridaemic
or
hypercholesterolaemic subjects, at
higher levels of intake.
German Federal 1.5 g/day of EPA and This recommendation was based on
Risk Assessment DHA from all sources the increased risk of bleeding
Agency
(BfR,
reported
in
one
study
in
2009)
children(Clarke et al., 1990).
Norwegian
EPA and DHA intakes No clear adverse effects were
Scientific
up to 6.9 g/day
associated with EPA and DHA
Committee
for
intakes up to 6.9 g/day and no UL
Food Safety (VKM,
could be established.
2011)
European
Long-term
Do not appear to increase the risk of
Commission
supplemental
spontaneous bleeding episodes or
(EFSA), the Panel intakes of EPA and bleeding complications, or affect
15
on
Dietetic DHA combined up to
Products,
about 5 g/day
Nutrition
and
Allergies
Supplemental
intakes of EPA and
DHA combined at
doses of 2-6 g/day,
and of DHA at doses
of 2-4 g/day
EPA at doses up to 4
g/day
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 adults.
Supplemental
intakes of DHA alone
up to about 1 g/day
glucose
homeostasis
immune
function or lipid peroxidation,
provided the oxidative stability of
the n-3 LCPUFA is guaranteed.
induce an increase in LDLcholesterol concentrations of about
3 % which may not have an adverse
effect on cardiovascular disease risk,
has no significant effect on LDL
cholesterol
Dietary recommendations for EPA
and DHA based on cardiovascular
risk considerations for European
adults are between 250 and 500
mg/day.
do not raise safety concerns for the
general population.
16
Abbreviations
n-3 PUFAs - polyunsaturated fatty acids
n-3 LCPUFA - n-3 Long chain polyunsaturated fatty acids
AMDR - acceptable macronutrient distribution range
AI - Adequate Intake
ALA - alpha-linolenic acid
CVD - cardiovascular disease
DRI - daily reference intake
DHA - docosahexaenoic acid
DPA - docosapentanoic acid
EPA - eicosapentaenoic acid
EAR - Estimated Average Requirements
FDA - US Food and Drug Administration
NHMRC - National Health and Medical Research Council in Australia
NRVs - Nutrient Reference Values
NRVs-R - Nutrient Reference Values - Requirements
NRVs-NCD - Nutrient Reference Values - Noncommunicable Disease
RNI - Recommended nutrient intake
RBCs - Red blood cells (erythrocytes)
SCD -Sudden cardiac death
UL - Upper tolerable nutrient intake
USPSTF - United States Preventive Services Task Force
17
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