E
Agenda Item 7 CX/NFSDU 16/38/8-Add.1
JOINT FAO/WHO FOOD STANDARDS PROGRAMME
CODEX COMMITTEE ON NUTRITION AND FOODS FOR SPECIAL DIETARY USES
Thirty-eighth Session
Hamburg, Germany
5 – 9 December 2016
PROPOSED DRAFT NRV-NCD FOR EPA AND DHA LONG CHAIN OMEGA-3 FATTY ACIDS
COMMENTS AT STEP 3
Comments of Canada, Colombia, Cuba, Ghana, Mexico, New Zealand, Paraguay, Philippines, CRN, ELC, GOED,
IADSA, ICGMA and ISDI
CANADA
GENERAL COMMENTS
At this time, Canada is not in a position to support the NRV-NCD proposed for EPA and DHA. Canada is of
the opinion that there has not been sufficient opportunity for discussion between the members of the eWG and
the co-chairs with regard to the rationale for the proposed NRV-NCD for EPA and DHA of 250 mg/day and that
further discussion is needed before a final recommendation can be made.
SPECIFIC COMMENTS
Paragraph 8: “In 2015, eWG members provided an extensive list of references and texts of scientific reports
related to the association of the EPA/DHA intake with cardiovascular health outcomes (see the list of
references in CX/NFSDU 15/37/7). Based on the PICO question formulated, co-chairs had identified
systematic reviews and meta-analyses published since 2009 and reviewed results related to the target health
outcome. The strength of evidence was assessed with the GRADEpro tool as described in CX/NFSDU 15/37/7.
Table 2 summarizes the systematic reviews and meta-analyses included in the review.”
The assessment of the strength of evidence other than that included in the reports of the selected RASBs is
outside the scope of work of this eWG. Any proposed NRV-NCD for EPA and DHA Long Chain Omega-3 Fatty
Acids should be based primarily on recommendations from RASBs’ publications as stipulated in the Annex:
General Principles for Establishing Nutrient Reference Values for the General Population in the Guidelines on
Nutrition Labelling (CAC/GL 2-1985).
Other scientific reports could be used as supporting evidence.
Paragraphs 9 to 17: Systematic reviews
Canada does not support using the meta-analyses described in the report to establish a NRV-NCD for EPA-
DHA because these meta-analyses have not been commissioned by a RASB for the purposes of providing
advice on daily intake values as per GP 3.1.2.
Paragraphs 18 to 29: “Fish or EPA/DHA”
Canada is of the opinion that members of the eWG should have an opportunity to comment on the analysis
of the evidence made by the co-chairs with regard to the source of EPA and DHA in support of an NRV-NCD
prior to reporting back to the committee.
Paragraph 33: “The following RASBs proposed by eWG members appeared to meet all of the criteria included
in the RASB definition (please see Appendix II for a detailed information):”
Canada would like to clarify that Item No. 5 in Table 3 should refer to the Authority as the U.S. Department of
Health and Human Services and the U.S. Department of Agriculture which jointly issued the RASB publication,
the “2015-2020 Dietary Guidelines for Americans”. This policy was based on the scientific reports of the Dietary
Guidelines Advisory Committee (2010, 2015). Canada supports the conclusion that with this correction, the 10
RASBs proposed by eWG members as listed in Table 3, meet all of the criteria included in the RASB definition
and should be considered for further discussion on establishing NRV-NCD for EPA and DHA Long Chain
Omega-3 Fatty Acids.
CX/NFSDU 16/38/8-Add.1 2
Paragraph 35: “Organisations 3, 8, 9 and 10 provided intake recommendations for minimising the risk of
CVD/CHD events, however, their recommendations did not mention the CVD/CHD-related mortality.”
Canada strongly recommends that all 10 RASB reports be taken into consideration for further discussion on
establishing NRV-NCD for EPA and DHA Long Chain Omega-3 Fatty Acids.
Canada is of the opinion that members of the eWG should have an opportunity to comment on the analysis of
the evidence made by the co-chairs.
Canada notes that the review of the evidence included in the reports of RASBs 3, 8, 9 and 10 covered studies
that examined the association between the intake of EPA and DHA or fish consumption and mortality due to
coronary heart disease. Furthermore, the recommendation for EPA and DHA of the 2003 WHO/FAO
report
entitled Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Disease
Technical Report Series 916, was based on convincing evidence for the reduction of risk of coronary heart
disease and ischaemic stroke and not CVD/CHD-related mortality. The recommendation from the report is
“Regular fish consumption (1-2 servings per week) is protective against coronary heart disease and ischaemic
stroke and is recommended. The serving should provide an equivalent of 200-500 mg of eicosapentaenoic
and docosahexaenoic acid”.
Therefore, the recommendations from RASB 3, 8, 9 and 10 should be included as part of the totality of the
evidence for further discussion on establishing NRV-NCD for EPA and DHA Long Chain Omega-3 Fatty Acids.
Paragraph 36: “Finally, the authorities 4 and 6 have not provided quantitative recommendations for EPA and
DHA intake. Australia’s NHMRC (4) has reviewed the evidence on the EPA/DHA intake-health outcome
relationship and found it inconclusive. Out of 11 systematic reviews studied, 7 focused on surrogate markers
of cardiovascular disease such as lipid profiles. Three studies have not established relationship with CVD risks,
and one was not relevant to EPA/DHA. It has been also noted that the major component of the NHMRC review,
study by Hooper et al 2006, was subject of extensive criticism [35].”
Canada notes that the report of the National Health and Medical Research Council (NHMRC)
1
concluded that
the evidence suggests that consumption of at least two servings a week of fish is associated with reduced risk
of mortality from cardiovascular disease, and with reduced incidence of cardiovascular disease. This brings
us back to the question of fish vs. EPA and DHA and the appropriateness of extrapolation from the
recommended servings of fish to a daily intake of EPA and DHA, which should be discussed through an eWG.
Paragraph 37: “The US IOM 2007 report has also come short of yielding an intake recommendation for
EPA/DHA
intake. The authors concluded that “while it is uncertain how much these omega-3s contribute to
improving health
and reducing risk for certain conditions such as heart disease, there is evidence for benefits
both to the general
population and to some groups of people. For those with existing heart disease there
may be benefits from
consuming EPA and DHA in seafood, although more research is needed in this area”. At
the same time, no strong
scientific evidence was established to suggest a threshold of consumption, such as
two servings per week, below
which seafood consumption provides no benefit and above which increasing
consumption provides additional
benefits.”
Although the US IOM report
2
did not recommend a specific value for EPA and DHA, several findings have
been reported with regards to the strength of the evidence. These findings should be used as part of the body
of evidence for establishing an NRV-NCD for EPA and DHA Long Chain Omega-3 Fatty Acids.
Paragraph 45: “Based on the data of systematic reviews and most recent scientific publications reviewed as
described in this report in addressing the critical points identified at the CCNFSDU37, and the
recommendations from the FAO/WHO Expert Consultations and other nominated RASBs, it is recommended
that CCNFSDU considers an NRV-NCD for EPA and DHA of 250 mg/day, for inclusion in paragraph 3.4.4.2
NRV-NCD of the Guidelines on Nutrition Labelling (CAC/GL 2-1985) as presented in Appendix I.”
Canada notes that there has not been sufficient opportunity for discussion between the members of the eWG
and the co-chairs with regard to the rationale for the proposed NRV-NCD for EPA and DHA of 250 mg/day. In
particular, this value is not consistent with some of the RASBs’ recommendations, such as the
recommendation for EPA and DHA intake made by the “Agence nationale de sécurité sanitaire de
1
A review of the evidence to address targeted questions to inform the revision of the Australian Dietary Guidelines
(https://www.nhmrc.gov.au/_files_nhmrc/file/publications/n55d_australian_dietary_guidelines_evidence_report.pdf)
2
Committee on Nutrient Relationships in Seafood: Selections to Balance Benefits and Risks, Food and Nutrition Board
(2007). Benefits for prevention of adult chronic disease. Seafood choices: balancing benefits and risks.
http://www.nap.edu/catalog/11762.html
CX/NFSDU 16/38/8-Add.1 3
l’alimentation, de l’environnement et du travail” (ANSES) in their report, “Actualisation des apports nutritionnels
conseillés pour les acides gras”
(https://www.anses.fr/fr/system/files/NUT2006sa0359Ra.pdf). ANESES recommended an intake of 500
mg/day of EPA and DHA for the reduction of the risk of cardiovascular mortality.
At this time, Canada is not in a position to support the NRV-NCD proposed for EPA and DHA. Considering the
differing conclusions from the various RASB reports included, Canada is of the opinion that further discussion
is needed before a final recommendation can be made. The discussion should include various aspects such
as dietary vs. supplementary EPA and DHA vs. fish, the health outcome (s), secondary vs. primary prevention
and the quality of the evidence.
Canada does not support using the data from systematic reviews and meta-analyses described in the report
to establish an NRV-NCD for EPA-DHA. Any proposed NRV-NCD for EPA and DHA Long Chain Omega-3
Fatty Acids should be primarily based on recommendations from RASBs reports as stipulated in the Annex:
General Principles for Establishing Nutrient Reference Values for the General Population in the Guidelines on
Nutrition Labelling. Scientific reports other than RASBs reports could be used as supporting evidence.
Appendix I: “The establishment of an NRV was based on convincing/generally accepted evidence for a
relationship with NCD risk as reported in the Diet, Nutrition and the Prevention of Chronic diseases. WHO
Technical Report Series 916, WHO, 2003; and in the FAO/WHO Expert Consultations. Technical report Series
91 and 978, WHO 2010.”
It is unclear to Canada why only the three WHO reports are cited as the basis for the NRV-NCD when other
reports from other RASBs could also be part of the evidence in support of the proposal.
As mentioned in our previous comment under paragraph 35, the recommendation for EPA and DHA of the
2003 WHO/FAO
report entitled Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of
Chronic Disease, Technical Report Series 916, was based on convincing evidence for the reduction of risk of
coronary heart disease and ischaemic stroke and not CVD/CHD-related mortality. The recommendation from
the report is “Regular fish consumption (1-2 servings per week) is protective against coronary heart disease
and ischaemic stroke and is recommended. The serving should provide an equivalent of 200-500 mg of
eicosapentaenoic and docosahexaenoic acid”.
COLOMBIA
In the Proposed Draft NRV-NCD for EPA and DHA long chain omega-3 fatty acids, where:
Colombia thanks Chile and Russia for the work they have done on the draft and it maintains its position from
2015 in support of the value of 250 mg for EPA and DHA, as well as the proposed footnote. However, it is
important to be cautious and examine the proposal by the Codex Commission slowly, as:
1. In Colombia, cardiovascular disease is the leading cause of mortality among adults aged 18 to 65, i.e.
the increased ingestion of DHA and EPA is important and relevant for our population.
2. However, attaining the recommended levels would require the recommendation that supplements be
taken, as the habitual consumption of fatty fish (one or two portions weekly) does not exist in our
population.
3. Countries that produce fatty fish, such as Chile, the Nordic countries, Japan, have dietary habits that
allow them to achieve the proposed targets; in Colombia, this is not possible with food alone.
4. Colombia supports the value of 250 mg of EPA and DHA, as well as the proposed footnote.
CUBA
With respect to document CX/NFSDU 16/38/8 Proposed Draft NRV-NCD for EPA and DHA long chain omega-
3 fatty acids, Cuba agrees in principle and it has no comments to add.
GHANA
Ghana supports the establishment of an NRV-NCD of 250mg for EPA and DHA.
Rationale
The establishment of NRV-NCD of 250mg for EPA and DHA was based on strong evidence from approved
by scientific bodies that meet the criteria on RASBs. Studies have also shown that, consumption of 250 mg
of EPA and DHA is associated with primary and secondary prevention of cardiac deaths.
CX/NFSDU 16/38/8-Add.1 4
MEXICO
Mexico appreciates the opportunity to comment on document CX/NFSDU 16/38/8 on the Proposed Draft
NRV-NCD for EPA and DHA long chain omega-3 fatty acids produced by an electronic working group led
by Chile and the Russian Federation, corresponding to Item 7 of the agenda for the next meeting of the
CCNFSDU.
Mexico agrees that the consumption of food that contains EPA and DHA long chain omega-3 fatty acids should
be promoted, as according to the 2006 Mexican National Health and Nutrition Survey (ENSANUT), the dietary
intake of saturated fatty acids among the population is high and the intake of polyunsaturated fatty acids
(PUFA) and in particular n-3 and n-6 is lower than the recommendations of the OMS, which represents a
predisposition to risk factors for chronic non-communicable diseases in the Mexican population
3
.
Therefore, we consider it important to establish the NRV-NCD for omega-3 long chain EPA and DHA proposed
by the eWG of 250 mg, in line with the recommended intake levels in section 3.4.4.2 of the Guidelines on
Nutritional Labelling (CAC/GL 2-1985), as this NRV-NCD may contribute to an increase in the consumption of
these fatty acids in the population.
However, we do not think that the scientific evidence that has been presented is sufficiently conclusive for the
establishment at present of an NRV-NCD value, as the indicated benefit (“the reduction of risk of coronary
heart disease mortality/fatal CHD events”) does not correspond to the proposal to establish an NRV-NCD
because it does not clearly meet the criterion established in the General Principles for Establishing NRVs,
which states that “relevant convincing/generally accepted scientific evidence or the comparable level of
evidence under the GRADE classification for the relationship between a nutrient and non-communicable
disease risk relationship, including validated biomarkers for disease risk, for at least one major segment of the
population (e.g. adults)”, as result of which it is recommended that we wait for more scientific evidence.
NEW ZEALAND
Significant progress has been made during the 2016 electronic working group to identify suitable recognised
authoritative scientific bodies (RASBs). New Zealand considers that the next step required is to evaluate these
RASBs against the Codex General Principles for establishing an NRV-NCD (CAC/GL 2-1985, Annex).
Specifically the level of evidence underpinning the relationship between EPA and DHA against the risk of
mortality from coronary heart disease. Once this has been completed the Committee will be in a position to
evaluate the suitability of establishing an NRV-NCD for EPA and DHA.
General Principles for establishing an NRV-NCD
As specified in the General Principles for Establishing Nutrient Reference Values for the General Population
(CAC/GL 2-1985, Annex), there are several steps involved in the derivation of an NRV-NCD:
1. Selection of suitable data source to establish NRVs;
2. Selection of nutrients and an appropriate basis for NRV-NCD;
a. Assessment of the level of evidence for the relationship between the nutrient and non-
communicable disease risk in accordance with WHO or WHO/FAO definitions;
b. Public health importance of the relationship among Codex Member Countries;
3. Consideration of Daily Intake Reference Values for Upper Levels.
It is acknowledged that steps 1 and 2b have been completed by the eWG; but further work is required to review
the level of evidence underpinning the RASB relationships to ensure that the relevant scientific evidence is
convincing/generally accepted (or comparable level of evidence under the GRADE classification).
The definition contained within the FAO/WHO report cited in the General Principles is as follows:
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.
3
Ramírez-Silva et al. Fatty acids intake in the Mexican population. Results of the National Nutrition Survey 2006. Nutrition
& Metabolism 2011, 8:33
http://www.nutritionandmetabolism.com/content/8/1/33
CX/NFSDU 16/38/8-Add.1 5
New Zealand has some concerns that a consistent association between the exposure and the primary outcome
has not been fully demonstrated. This is reflected in the differing levels of evidence ascribed by various RASBs
regarding EPA and DHA.
WHO Nutrition Guidance Expert Advisory Group
At CCNFSDU37 the Representative of WHO highlighted the ongoing work of the Nutrition Guidance Expert
Advisory Group (NUGAG) Subgroup on Diet and Health which was in the process of initiating work on review
of polyunsaturated fatty acids (PUFAs) which could be used to inform this Agenda item (REP16/NFSDU,
para 76).
At the ninth NUGAG subgroup on diet and health meeting, the group reviewed and finalised the PICO
questions, priority outcomes and effects on health and other issues related to the consumption of
polyunsaturated fatty-acids
4
. The methods for the systematic review related to polyunsaturated fatty acids and
the outcome of interest, prevention of cardiovascular disease (including mortality from coronary heart disease),
are now published on the Cochrane Database of Systematic Reviews
5
. The systematic review will include all
eligible trials which compare higher with lower total polyunsaturated fat intake, either through dietary
supplementation, dietary interventions, or advice on diet. Subgroup analyses will be conducted on a variety of
factors including omega-3: omega-6 ratios; replacement of saturated or monounsaturated fats with
polyunsaturated fats, and dose response trials. As such this work will inform the questions raised by some
eWG members regarding the level of scientific evidence and need to consider the omega-3: omega-6 ratio.
Noting the divergence of opinions of RASBs and authors of recent systematic reviews, New Zealand considers
it appropriate to await the results of the WHO NUGAG work. This approach is consistent with the conclusions
at CCNFSDU37, which acknowledged that this work should progress taking into account the work of NUGAG,
as was done when establishing the NRV-NCD for sodium and potassium (REP16/NFSDU, para 79). Based
on the update of the Representative of the WHO regarding the progress of the WHO NUGAG group, the
Committee may need to consider whether the best approach is to await the results of the systematic reviews,
or continue work on the Agenda item to evaluate the scientific evidence which underpins the assessment of
the RASBs until the NUGAG review is available.
PARAGUAY
General Comments
Given that Paraguay is a landlocked country, the consumption of seafood is practically impossible, as a result
of which supplements are a valid option for ingesting fatty acids in view of their preventive ability to reduce the
risk of mortality from coronary heart disease.
Therefore, Paraguay supports the inclusion of the NRV-NCD for EPA and DHA in the Guidelines on Nutritional
Labelling (CAC/GL 2-1985).
Specific comments
3.4.4.2 NRV-NCD
EPA1 and DHA2 250 mg
1 Eicosapentaenoic acid
2 Docosahexaenoic acid
Paraguay agrees with the value proposed by the eWG.
PHILIPPINES
General Comments:
The Philippines supports the proposed Draft Nutrient Reference Value for diet-related non-communicable
diseases (NRV-NCD for Eicosapentanoic acids (EPA) and docosahexanoic acids (DHA) Long Chain Omega-
3 Fatty Acids at 250 mg based on convincing/generally accepted evidence showing the beneficial relationship
between the long chain omega-3 fatty acids EPA plus DHA in the diet as well as the reduction ofrisk of coronary
heart disease (CHD) mortality/fatal CHD events. It was concluded that the totality of the evidence is convincing
for a risk-reducing effect of EPA +DHA on CHD.
4
http://www.who.int/nutrition/events/2016_9th_NUGAG_meeting_15to18March/en/
5
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012345/full
CX/NFSDU 16/38/8-Add.1 6
Rationale
Specific Comments:
Wesupport the proposed NRV-NCD for EPA and DHA Long Chain Omega-3 Fatty Acids at 250 mg based on
consistent and recent scientific evidence. The Joint FAO WHO Expert Consultations in 2010 found convincing
evidence that moderate consumption of oily fish lowers mortality from coronary heart disease (CHD) in general
population. Epidemiologic studies and trials showed the benefits of polyunsaturated fatty acids (PUFA),
specifically EPA and DHA, in cardio vascular disease (CVD) prevention and in stroke risk reduction(Asif, 2014,
Arkesteijn et al, 2013;Mozaffarian& Wu, 2011; Kris-Ehterton et al, 2003; Harris et al, 2008).
The beneficial effect in increasing the dietary intake of EPA and DHA Long Chain Omega 3 Fatty acids will
have substantial global benefits in particular taking into account the gap between current consumption and
recommendations.
a. It is recommended that the level of NRV-NCD for EPA & DHA be 250mg/day;
i. The World Health Organization (2010) recommended a daily EPA and DHA intake of 0.3-0.5 grams
and a daily ALA intake of 0.8-1.1 grams.
The overall efficiency of conversion from αLNA is 0.2% to EPA, 0.13% to DPA & 0.05% to DHA
(Burdge and Calder, 2005);
Newer findings using tracer isotope showed that the rate of conversion by humans of ALA to EPA is
low, with estimates ranging from 0.2% to 8%, as is the conversion of EPA to DHA (Goyens et al, 2006,
AJCN);
The rate of conversion by humans of ALA to EPA is low, with estimates ranging from 0.2% to 15%, as
is the conversion of EPA to DHA. Thus, both n-3 & n-6 PUFA are entirely derived from the diet and
are necessary for human health (Andiz&Ünlüsayın, 2015, Rubio-Rodríguez et al., 2010)
The meta-analysis evidence from several RCTs indicated that provision of EPA+DHA at 2g or more per day
may reduce both systolic blood pressure and diastolic blood pressure. The strongest benefits were noted in
hypertensive individuals without antihypertensive medication. Randomized control trials (RCTs) in the context
of secondary prevention also indicated that the consumption of EPA plus DHA is protective at doses <1 g/d.
The therapeutic effect appears to be due to suppression of fatal arrhythmias rather than stabilization of
atherosclerotic plaques. From a clinical and public health perspective, provision of EPA+DHA may lower blood
pressureand other risk factors which could ultimately reduce the incidence of CVD (Miller et al 2014; Flock et
al, 2013, Breslow, 2006). Several scientific studies showed the beneficial effects of EPA and DHA on reducing
the risks of cardiovascular diseases (;Burr et al, 1989;; Kris-Etherton et al 2003; Leaf, 2009; Mozzafarian,
2006; Mozzafarian and Hu, 2006;Chowdury et al, 2014)particulary coronary heart disease (Breslow, 2006; De
Goede et al, 2010; Harris et al, 2006) and cardiac death (Mozaffarian, et al 2011). Hence, the proposed draft
NRV-NCD for EPA and DHA is acceptable since it is based on scientific judgement and consensus.
We are of the opinion that the evidence of both primary and secondary prevention is acceptable in the
establishment of an NRV-NCD for EPA+DHA for the general population.
Thus, it is recommended that CCNFSDU consider a harmonized NRV-NCD for EPA and DHA of 250 mg/day,
for inclusion in paragraph 3.4.4.2 NRV-NCD of the Guidelines on Nutrition Labelling (CAC/GL 2-1985).
References
Andizand Ünlüsayın, J Food HealthSc; 2015
Asif, D.A. 2014. The Role of Omega-3 Fatty Acids in Heart Disease Prevention. J Pharma Care 16 (7):323-326.
Arkesteijn et al, 2013, Rev Unilever R & D
Breslow, JL. N-3 Fatty acids and cardiovascular disease.https”//www.ncbi.nlm.nih.gov/pubmed/16841857.American
Journal of Clinical Nutrition. 2006. 83 (6 Suppl):14775-14825.
Burdge, GC and Calder, PC. Conversion of α-Linolenic acid to longer-chain polyunsaturated fatty acids in human adults.
Reprod. Nutr. Dev. 2005; 45: 581-597.
Burr ML, Fehily AM, Gilbert JF, et al. Effect of changes in fat, fish, and fibre intakes on death and myocardial reinfarction:
Diet AndReinfarction Trial (DART). Lancet 1989;2:757–61
Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L,Franco OH, Butterworth AS, Forouhi NG, Thom
pson SG, et al Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and
meta-analysis. Ann Intern Med 2014;160:398–406.
CX/NFSDU 16/38/8-Add.1 7
De Goede J et al. Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and non-fatal coronary heart
disease in a large population of Dutch adults with low fish intake. https://www.ncbi.nlm.nih.gov/pubmed/20335635. Journal
of Nutrition. 14-(5);1023-8.
Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA and Kris-Ehterton PM. Determinants of Erythrocyte
Omega-3 Fatty Acid Content in Response to Fish Oil Supplementation: A Dose-Response Randomized Controlled Trial.
Journal of the American Heart Association. 10 (1161):1-12.
Goyens PL, Spilker ME, Zcok PL, Katan MB and Mensink RP. Conversion of α-linolenic acid in human is influenced by
the absolute amouts of α-linolenc acid and linoleic acid in the diet and not by their ration. Am J ClinNutr. 2006;(84): 44-53.
Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B. N-3 fatty acids from fish or fish-oil supplements, but not α-
linolenic acid, benefit cardiovascular disease outcome in primary- and secondary- prevention studies: a systematic
review. Am J ClinNutr 2006;84:5–17.
Harris, W.L. et al. Of long chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in
healthy adults. https://blm.nih.gov/pubmed. d/18937898; 2008 Dec; 10(6):503-9.
Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease: New
Recommendations from the American Heart Association. AretriosclerThrombBascBiol2003; 23:151-152.
Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747–57.
Leaf, DA. The Role of Omega-3 Fatty Acids n Heart Disease Prevention. JCOM. 2009; 16 (7); 323-326.
Mozaffarian, F and Wu, JH. 2011. Omega 3 Fatty Acids and Cardiovascular Disease. J Am CollCardiol. 58 (30):3047-
3060.
Miller PE, Elswyk MV, Alexander DD. (2014).Long Chain Omega-3 Fatty Acids Eicosapentanoic and Docosahexanoic Acid
and Blood Pressure: A Meta-Analysis of Randomized Controlled Trial. American Journal of Hypertension 27 (7): 885-893.
Mozaffarian D, Rimm EB. (2006). Fish intake, contaminants, and human health: evaluating the risks and the benefits.
JAMA;296:1885–99.
Mozaffarian D, Ascherio A, Hu FB, et al. Interplay between different polyunsaturated fatty acids and risk of coronary heart
disease in men.Circulation 2005;111:157–64.
WHO Technical Report Series 916, WHO, 2003; and in the FAO/WHO Expert Consultations. Technical report Series 91
and 978, WHO, 2010.
CRN
Previous CRN Comments – Written, June, 2015
CRN respectfully submitted comments to the chairs of the electronic Working Group (eWG) regarding a series
of ten questions, related specifically to the development of a NRV-NCD for Omega 3 (DHA/EPA). We remain
committed to this process and our response to Question 4 remains relevant and has not been dismissed.
Justification of NRV-NCD
Do you agree that DHA and EPA intake is
sufficiently important for public health,
and that all information reviewed so far
justifies the establishment of an NRV-
NCD for food labelling purposes? If you
disagree, please justify your answer
supported by scientific references.
CRN and CRN Members agree that the intake of DHA and EPA
is sufficiently important for public health, and that all information
reviewed so far does justify the establishment of an NRV-NCD
for food labelling purposes. Further, several robust and
adequately controlled “health care cost analyses” have reported
that intake of DHA and EPA can lead to demonstrable public
health and personal health benefits, and the reduction of
significant hospitalization events. Shanahan C.J & deLorimier,
R. (2014) From Science to Finance-A Tool for Deriving Economic
Implications from the Results of Dietary Supplement Clinical
Studies. Jrnl. Diet. Suppl. DOI:10.3109/19390211.2014.952866.
Previous CRN Comments – Written, August, 2015
After the Codex Alimentarius Commission (CAC) meeting in Geneva, CRN and CRN Members submitted a
response to the second consultation and again applauded the
scientifically-relevant process and conclusion by the chairs of the electronic Working Group. The CRN
statement in support of the conclusion by the chairs of the electronic Working group is below.
“CRN is wholly in agreement with the text of the Second Consultation Document on an NRV-NCD for
EPA+DHA and supports its submission for discussion at the 37
th
session (November 2015) of the Codex
Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU).
CX/NFSDU 16/38/8-Add.1 8
New Information; Omega-3 Acid Ethyl Esters and Post-Myocardial Infarction
A prospective multicenter, double-blind, placebo-controlled clinical trial (RCT) funded by the National institutes
of Health was conducted as the OMEGA-REMODEL (Omega-3 Acid Ethyl Esters on Left Ventricular
Remodeling After Acute Myocardial Infarction) trial to evaluate the hypothesis that 4 g/day of omega-3 fatty
acids for 6 months post-acute myocardial infarction would provide cardia remodeling benefits, as determined
by the primary study endpoint, change in left ventricular systolic volume index and secondary endpoints of
change in noninfarct myocardial fibrosis, left ventricular ejection volume and infarct size (Heydari, et al., 2016
6
).
The results published indicate that patients randomly assigned to the Omega-3 fatty acids treatment group
had a significantly reduced left ventricular systolic volume index (-5.8%, P=0.17) and noninfarct myocardial
fibrosis (-5.6%, P=0.026) in comparison to the placebo control. Further, patients treated with Omega-3 fatty
acids also had a reduction in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis.
There were no adverse effects associate with the 4 g/day dose. This recent study provides important context
to the importance of omega-3 fatty acids and a marker for cardiovascular disease.
Conclusion
Nothing has been proposed in the scientific literature and/or amongst national regulatory bodies that in any
way changes the conclusion of CRN and CRN Members, as echoed by the chairs of the electronic Working
Group. In fact the current recommendations set by the European Food Safety Authority (EFSA) identify a 250
mg intake of EPA and DHA per day for the general adult population with a maximum tolerated dose of 5 g per
day. CRN and CRN Members are in agreement with EFSA on their analysis, conclusion and recommendation!
Q10
Proposed NRV-NCD value
If you replied affirmatively to question 9,
what Reference Value amount for EPA
and DHA would you propose, expecting
the mentioned health benefits? Please
justify your answer.
CRN and CRN Members support the establishment of a
single internationally harmonized NRV-NCD for EPA and
DHA combined for the general population for labeling
purposes in an amount between 250-500 mg/day.
ELC
We agree with the analysis of systematic reviews and meta-analysis compiled by the e-WG and using the
GRADE classification as explained in CX/NFSDU 16/38/8. Most RASBs selected provide quantitative
recommendation for intake of EPA and DHA either for reduction of risk of coronary heart disease or for
CVD/CHD events.
In addition, as indicated in CX/NSFDU 16/38/8, three reports from WHO and/or FAO underline the convincing
level of evidence for EPA and DHA in the field of coronary heart disease:
“Convincing evidence for reduced risk of CVD for fish and fish oils (EPA and DHA)” in Diet, nutrition and
the prevention of chronic diseases, Report of the joint WHO/FAO expert consultation WHO Technical
Report Series, No. 916 (TRS 916)
“Convincing evidence that fish consumption and EPA plus DHA intake lower the risk of coronary heart
disease mortality” in FAO/WHO (2011). Report of the Joint FAO/WHO Expert Consultation on the Risks
and Benefits of Fish Consumption. Rome, Food and Agriculture Organization of the United Nations;
Geneva, World Health Organization, 50 pp.
“Convincing decrease risk for CHD events and probable decrease risk for fatal CHD” in FAO Fats and fatty
acids in human nutrition - Report of an expert consultation. Technical report 91, 2008.
Recalling that CVD/CHD is globally a critical NCD, and recalling that the work on NRV-NCD is based on a WHO
mandate to CCNFSDU for contributing to the Global Strategy on Diet, Physical Activity and Health, and that this
work of CCNFSDU on NCDs was deemed an important contribution to achieving the goals of this strategy, ELC
supports the proposed NRV-NCD for EPA and DHA at 250 mg/d and its timely inclusion in the guidelines on
nutrition labelling.
6
Heydari B, Abdullah S, Pottala JV, Shah R, Abbasi S, Mandry D, Francis SA, Lumish H, Ghoshhajra BB, Hoffmann U,
Appelbaum E, Feng JH, Blankstein R, Steigner M, McConnell JP, Harris W, Antman EM, Jerosch-Herold M, Kwong RY.
(2016).Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-
REMODEL Randomized Clinical Trial. Circulation;134(5):378-91. doi: 10.1161/CIRCULATIONAHA.115.019949.
CX/NFSDU 16/38/8-Add.1 9
GOED
General Comments
GOED applauds the continued diligence of Chile and Russia as the co-chairs of the electronic working group
(e-WG). They have done a fantastic job soliciting feedback and turning it into an extremely coherent, not to
mention well-supported, discussion document. GOED continues to support the proposed draft NRV-NCD
of 250 mg/day for EPA+DHA for inclusion in the Guidelines on Nutrition Labelling (CAC/GL2-1985).
Discussions to adopt an NRV-NCD for EPA+DHA remain timely. A recently published global survey of EPA
and DHA in the bloodstream of healthy adults indicates that the majority of the world has low to very low blood
levels of these fatty acids resulting in an increased risk of chronic diseases (i.e. heart).
7
Since last year’s discussion on this topic at the 37
th
Session of the CCNFSDU, a very large, extremely relevant
study was published.
8
The study is the first output from the Fatty Acids & Outcomes Research Consortium
(FORCe), a collaboration of scientists who have conducted 19 different observational studies but have pooled
their data to identify the role of fatty acids in a wide variety of diseases. The study correlated status of individual
omega-3 fatty acids with, among other things, coronary death. A one-standard deviation increase in DHA was
associated with a 10% reduction in coronary death, which is very similar to the risk reductions observed in
meta-analyses of randomized, controlled trials. EPA status achieved a similar reduction but was only of
borderline statistical significance [RR, 0.91; 95% CI, 0.82-1.00]. Since the risk reductions presented are per
one standard deviation of fatty acid status, presumably those with higher status should have greater risk
reductions, and this is borne out in the data where the first and fifth quintiles of status are compared. The fifth
quintiles seem to coincide with an omega-3 index between 7 and 8, or the levels observed in Japanese
populations, and at that level DHA was associated with a 24% reduction in coronary death risk.
Specific Comments
Page 2, Paragraph 8: "Comparison" "Diet with an EPA and DHA level lower than in the intervention"
GOED’s Comment: It seems that there needs to be more than one comparison. In observational
(i.e. prospective cohort) studies, you typically compare different dietary levels of EPA/DHA. In intervention
trials, you may do the same, but if you are referring to dietary/food supplement trials, then you would be
comparing different amounts of EPA/DHA intake from dietary/food supplements to a placebo (no EPA/DHA).
Page 4, Table 2: "Filion, 2010"
GOED’s Comment: Filion, 2010 should be excluded. The primary outcome was all-cause mortality, not cardiac
mortality and the secondary outcome had nothing to do with death. The cardiac death analysis referenced in
the paper was an analysis based on the collection of safety data, so it isn’t considered an appropriate outcome
measurement.
Page 4, Table 2:
GOED’s Comment: Casula et al., 2013 [RR, 0.68; 95% CI, 0.56-0.83] should be considered for inclusion.
Page 5, Paragraph 14: “Kwak concluded that supplementation with omega-3 fatty acids had no beneficial effect
on CVD events, including sudden cardiac death and CVD-related fatal events…”
GOED’s Comment: An important detail is missing. Kwak did conclude that omega-3 fatty acid supplementation
significantly reduced cardiovascular death (RR, 0.91; 95% CI, 0.84-0.99).
Page 5, Paragraph 17: "Finally, we would like to mention..."
GOED’s comment: It's not clear why the paragraph beginning with the above sentence is included. The
discussion by the eWG and CCNFSDU should be specific to the efficacy of the nutrients, EPA and DHA, not
to the quality of a particular source, fish oil. While the cited papers have serious limitations, GOED has chosen
not to address them given that they are irrelevant to the discussion at hand. Any discussion on quality should
be directed to the appropriate committee. Specifically, fish oil quality issues are currently being discussed by
the CCFO as part of its discussion on establishing a fish oil standard. Even then, the issue raised within this
paragraph is not appropriate since the CCFO is discussing limits, not deviations from those limits. GOED
proposes to remove this paragraph.
7
Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr (2016). Global survey of the omega-3 fatty acids,
docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Prog Lipid Res. 63:132-52.
8
Del Gobbo LC et al.; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and
Outcomes Research Consortium (FORCe). ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease:
Pooling Project of 19 Cohort Studies. JAMA Intern Med. 2016;176(8):1155-66.
CX/NFSDU 16/38/8-Add.1 10
Page 7, Paragraph 29: “Most recently, Kleber et al. [31] have studied omega-3 index association with CVD
and all-cause mortality in 3259 participants of the Ludwigshafen Risk and Cardiovascular Health Study
(LURIC) [32].”
GOED’s Comment: Change CVD to cardiovascular.
Page 9: “One member country (CMC) has commented that the selection of RASBs should not be limited to
those that established DIRVs but also should consider opinions of those scientific bodies which did not think
that the totality of evidence amounted to the establishment of a DIRV as was the case in the work on
establishing NRV-R (REP 16/CCNFSDU).”
GOED’s Comment: Is this in reference to chromium? If yes, that should be specified so it directs reviewers of
the discussion paper to the correct place in the report. If it’s in reference to another discussion, please specify.
IADSA
General Comments
The International Alliance of Dietary/ Food Supplement Associations (IADSA) welcomes the proposed draft
NRV non-communicable disease (NCD) for EPA and DHA long chain omega-3 fatty acids and would like to
support the setting of NRV-NCD for EPA and DHA at a level of 250 mg/day.
IADSA is of the view that the new document provides an excellent summary and employs the WHO PICO
format (P-Patient; I-Intervention; C-Comparison; O-Outcome) to frame the healthcare research question.
The Co-Chairs and eWG have identified systematic reviews and meta-analyses published since 2009 and
reviewed results related to the specific health outcome. The strength of the evidence was assessed with the
GRADEpro tool, which had been described in 2015 (CX/NFSDU 15/37/7). IADSA believes the new document
provides a thorough and comprehensive review of the available scientific data, and then summarises and
tabulates the evidence. Thirteen systematic reviews and meta-analyses were identified that covered
randomised clinical trials and prospective cohort studies relevant to the PICO question. Based on statistical
assessment of relative risk, the impact of all but three studies were ranked as conclusive, thus demonstrating
a strong association between the EPA and DHA intake and cardiac mortality.
With regard to the questions of fish or EPA and DHA, the Co-Chairs and eWG highlighted, and IADSA strongly
supports their interpretation, that the principal bioactive components of fish are EPA and DHA, based on the
following:
1. A recent scientific report of the US Dietary Guidelines Advisory Committee, which stated that the
health benefits of seafood are likely to be associated with EPA and DHA.
2. Most of the RCT studies were based on supplementation of the intervention group with pure EPA
and DHA or fish oil supplements.
3. There were no RCT-based studies of fish intake in association with CVD health outcomes—all the
fish studies were epidemiological prospective cohort studies.
4. The conclusions from the Joint FAO/WHO expert consultation on the risks and benefits of fish
consumption (WHO, 2011) concluded that there was convincing evidence for the benefits of EPA +
DHA intake on CHD mortality.
5. As fish and seafood are recognised as primary sources of EPA and DHA, it has become a standard
practice to quantify fish intake in amounts of EPA and DHA.
6. The reliance in RCTs on the level of EPA and DHA biomarkers in evaluating intake associations with
a particular health outcome
7. The use of the omega-3 index
9
as a powerful risk factor for sudden cardiac death rather than
traditional risk factors such as cholesterol, triglycerides and C-reactive protein
The document also includes a 2016 publication by Kleber et al.
10
that studies omega-3 index association with
CVD and all-cause mortality in 3259 participants. Proportions of EPA and DHA were strongly and inversely
associated with all-cause and cardiovascular mortality in models adjusted for conventional CVD risk factors.
With regard to the RASBs selected by the eWG, the new document lists 10 potential RASBs. Of the 10, four
produced a quantitative recommendations for the EPA and DHA intake in relation to the target outcome:
9
Red blood cell omega-3 PUFAs expressed as the percentage of EPA + DHA in red cell lipids
10
Kleber ME et al. Omega-3 fatty acids and mortality in patients referred for coronary angiography. The Ludwigshafen
Risk and Cardiovascular Health Study. In Atherosclerosis(2016). http://dx.doi.org/10.1016/j.atherosclerosis.2016.06.049
CX/NFSDU 16/38/8-Add.1 11
reduction of risk of CHD mortality/fatal CHD events. These RASBs are in addition to the supporting evidence
from three reports from the primary sources WHO and FAO/WHO.
Conclusion
IADSA believes that the document CX/NFSDU 16/38/8, will help direct the discussion at the CCNFSDU
meeting in December 2016.
IADSA supports the recommendation that, based on the totality of the available data and strength of the
evidence from systematic reviews and the most recent scientific publications, the CCNFSDU set an NRV-NCD
for EPA and DHA of 250 mg/day.
Specific Comments
Page 5, Paragraph 17
17. Finally, we would like to mention recent reports on the quality of the EPA/DHA sources used in the RCT
studies, the factor which remains largely beyond researchers’ control and hidden in the GRADE evaluation.
There are several studies recently published that examined the contents of EPA/DHA supplements in New
Zealand [17], the USA [18] and South Africa [19], concluding that a substantial share of products did not meet
requirements for oxidative markers or had active contents below values declared in labeling. In the USA out
of 173 long-chain PUFA supplements tested, 50% exceeded the voluntary recommended levels for markers
of oxidation. The oxidation of PUFAs is a well-known process that imparts quality and gives specific smell to
fish oils. The process is impacted by light and temperature conditions and cannot be controlled in RCT and
PC that involved hundreds of participants.
IADSA would like to propose the removal of the above paragraph 17 page 5. It is to be noted that fish oil quality
issues are currently being discussed by the CCFO as part of its discussion on establishing a fish oil standard.
ICGMA
ICGMA supports the proposed draft NRV-NCD for EPA and DHA of at least 250 mg EPA + DHA per day for
inclusion to Section 3.4.4.2 of the Guidelines on Nutrition Labelling (CAC/GL 2-1985). ICGMA also supports
the inclusion of the additional footnote, “The establishment of an NRV was based on convincing/generally
accepted evidence for a relationship with NCD risk as reported in the Diet, Nutrition and Prevention of Chronic
Diseases. WHO Technical Report Series 916, WHO, 2003; and in the FAO/WHO Expert Consultations.
Technical Report Series 91 and 978, WHO, 2010.”
Strong scientific evidence and support from Recognized Authoritative Scientific Bodies (RASBs),
including the European Food Safety Authority (EFSA), the National Institute of Health and Nutrition –
Japan (NIHN), the Norwegian Scientific Committee for Food Safety/Nordic Council of Ministers, as
well as two World Health Organization Technical Report Series (916 and 91) and the Joint
FAO/WHO Expert Consultation on the risks and benefits of fish consumption (2010), support the
establishment of a NRV for EPA and DHA for the general population (ages 4+).
There is convincing and generally accepted evidence of the risk-reducing effect of EPA + DHA on
Coronary Heart Disease (CHD) in the general population.
The risk of adverse effects in consuming EPA and DHA have not been seen, with many populations
consuming minimal levels. EFSA concluded that intakes up to about 5 g/day do not cause adverse
effects (2012).
The proposal meets the conditions established in the Codex General Principles for Establishing
NRVs.
ISDI
General Comments
ISDI appreciates the work of the eWG, led by Chile and the Russian Federation, to further develop the NRV-
NCD for EPA and DHA long chain omega-3 fatty acids in accordance with the General Principles for
Establishing Nutrient Reference Values for the General Population (Annex to the Guidelines on Nutrition
Labelling (CAC/GL 2-1985)
ISDI supports the health outcome for the proposed NRV-NCD for EPA and DHA:
REDUCTION OF RISK OF CORONARY HEART DISEASE MORTALITY/FATAL CHD EVENTS
CX/NFSDU 16/38/8-Add.1 12
Specific Comments
Paragraph 45
ISDI supports the eWG recommendation that CCNFSDU considers an NRV-NCD for EPA and DHA of
250 mg/day, for inclusion in paragraph 3.4.4.2 NRV-NCD of the Guidelines on Nutrition Labelling (CAC/GL 2-
1985).
