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ARCHIVED - Essential Fatty Acids - Discussion Paper

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Report submitted to the Natural Health Products Directorate, Health Canada

March 2005

Nutritech Consulting
Winnipeg, Manitoba
Prepared by: K.C. Fitzpatrick

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Executive Summary

The focus of this discussion paper is Essential Fatty Acids (EFAs) which occur naturally in plant and animal oils and are available to consumers in capsules or supplements as well as in bulk liquid form that are commonly sold in a medicinal or "dosage" form. Specific emphasis is given in this paper to an overview of Canadian EFA research and issues related to conducting EFA research in Canada.

An extensive internet search was conducted and thirty interviews were initiated with researchers across Canada . The results of twenty-five are summarized in this report as is information taken from internet searches of individual researcher profiles.

Key Themes And Suggested Next Steps

The following were identified as priority areas for EFA research by the Natural Health Products Directorate (NHPD) and the Natural Health Products Research Program (NHPRP) in the development of this discussion paper. It must be emphasized that the priorities identified are the result of a very limited sampling of the EFA research community and are meant to serve as a starting point for further consultations.

1. Developing a National Research Agenda

Research in the areas of EFAs, and Natural Health Products ( NHPs) in general, appears to be done on an ad hoc basis with no long term strategy and few effective communication strategies for researchers in place. Exploring the development of a mechanism(s) whereby various association and government (federal, provincial, regional) research agendas are better aligned was suggested. The need to build partnerships , involve i ndustry and funding partners and better coordination of research to improve funding success was highlighted.

2. Greater Interactions between EFA and other NHP researchers

There are numerous research themes and areas under investigation that cut across both the EFA and NHP communities. Mechanisms should be established to provide more opportunities for interactions between the two groups to encourage synergies of activities and avoid duplication. A joint conference possibly hosted by the NHP Research Society and the Advanced Foods and Material Network (AFMNet) with the focus being aligning these two groups and providing the venue for networking and scientific exchanges is one suggestion. A focus of a national conference should be on the participation of current and recent graduates and mechanism(s) established to allow for attendance at national conferences.

3. Need for NHPRP information sessions

There appears to be a lack of awareness among EFA scientists regarding the NHPD, the NHP regulations and the NHPRP, including the partnership program with the Canadian Institutes of Health Research (CIHR). It is recommended that any consultations that the NHPD may undertake with the EFA research community include an overview of the NHPD, NHP regulations and the research priorities of the NHPRP. In addition, information should be provided regarding how the partnership program with CIHR operates.

4. EFA and NHP Database

A common area of priority identified in this project and seen in other NHPD consultations is the need for a national database to include not only EFA and NHP basic and applied researchers and scientific activities but also to include industry, associations, funders and government departments involved in the sector. Such a database needs to be comprehensive and to remain current.

5. Peer Review Process

The EFA scientific community in Canada has expressed concerns related to the expertise of CIHR review panels as well as perceived issues with a lack of credibility regarding this area of research within the CIHR. It is recommended that this be an area of focus for NHPD consultations with this sector. It should be noted that the researchers surveyed commented specifically on the CIHR as the agency most associated with NHP research, the NHPD and NHPRS. The NHPRS and CIHR partnership was discussed in this project and most researchers surveyed have in the past, or are planning to, apply to CIHR for clinical health related projects. Thus it is not surprising that comments would be made about the CIHR in particular as related to EFA research and funding in Canada.

6. Requirement for greater funding support of EFA research

Support for research in the application of EFAs and NHP as alternatives to conventional health care was frequently identified as a priority with the need emphasized for specific funding mechanisms. Encouraging the continued funding support for EFA research through industry associations and provincial agriculture and health departments is important as often this funding is for smaller scale research that is conducted as 'proof of concept' to accumulate the necessary data for submission to granting agencies such as CIHR. This data is often also required to leverage industry dollars for larger scale research.

These six themes are areas that could be explored further through consultations with the EFA research community. Involvement of 'non-traditional' key funders identified in this paper - industry associations and provincial agriculture and health departments, is essential to ensure that such funding is maintained, and if possible increased, that dialogue continues and ties between all stakeholders are strengthened further.

Conclusion

This discussion paper identified an extensive research community actively involved in EFA research in Canada. Research is being conducted to various extents across the country with the Prairie Provinces being more focused upon plant based oils and the Eastern regions of the country conducting research primarily on marine based EFAs. Research activities are very comprehensive with many areas of health and disease conditions being studied at both the basic and applied levels. Six broad topics and issues related to conducting EFA research in Canada and with significance to the NHPD, NHP Regulations and NHPRP were identified. These topics are presented as suggestions to form the basis for future priority setting consultations that the NHPD may wish to undertake on the subject of EFA research.

Table of Contents

Introduction

In March of 1999, on the recommendation of the Standing Committee on Health, the Office of Natural Health Products, now the Natural Health Products Directorate (NHPD) was created. The mission statement of the NHPD is to ensure that all Canadians have ready access to natural Health products that are safe, effective, and of high quality, while respecting freedom of choice and philosophical and cultural diversity.

With the enactment of the Natural Health Product (NHP) Regulations in January 2004, the NHP category is legally recognized within the Canada Food and Drug Act as a special sub-section of drugsFootnote 1. NHPs are defined in the Regulations as vitamins and minerals, herbal remedies, homeopathic medicines, traditional medicines, probiotics, and other products like amino acids and essential fatty acids, and that are used to diagnose, treat and/or prevent disease, restore or correct function or maintain or promote health. This definition includes "nutraceuticals" that were originally proposed by Health Canada in 1998 to be "a product that has been isolated or purified from foods and generally sold in medicinal forms not usually associated with food. Nutraceuticals have been shown to exhibit a physiological benefit or provide protection against chronic disease"Footnote 2. Even though not explicitly identified as a part of the definition for NHPs, these products are assumed to be available to consumers in "dosage form" as capsules, pills, tablets or in liquid form and not to include products in a food mediumFootnote 3.

The focus of this discussion paper is Essential Fatty Acids (EFAs) which naturally occur in plant and animal oils and are available to consumers in capsules or supplements that are commonly sold in a medicinal or "dosage" form. Until enactment of the NHP Regulations, EFA supplements were considered as 'nutraceuticals' and confusion still exists as to their regulation within the EFA research community. Specific emphasis is given in this paper to an overview of Canadian EFA research and issues related to conducting EFA research in Canada . Although the development of technologies and the use of EFAs in conventional foods (as 'functional foods') is an important area for both researchers and industry, a discussion of this topic is not included as it does not relate directly to NHP regulations or the NHPRP.

An extensive internet search was conducted to ensure that the majority of EFA researchers were captured for a Canadian database. In total, sixty-six researchers are included and twenty-two of the key and most prominent EFA researchers are highlighted. In addition, thirty interviews were initiated with researchers across Canada . The results of twenty-five are summarized in this report as is information taken from internet searches of individual researcher profiles.

As per the definition of NHPs, this discussion paper does not explore research activities in the area of genetic modification (for example, introducing genes to enhance the levels of n-3 eicosapentaenoic acid - EPA and docosahexaenoic acid - DHA as for EPA in flaxseed); traditional plant breeding; aquaculture (for example, flax oil is being tested as a feed alternative to fish oils in salmonoid diets) and animal based human foods (such as n-3 enriched eggs, dairy and meat products).

Perspectives On Natural Health Products - Stakeholder Consultation, 2001-2002

Over the period of 2001-03, a series of consultations were held which resulted in four central themes that served as cornerstones in the development of the NHP regulatory framework and the NHP Research Program: Quality and Safety; Research; Population Groups and Issue Areas; and Information, Informed Choice and UtilizationFootnote 4. Recommendations relevant to research priority setting in each of these four areas, where relevant, are briefly described.

1. Quality and Safety

Since many Canadians use NHPs in the management of their health, ensuring that these products are safe, effective and of high quality was a key area of discussion during the consultation process.

Drug Interactions with Natural Health Products - Interactions between NHPs and pharmaceutical drugs (both their positive and negative effects), in particular, biomedical, clinical and epidemiological research on NHP-drug interactions and research related to reporting, dissemination and use of information about interactions were identified during stakeholder consultations as important research foci for the NHPD.

Quality Controls and Product Standards - The crucial goal of establishing standards of the quality and safety of NHPs was examined. Research priorities including the d evelopment of methods for assessing botanical identity; the establishment of information and information dissemination related to purity specifications; the identification and development of reference materials; the development of analytical methods to determine markers, to evaluate and identify biologically active components, and methods to monitor outcomes were identified.

2. Research

Building Complementary and Alternative Health Care (CAHC)and Natural Health Products Research Networks - The need to network and to develop formal or informal networks in order to create and transfer knowledge, encourage research uptake, and build research capacity between the areas of CAHC and NHP has been emphasized. The development of a conceptual framework; a national CAHC/NHP network, possibly consisting of different types of networks; and external relationships with the government, funding agencies and existing networks, was recommended.

3. Population Groups and Issue Areas

The Role of Natural Health Products and Complementary and Alternative Health Care in HIV/AIDS - Developing a Research Agenda - identified research priorities concerning the use of NHPs and CAHC with regard to individuals with HIV/AIDS including research on beneficial and detrimental interactions among NHPs and interactions between NHPs and drugs used by people with HIV/AIDS; focus on NHPs used in treatment and support of HIV/AIDS-related conditions and prioritize the NHPs to be researched first. Research to advance integration across the continuum of health care practices and services, with a special focus on CAHC and NHPs; building research capacity; developing standards of evidence and research skills, build partnerships, explore opportunities and increase the profile of CAHC and NHPs in existing HIV/AIDS networks and programs, were also emphasized.

Natural Health Products Research in Children and Youth: A Priority-Setting Conference- reported recommendations including the creation of a usage database and evaluate current data on NHPs, explore both basic and clinical science issues to identify gaps in knowledge of NHPs and children and youth; set priorities for knowledge translation and transfer to consumers and research ethical questions related to the healthcare of children and research methodologies for the study of NHP use in children.

4. Information, Informed Choice and Utilization

The fundamental importance of the ability of Canadians - both the general public as well as health care professionals - to make informed choices concerning the use of NHPs was examined through several consultations. Information and Informed Choice in the Use of CAHC and NHP: An Invitational Roundtable detailed the challenges in this area. Key legal and ethical issues related to NHPs and CAHC were explored in Health Law and Ethics in Relation to the Use of CAHC and NHP: An Invitational Roundtable. Further discussion on health law and ethics issues and on current initiatives in this area is presented in Reflections on Health Law and Ethics in CAHC. Information and informed choice issues concerning health care practitioners as well as the public are addressed in Reflections on Education, Information and Informed Choice in CAHCe. Information currently available on CAHC in the context of initiatives to gather data on the health of Canadians and on health care in Canada is presented in CAHC - Current Status and Future Development: A Discussion Paper.

Overview Of The Natural Health Products Regulations

The NHP RegulationsFootnote 5 include provisions on definitions, product licensing, site licensing, good manufacturing practices, clinical trials, labeling and packaging requirements, and adverse reaction reporting. The Regulations came into force on January 1, 2004 and provide for a transitional period that will span from 2 to 6 years (2 years for site licensing and 6 years for products with Drug Identification Numbers (DIN).

The definitions include the definition of a natural health product (including, for example, vitamins, minerals, herbal remedies and homeopathic medicines) and other terms (recommended conditions of use, adverse reaction, etc.). All licensed products must display a product identification number issued once a product is authorized for sale in Canada by the NHPD. Product authorization requires either: I) reference to a NHP monograph, or ii) submission of other evidence of the safety and health claim. All monographs developed for NHP ingredients to date have been based on the requests from Industry. The two monographs that have been developed - for evening primrose oil and flax oil - are accessible on the NHPD websiteFootnote 6. Product licence applicants may cite these monographs to support the safety and efficacy of the EFA ingredients in their product.

Site licensing requires that all manufacturers, packagers, labelers, and importers be licensed; sites have procedures in place respecting distribution records and product recalls; where applicable, sites have procedures in place for the handling, storage and delivery of their products, and sites meet good manufacturing practice requirements (GMPs). GMPs are to be employed to ensure product safety and quality, and include standards and practices regarding all stages of product manufacture. Standard labeling requirements are established to ensure consumers can make informed choices. An adverse reaction reporting system requires product licence holders to monitor all adverse reactions associated with their product and to report serious adverse reactions to Health Canada.

Clinical trials conducted in Canada using NHPs are also subject to the NHP Regulations and thus such research conducted on EFAs falls within the mandate of the NHPD. A clinical trial is an investigation of an NHP that involves human subjects and that is intended to discover or verify the product's clinical, pharmacological or pharmacodynamic effects, to identify any adverse events that are related to its use, to study its absorption, distribution, metabolism and excretion, and to ascertain its safety or efficacy. The clinical trial sponsor is responsible for applying for clinical trial approval from the NHPD, and research ethics approval from an independent research ethics board.

Evidence from clinical studies provides valuable information about the efficacy and safety of EFAs. Clinical studies identified by the NHPD that EFA researchers across Canada have expertise in conducting include the following:

  • systematic reviews, such as meta-analyses of randomized controlled trials or other trials;
  • randomized controlled trials (preferably multicentred);
  • studies without randomization and/or control groups; and
  • non-experimental observational studies, such as epidemiological, cohort studies, or case-control studies.

The NHP Regulations set out obligations for the clinical trial sponsor, which include good clinical practices, product labeling, record keeping, information and samples submission, and adverse reaction reporting. The site licence provisions do not apply to clinical trials, and sponsors are not required to have a site licence to conduct a clinical trial. Health Canada inspects clinical trial sites for compliance with good clinical practices. NHPD is in the process of finalizing the necessary guidance document and forms on clinical trials. In the meantime, as clinical trial requirements are very similar to those required for drugs, the Therapeutic Products Directorate (TPD) guidance documents and forms are being accepted as per TPD requirements.

Researchers conducting pre-clinical trials with the primary focus on accumulating evidence supporting safety and efficacy of EFAs must also be aware of the NHP Regulations. Pre-clinical studies involving in vitro and in vivo studies (e.g. animal studies) can provide valuable information to the NHPD in their assessment of a novel EFA product.

The Natural Health Products Research Program

As part of its recommendations, the Standing Committee on Health also identified the need for more focused research in NHPs. On April 1st, 2003 , the NHPD launched the Natural Health Products Research Program (NHPRP)Footnote 7. Over the next five years, as approved by the Treasury Board, the NHPRP will provide $5 million to support NHP research with $2 million dollars allocated to a partnership with the Canadian Institutes of Health Research (CIHR). The NHPRP supports projects through g rants, contributions and operating funds. The primary interest of the NHPRP is to support product based rather than practice based projects. Thus, for example, proposals exploring complementary and alternative health care (CAHC) must have a significant focus on NHP research.

Essential Fatty Acids As Natural Health Products

Essential fatty acids (EFAs) cannot be synthesized in the body; hence, they must be supplied through the diet or a supplement. The two established EFAs are linoleic acid (C18:2) and alpha-linolenic acid (C18:3). According to the NHP RegulationsFootnote 8, all other fatty acids (such as oleic acid - OA, conjugated linoleic acid - CLA, gamma-linoleic acid - GLA, arachidonic acid - AA, eicosapentaenoic acid - EPA, and docosahexaenoic acid - DHA) are considered extracts or isolates ( An extract is a substance prepared by treating a plant or a plant material, an alga, a bacterium, a fungus or a non-human animal material with solvents to obtain the desired compounds).

Lack of the EFAs over a period of time results in adverse clinical symptoms such as impaired growth, skin lesions, and neurological abnormalitiesFootnote 9.

There are two subclasses of long-chain polyunsaturated fatty acids (PUFAs): omega-3 (n-3) fatty acids and omega-6 (n-6) fatty acids. Important examples of the omega-3 PUFAs are alpha-linolenic acid ( ALA ), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is the precursor to EPA and DHA. The n-6 PUFA family includes LA, gamma-linolenic acid (GLA), and arachidonic acid (ARA).

Sources of EFAs

Rich sources of EPA and DHA are fatty fish and fish oils. Plant based oils contain ALA with flax having the highest level, about 55%. Hemp oil contains 15-20% ALA , followed by walnut (~14%), canola (~11%) and soy oil (~7%). LA is found primarily in vegetable and plant oils, such as corn, safflower, soybean, and sunflower and is the precursor for the longer chain PUFAs, GLA and ARA. GLA is found mostly in plant oils including evening primrose oil, borage oil, and black current seed oil. Hemp oil is unique in that it contains high levels of LA (~ 55%) as well as GLA (~ 4%). ARA is found in animal products such as meat, poultry, and eggs.

Although not technically an EFA, conjugated linoleic acid (CLA) is a relatively new supplement and food ingredient that has received interest as an NHP from the industry and is being actively studied by the Canadian and international research community. The Dairy Farmers of Canada as well as several large European and US based companies have provided generous funding for CLA health related research in Canada over the past five years. CLA is a generic term used to describe a mixture of positional and geometric isomers or forms of LA. Whereas the chemical structure of linoleic acid is cis-9, cis-12-octadecadienoic acid, the two double bonds in CLA can occur in several positions along the carbon chain. The different CLA isomers appear to have different biological effects with the most widely studied being the cis-9 trans-11 (c9t11) and trans-10 cis-12 (t10c12) isomers.

CLA occurs naturally in food products from ruminants. Commercial supplements of CLA are produced through isomerization processes from oils containing high levels of LA (safflower, sunflower and high LA flax - Linola, trademark name of Canadian company AgriCore United) and typically consist of an approximate 50/50 mixture of c9, t11 - CLA and t10, c12 - CLA, although the ratio and purity of these isomers in supplements is not always assuredFootnote 10. Conjugated isomers of ALA (CLnA) based on flax oil are also being developed by the Quebec based company, Naturia Inc. Projected to be available on the North American market by 2006, this innovative lipid product will also contain naturally occurring ALA. The company is positioning the supplement as offering the synergistic health benefits of glycemic and lipid control, immune modulation and improved fat metabolism.

Omega-3 and Omega-6 Fatty Acids
Long-chain PUFAs Name Abbrevation Structure Food Source
Omega-3 alpha-linolenic acid ALA 18:3n-3 Walnuts, flaxseed oil, hemp and canola oil
eicosapentaenoic acid EPA 20:5n-3 Fatty fish and fish oils
docosahexaenoic acid DHA 22:6n-3 Fatty fish and fish oils
Omega-6 linoleic acid LA 18:2n-6 Hemp, corn, safflower, soybean, cottonseed, wheat germ and sunflower oils
Conjugated linoleic acid CLA 18:2n-6 Safflower, sunflower and Linola
gamma-linolenic acid GLA 18:3n-6 Evening primrose oil, borage oil, hemp and black current seed oil
arachidonic acid ARA 20:4n-6 Meat, poultry, and eggs

Health Effects of EFAs

LA and ALA are components of cellular membranes and act to increase membrane fluidity. These fatty acids are necessary for cell membrane function, as well as for the proper functioning of the brain and nervous system. ARA and EPA, derived from LA and ALA , respectively are further metabolized into hormone-like substances known as eicosanoids, which include a series of compounds. As reviewed by Harper and JacobsonFootnote 11, the eicosanoids derived from n-3 fatty acids generally exert beneficial effects in the body including platelet anti-aggregation, anti-inflammation, and vasodilation, while eicosanoids derived from ARA appear to have opposite effects. An overproduction of AA derived eicosanoids has been associated with an elevated risk for numerous diseases including heart disease, cancer, diabetes, osteoporosis, and a several immune/inflammatory disorders. Diets supplemented with n-3 fatty acids lead to a partial replacement of n-6 fatty acids in the membranes of virtually all cells, thus reducing the formation of n-6 derived eicosanoidsFootnote 12.

The role of EFAs in growth and development as well as in health and disease, particularly in coronary heart disease (CHD), is currently one of the fastest growing research areas in nutritional science. As a result, knowledge of EFAs has grown significantly.

With regard to the n-3 EFAs, cardiovascular benefits from their consumption have been documented in several prospective studies and randomized clinical trialsFootnote 13. The n-3 PUFAs - ALA and EPA, have been reported to lower triglyceride levels and reduce cardiac artery blockage, reduce the risk of abnormal thickening of arteries due to fatty deposits on arterial inner walls (atherosclerosis)Footnote 14 and decrease overall mortality and risk of cardiac deathFootnote 15. Omega-3 fatty acids are also shown to be beneficial at various life stages and with several health conditions. Evidence is emerging indicating benefits from n-3 fatty acid consumption in health conditions such as hyperglycemia (diabetes), depression, cancer, lupus, asthma and rheumatoid arthritisFootnote 16.

Of the n-6 PUFA family, GLA is converted into eicosanoids that exhibit anti-inflammatory, vasodilator and anti-thrombotic properties and inhibit the formation of AA-derived metabolites. Thus, research in GLA has focused upon its therapeutic effects in a wide variety of disorders, including hypertension, atopic dermatitis, immune modulation, diabetic neuropathy, reduction of blood lipids, and rheumatoid arthritisFootnote 17.

The two CLA isomeric forms ( c9, t11 - CLA and t10, c12 - CLA) , alone and combined, appear to have different health effects. The 50/50 commercial blend is being studied for impact on body mass, that is, to reduce body fat while maintaining lean muscle mass, when ingested at a recommended daily intake level of 3 grams. The c9t11 isomer shows anticarcinogenic responses, inhibiting tumor development in the skin, mammary gland and fore stomach of humans and rodents and to inhibiting tumour development at initiation, promotion and progressionFootnote 18. CLA has been shown to improve oral glucose tolerance and lower serum insulin levels in patients with type 2 diabetesFootnote 19. CLA may be antiatherogenic as it can decrease triglyceride concentrations significantly, with no change or a modest decrease in HDL cholesterolFootnote 20.

Dietary Recommendations for EFAs

In general, the scientific community has not yet arrived at a consensus in terms of the ideal LA to ALA ratio, the optimal intake of n-3 fatty acids, or the comparative efficacy of plant and marine n-3 fatty acids. Based on limited studies in animals, children, and adults, the Institute of Medicine has determined that a LA to ALA ratio range from 5:1 to 10:1 is a reasonable recommendation for adults. The Dietary Reference Intakes (DRIs), released by the Institute of Medicine in collaboration with Health Canada , recommend an ALA intake of 0.6-1.2 percent of energy, or 1.3 to 2.7 g/d, on the basis of a 2000-calorie dietFootnote 21. The American Heart Association recommends 0.5 to 1.8 g/d of EPA + DHA to reduce cardiac disease and 1.5 to 3 g/d of ALA for beneficial health effectsFootnote 22. The current average intake of n-3 fatty acids in North America is about 1.6 g/d (~0.7% of total calories); of this, only 0.1-0.2 g/d is EPA+DHAFootnote 23.

As a result of such discrepancy between recommended and actual intakes, consumers have been advised to increase their intakes of n-3 PUFAs. For many individuals, this is not possible through diet and thus a market for EFAs in supplement form - not only n-3 but also of GLA, CLA and combination oils - has emerged over the past few years.

Commercial EFA Products

EFA products were evaluated by the consultant during in January and February 2005, at the following retail locations:

  • Vancouver , BC - One natural health products independent merchandiser, One pharmacy
  • Winnipeg , MB - One natural health products national chain, One pharmacy
  • Toronto , ONT - One natural health products independent merchandiser, One pharmacy

Six major brand labels were found at the chain stores, both NHP retailers and pharmacies. The NHP national retailer also stocked one additional line while the NHP independent merchandiser stocked three of the national brands and two smaller lines.

1. Plant oils

The EFA products available in these locations as NHPs derived from plant oils included:

  • ALA - flax, hemp
  • LA and Oleic acid - Wheat germ oil
  • GLA -borage, evening primrose (EPO) and blackcurrant
  • Oleic acid (n-9) - Pumpkin seed, olive (in blends)
  • CLA - (source not identified)

Examples of common products:

  • Flax Oil - 53 - 55% ALA
  • Hemp Oil - 15-20% ALA and 3-4% GLA
  • Borage Oil - 22 - 24% GLA
  • Evening Primrose Oil - 9 - 10% GLA
  • Blackcurrant Oil - 15 - 17% GLA

Recommended intakes and pricing (low versus high intakes):

  • Flax - 3000 mg to 8000 mg /day ~ $0.25 - 0.4 to $0.7 - $1.10 / day
  • EPO - 1000 mg to 4000 mg /day ~ $0.15 - 0.25 to $0.6 - 0.75 / day
  • Borage (only one product available) - 1000 mg to 2000 mg /day ~ $0.55 to $1.13 / day
  • 3, 6, 9 combinations (flax, fish and borage oils) - 1000 mg to 3000 mg /day ~ $0.2 - 0.25 to $0.5 - 0.75 / day

2. Animal oils

The EFA products available in these locations as NHPs derived from animals include:

  • EPA / DHA - fish ( Anchovies, mackerel, sardines, tuna, salmon, cod or a mixture)
  • DHA - from algae sources is available for vegetarians on the internet.

Examples of common products:

  • Fish Oil Blends - 18% or 30% EPA and 20% DHA as TG or ethyl esters
  • Salmon Oil (pure) - 6% EPA/9% DHA
  • Salmon Oil Blend - 18% EPA/12% DHA

Recommended intakes and pricing (low versus high intakes):

  • Halibut Oil (one product) - 1000 mg to 3000 mg /day ~ $0.05 to $0.15 / day
  • Salmon Oil blend (18% EPA/12% DHA) - 1000 mg to 3000 mg /day ~ $0.14 - 0.2 to $0.28 - 0.6 / day
  • Fish oil (EPA 400 / 200 DHA, one product) - 1000 mg to 2000 mg /day ~ $0.25 to $0.50 / day

Plant and animal oils are generally sold to consumers in the form of soft gels with fill weights from 500 mg to 1200 mg, oval to oblong in shape, and natural, or carob color. Such products supply omega-3 and 6 oils alone or as multi-EFA combinations with n-9 oils. EFA concentrates are also marketed although these are not as common.

Mixed tocopherols (Vitamin E) are added to encapsulated products as antioxidants to improve stability. O ther EFA products found on the internet included those with bioactives such as saponins and phytosterols (for cholesterol lowering); isoflavones and lignans (for menopause), vitamins, herbs etc added for particular health conditions.

Commercial CLA is commonly a 50/50 mixture of c9t11 and t10c12 isomers with both di- and triglyceride forms available and averaging 80% to as high as 95% concentrated CLA isomers . Currently, sales for commercially produced CLA supplements focus on body composition and weight loss. Only one CLA supplement as a branded product was found (600 mg, $15 for 90 caps). Recommended dosage level was 4-6 caps per day (2.4 to 3.6 g or ~ $0.6 to $1.00 per day). In addition, one weight loss product consisting of a bottle of green tea extract and a bottle of CLA was found (Price for a month supply was $30.00).

Bottled products are also available, the most common being flax, borage, hemp, fish oils and combinations thereof. Mixed tocopherols (vitamin E) are added as antioxidants to improve stability. For 500 ml bottle: Flax ($13.50 to $18.00); Flax, borage and fish oil (3,6,9 blends - $18.00 to $22.50).

Standard EFA oil label information

Only one of the brands carried DIN numbers for all its EFA products, and except for these products, no EFA supplement specifically carried information regarding recommended use or purpose . All products complied with the NHP Regulations as per supplying the product name, the quantity of product in the bottle, recommended conditions of use (including dosage form, route of administration, and recommended dose). No cautionary statements, warnings, contra-indications and possible adverse reactions appeared on any products.

1. Health

Flax, Fish oils and 3,6, 9 combos: "heart health"(both DIN and food capsules) "omega potency" "n-3 support" "cardio support" "EFA supplement" "Rich in n-3"

Borage: "EFA supplement"

EPO: "EFA supplement" "Women's health" "Women's natural health"

Some products also included on the label various logos identifying "potency assured", "standardized" or "purity assured".

2. Processing and labeling

Non - GMO oil seed

Cold-pressed, Hexane free

  • Extraction by mechanical means

Cold Processed, Hexane free

  • Extraction with organic solvents (ie alcohol)
  • Temperatures < 120 F

Certified Organic

Pesticide Free

Unrefined and Unfiltered

Essential Fatty Acids In The Self-care Continuum

In developing the NHP Regulations, Health Canada 's intent was to cover products that consumers can select and use themselves, without the need to consult a health care provider or obtain a prescription. According to the NHPD, self-care involves the activities individuals undertake for the prevention , treatment, and symptomatic relief of diseases, injuries or chronic conditions that individuals can recognize and manage on their own behalf, either independently or in participation of with a health care providerFootnote 24. This includes the use of self-care products, such as NHPs and including EFAs, that are safe, effective and of high quality.

The evidence applicants provide with the product licence application enables the NHPD to determine whether the NHP is or is not appropriate for self-care. Generally speaking, high quality EFA supplements do not pose a risk when consumed at the levels recommended by responsible marketers and as indicated above. Levels of 10 - 15 g of fish and plant based oils have been reported to be safe, although intestinal discomfort including bloating and flatulence have been associated with these intakesFootnote 25. EFA supplements should be taken with meals to ensure absorption and reduce the risk of stomach upset. For children over the age of five, recommended intakes of one-third to one-fifth that of an adult are advised. Children under the age of five, pregnant and lactating women are not advised to consume EFA supplements.

EFAs in Foods

Although not within the scope of the NHP regulatory definition, it is important to note that foods are being produced through the enrichment of animal feeds with EFAs (for example, omega 3 eggs) as well are being fortified with EFAs. Spreads (margarines) and salad dressings are becoming popular mediums for delivering n-3's. In 2004, n-3 fortified milk appeared on Canadian shelves produced through fortifying milk with flax oil or by supplementing the diets of dairy cattle with DHA rich oils (such as tuna). Chocolate bars that provide the recommended daily requirement of EFAs (Omega-3 and 6) and omega-9 fatty acids through addition of flax, sunflower and evening primrose oils are being sold in health food stores across North America. EFA enriched beverages and powered drink mixes, frozen desserts, energy bars, breads, yogurt, muffins, cookies, cereals, crackers, snack foods, sauces, pastas and soups are available to consumers. Powered EFAs with improved dispersion properties in liquids, bioavailability, and stability are used in many food products, especially those that are not lipid based. EFA oils are emulsified, microencapsulated, and freeze-dried into powders with concentrations ranging from 33% - 50%. These powders are finely ground, with negligible taste and odor.

Essential Fatty Acid Research In Canada

An extensive internet search was conducted to ensure that the majority of EFA researchers were captured for a Canadian database. The results of the search are found in Appendix C. In total, sixty-six researchers are included and a brief overview of their principal activities in the area of EFAs is provided. Twenty-two of the key and most prominent EFA researchers are highlighted in the database by italics. It is recommended that the NHPD invite these individuals to any future consultations.

In addition, thirty interviews were initiated with researchers across Canada . The results of twenty completed to date are summarized in this report as is information taken from internet searches of individual researcher profiles. The interview list appears in Appendix A and the questionnaire in Appendix B.

Overall, EFA r esearch is being conducted to various extents across the country with the Prairie Provinces having more focus upon plant based oils and the Eastern regions of the country conducting research primarily on marine based EFAs.

Research Activities

Each researcher was asked to summarize his/her research in the area of EFA. The detailed information appears in the Researcher database (Appendix C). As per the definition of NHPs, this discussion paper did not solicit specific information describing research activities in the area of genetic modification (for example, introducing genes to enhance the levels of n-3 EPA and DHA in flax); traditional plant breeding; aquaculture (for example, flax oil is being tested as a feed alternative to fish oils in salmonoid diets) and animal based human foods (such as n-3 enriched eggs, dairy and meat products). However, some of the researchers involved in animal based human food development have been included in the database as NHPD (or the Food Directorate of Health Canada ) may wish to contact these individuals at a later date.

The majority of EFA researchers in the traditional health sciences area have conducted pre-clinical trials involving in vitro and in vivo studies (e.g. animal studies) prior to clinical studies in humans. Research activities encompass all health and disease related conditions, basic and applied, with the principal areas of focus being cardiovascular, diabetes and the immune system, and for CLA, body composition.

The Canadian EFA research community has expertise in EFA clinical trials and conducts a wide range of studies including the following:

  • systematic reviews, such as meta-analyses of randomized controlled trials or other trials;
  • randomized controlled trials - several EFA researchers are involved in multicentre trials;
  • studies without randomization and/or control groups (for EFA these are usually conducted in healthy populations); and
  • non-experimental observational studies, such as epidemiological, cohort studies, or case-control studies - these types of studies are not as common for the Canadian EFA community, in general.

Research activities focused upon basic (that is mechanistic research at the cellular level) versus applied (that is focused upon human disease and health at an animal and human level) varied amongst the group. Basic research ranged from 30% to 95% and applied from 5% to 70%. Those who identified the highest level and most consistent degree of funding success for human clinical studies were most active in applied research.

The EFA research community is well established in Canada with the majority of those interviewed having been involved in this field of research for more than 10 years (range of 10 to 30 years). The remaining individuals have been involved in EFA research for a minimum of five years. This was also a trend apparent when the internet profiles of EFA researchers not included in this survey were assessed. This is not surprising as this project did focus on "major" researchers and research groups and thus would not have captured younger scientists entering the field and/or working in conjunction with more senior scientists.

The number of publications in the EFA area is reflective of the years of involvement in EFA research and the success in funding initiatives related to the field. Senior scientists, with fifteen or more years of experience, had the highest publication record ranging from 25 to 100 publications. Of the most successful in the funding arena, one researcher identified 160 peer reviewed papers, 160 abstracts and 8 book chapters and another indicated 45 peer reviewed papers, 3 books and 8 book chapters, all included primary and secondary EFA research.

Funding for EFA Research

Current funding for EFA research is not significant for most of the researchers surveyed, averaging $50,000 to $100,000 per year, although more 'senior' scientists indicated funding ranging from $140,000 to $300,000 in total. Funding has increased generally for NHP/nutraceutical research but in the EFA area it is has remained relatively constant over the last five years. Most funds came from external sources although internal (core) funding was identified as necessary for work in the clinical area.

Funding sources for EFA research are identified in Appendix D. For the most part, these are the primary funding agencies for all Canadian NHP and nutraceutical research. The most important federal funding source identified by all those surveyed is CIHR - it is viewed as the 'gold standard' and most prestigious of funds awarded for clinical and health research in Canada . NSERC is also a very important funder, especially in the area of biomedical research.

Over 50% of the scientists interviewed working in this area have received matching funding from industry associations with the most important being Dairy Farmer's of Canada (CLA research), the Flax Council of Canada and the Saskatchewan Flax Development Commission. Similar industry associations do not exist for the marine industry although international companies developing and marketing fish oil supplements (see Appendix D) have provided some funding to the Canadian research community. Funding from Canadian EFA companies has been very limited with less than $25,000 identified on average for research projects conducted outside of the companies.

Provincial agencies that provide funding in agriculture and health also represent significant sources of matching dollars for EFA research in Canada .

When submitting proposals to provincial funders and industry associations, most of those surveyed indicated an average funding success rate of about 50%, especially for projects emphasizing product development and with commercial potential. This was not the case with proposals submitted to federal granting agencies, especially CIHR and NSERC, where the success rate appears to be much lower, especially for clinical trials on EFAs.

NHP and "Nutraceutical" Research

Only half of those interviewed identified themselves as both NHP and nutraceutical researchers. Most categorized themselves as basic or applied nutritional scientists and several added "with a NHP/nutraceutical focus". Other categories included medical researcher, nutrition and metabolism researcher.

Those who identified themselves as nutraceutical researchers qualified this by indicating that they are also interested in food ingredient applications for their EFA products and thus have expanded their research focus beyond the capsule delivery system to also include the food delivery system. This involves ensuring that EFA bioactives can be incorporated into foods and will remain bioavailable in food matrices. These researchers tended to be affiliated with Food Science and Nutrition departments in Universities (rather than departments in Medical Faculties or University teaching Hospitals) or with Agriculture Canada which has a strong focus on the development of bioactives from crops for use in both NHPs and as food ingredients.

The majority of those surveyed were familiar with NHP research in general, and did not perceive research in this area as focused solely on herbal medicines/cultural medicines and/or "dietary supplements".

The number of scientists who indicated that their focus was upon basic science versus those in which patentability and/or commercial potential was an important prerequisite in the selection of research projects, was about equal among those interviewed. Several within the latter group noted a rising emphasis on intellectual property (IP) in order to engage industry partnerships and funding. Several in the food/nutrition and agriculture disciplines did indicate an increasing necessity to secure patents and IP for professional advancement.

The NHPRP and CIHR Partnership Programs

Almost half of those interviewed were not aware of the NHPRP and the partnership program with CIHR. About ten of those surveyed were planning to apply to CIHR and identify the NHPRP as an alternative for funding.

The scientists surveyed, although fairly familiar with NHP research, for the most part lacked knowledge of the NHPD, the NHP Regulations and the NHPRP. In fact, very few interviewees were aware of the research priorities of the NHPRP and were confused regarding which CIHR Institute priorities were relevant to the NHPRP - this was especially apparent with the obesity focus of the Institute of Nutrition , Metabolism and Diabetes. For example, no research in n-3 EFA currently fits this priority, although CLA research is on-going in the area of obesity.

General Observations

A. The following section highlights comments made regarding the amount of funding available for EFA and NHP research in Canada

  • Functional food and nutraceutical (FFN) research is more applied than that of traditional NHP and requires different funding mechanisms.
  • Specific funding programs should be available for EFA research as EFAs fall into many of the goals of the various funding agencies.
  • Many researchers are unaware of which agencies fund EFA research and research funding is very fragmented in Canada - need a central database of funding available.
  • It has been very difficult to get some of the conventional health agencies, for example the cancer societies (who are among the best funded non government agencies in the country) to fund research in the area of nutrition and NHP - these simply are not recognized within the drug paradigm of disease treatment.
  • Nutraceutical research including on EFA often falls between the cracks - it is not seen as food or drug related.
  • There is a bias against funding preventive measures for disease and thus EFA, NHP, nutraceutical and nutrition research is often overlooked in preference to drugs and disease treatment. These areas simply are not a priority within funding agencies.
  • To promote good research in this area, a pool of funds specifically targeted at EFAs and/or NHP/nutraceuticals should be established.
  • This is not gene discovery or traditional medical research (which CIHR prefers to fund) - however, it is as stringent in its requirements for good science and is very important to the health of Canadians and the industry.
  • It has been very difficult to receive funding for NHP and EFA research and almost impossible to secure money for clinical trials.
  • Industry association funding is critical to 'proof of concept' research - to accumulate the necessary data for submission to granting agencies such as CIHR. This data is also required to leverage industry dollars.

B. The following section highlights comments made regarding the roles of the NHPD and CIHR in research funding in Canada

Note that the researchers surveyed commented specifically on the CIHR, rather than other agencies such as NSERC, as it is the agency most associated with NHP research, the NHPD and NHPRS. The NHPRS and CIHR partnership was also discussed in this project. In addition, most researchers surveyed have in the past, or are planning to, apply to CIHR for clinical health related projects.

Several concerns raised regarding the funding of EFA and NHP research within CIHR:

  • Need to strengthen the EFA and NHP knowledge base and awareness within the CIHR review committees.
  • Peer review process needs to be improved - there is a current bias in CIHR toward molecular and biomedical research, drug discovery and testing.
  • Several suggestions made to create an Institute specific to NHPs such as EFAs within CIHR.
  • Suggestion that EFA and NHP research should be positioned as a theme across several institutes.
  • Competition for funding within CIHR is growing but there appears to be greater industry support for research with matching cash, as well as in-kind contributions.
  • EFA researchers are competing with traditional biomedical research and are being evaluated by reviewers who do not understand the area.
  • Several institutes in which EFA are applicable are very drug oriented and biased towards molecular biology, cellular testing etc in their funding approach, including the Institute for Cancer Research and the Institute for Circulatory and Respiratory Health.
  • Several researchers expressed their concern regarding a CIHR/NHPRP partnership in that the same Institutes and peer review committees will be assessing the grant proposal under their 'traditional' operating parameters.

C. The following section highlights comments made regarding NHP regulations in Canada

  • Industry and researchers are still waiting for the criteria to come out as to what is needed to make a claim. Industry may be excited about the possibilities but researchers are having a difficult time "getting their heads around it".
  • New regulations are being driven by consumers and industry - it is a marketing ploy - but it does have the potential to assist population health. But if the research isn't done correctly then "nutrition will go back 25 steps".
  • Industry wants claims and wants the research done quickly and cheaply. Testing is required and researchers want to do research - basic and applied - not necessarily specific product testing. Universities want researchers to publish not conduct product testing - this isn't recognized by universities. Industry needs greater access to more contract research organizations that provide timely testing at reasonable costs.
  • Need to organize regulatory approval and ethics approval process.
  • A couple of comments related to NHPs - "Are these foods or drugs?"

Key Themes And Suggested Next Steps

The following were identified as priority areas for EFA research by the NHPD and the NHPRP in the development of this discussion paper. It must be emphasized that these issues are the result of a very limited sampling of the EFA research community and are meant to serve as a starting point for further consultations.

1. Developing a National Research Agenda

Research in the areas of EFAs, and NHP in general, appears to be done on an ad hoc basis with no long term strategy and few effective communication strategies for researchers in place. Exploring the development of a mechanism(s) whereby various association and government (federal, provincial, regional) research agendas are better aligned was suggested. Maintaining the current diversity of agendas will result in continued confusion and diffusion of efforts. The need to build partnerships , involve i ndustry and funding partners and better coordination of research to improve funding success was highlighted.

2. Greater Interactions between EFA and other NHP researchers

There are numerous research themes and areas under investigation that cut across both the EFA and NHP communities. Mechanisms should be established to provide more opportunities for interactions between the two groups to encourage synergies of activities and avoid duplication. A joint conference possibly hosted by the NHP Research Society and the AFMNet with the focus being aligning these two groups and providing the venue for networking and scientific exchanges is one suggestion. Such a conference would be similar to the two highly successful events hosted by the NHP Research Society, but more broadly based. Another suggestion would be to host a series of regional workshops.

During the development of this discussion paper, it was difficult to identify junior scientists involved in EFA research. A focus of a national conference should be on the participation of current and recent graduates. Travel bursaries should be provided to allow young investigators to attend such conferences. Sessions specific to student research should be organized and awards offered for best oral and poster presentations.

3. Need for NHPRP information sessions

There appears to be a lack of awareness among EFA scientists regarding the NHPD, the NHP Regulations and the NHPRP, including the partnership program with CIHR. It is recommended that any consultations that the NHPD may undertake with the EFA research community include an overview of the NHPD, the NHP Regulations and the research priorities of the NHPRP. In addition, information should be provided regarding how the partnership program with CIHR operates. Such information sessions may help to negate concerns regarding a CIHR/NHPRP partnership and the question "What has changed?" - as it is viewed by some that since the same Institutes and peer review committees will be assessing EFA and NHP grant proposals under their 'traditional' operating parameters, success rates for funding in these areas will be compromised.

Although it is recognized that this partnership program only began this year, it would be of value for the NHPD to provide informational workshops to the EFA and NHP research community.

4. EFA and NHP Database

A common area of priority identified in this project and seen in other NHPD consultations is the need for a national database to include not only EFA and NHP basic and applied researchers and scientific activities but also to include industry, associations, funders and government departments involved in the sector. Such a database needs to be comprehensive and to remain current.

5. Peer Review Process

The EFA scientific community in Canada has expressed concerns related to the expertise of CIHR review panels as well as perceived issues with a lack of credibility regarding this area of research within the CIHR. It is recommended that this be an area of focus for future NHPD consultations with this sector.

6. Requirement for greater funding support of EFA research

Support for research in the application of EFAs and NHP as alternatives to conventional health care was frequently identified as a priority with the need emphasized for specific funding mechanisms. There has been a reduction in direct funding and 100% grant programs over the past decade, and an increasing number of partnership programs with higher funding success rates (examples include industry associations and provincial funding) compared to investigator-initiated grants (i.e. through agencies such as CIHR).

Encouraging the continued funding support for EFA research through Industry associations and provincial agriculture and health departments is important as often this funding is for smaller scale research that is conducted as 'proof of concept' to accumulate the necessary data for submission to granting agencies such as CIHR. This data is often also required to leverage industry dollars for larger scale research. Additional funding from such sources could be encouraged through matching programs whereby the industry association and the government agency (federal and/or provincial) could each provide 50:50 funding.

In addition, industry research initiatives should be encouraged. A potential model is Agriculture and Agri-Food Canada (AAFC)'s Matching Investment Initiative Program (described in Appendix D of this report) where industry and AAFC match funding for AAFC directed research projects conducted on behalf of the industry. Perhaps this type of model could be explored as a way to establish partnership funding mechanisms from industry, association(s), provincial and federal sources for University health related research in NHPs.

These six themes are areas that could be explored further through consultations with the EFA research community. Involvement of 'non-traditional' key funders identified in this paper - industry associations and provincial agriculture and health departments, is essential to ensure that such funding is maintained, and if possible increased, that dialogue continues and ties between all stakeholders are strengthened further. It is recommended that these funders are invited to any future consultations to explore ways to further support funding in this area.

Conclusion

This discussion paper identified an extensive research community actively involved in EFA research in Canada . Research is being conducted to various extents across the country with the Prairie Provinces being more focused upon plant based oils and the Eastern regions of the country conducting research primarily on marine based EFAs. Research activities are very comprehensive with many areas of health and disease conditions being studied at both the basic and applied levels. Six broad topics and issues related to conducting EFA research in Canada and with significance to the NHPD, the NHP Regulations and the NHPRP were identified. These topics are presented as suggestions to form the basis for future priority setting consultations that the NHPD may wish to undertake on the subject of EFA research.

Footnotes

Footnote 1

Food and Drugs Act. Natural Health Product Regulations.
http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpdpsn/regs_cg2.pdf

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Footnote 2

Health Canada. Final Policy Paper on Nutraceuticals/Functional Foods and Health Claims on Foods. November 1998. Internet : http://www.hc-sc.gc.ca/food-aliment/ns-sc/ne-en/
health_claims-allegations_sante/e_nutra-funct_foods.html.

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Footnote 3

Food and Drugs Act. Natural Health Product Regulations. http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpdpsn/regs_cg2.pdf

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Footnote 4

Natural Health Products Directorate. 2004. Perspectives on Natural Health Products: http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/hp_perspectives_1_e.html and NHP Research Program: http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/research_links_e.html

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Footnote 5

Natural Health Products Regulations. 2004. www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/overview_nhp_regs_e.html#1

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Footnote 6

Natural Health Products Regulations. 2004. www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/mono

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Footnote 7

NHP Research Program: http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/research_links_e.html

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Footnote 8

Scope of the Natural Health Products Regulations. 2004. "Essential Fatty Acids" Natural Health Products Directorate. www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/overview_nhp_regs_e.html#1.

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Footnote 9

Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Institute of Medicine. 2002.

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Footnote 10

Gaullier J-M, Berven G. Blankson H and Gudmundsen O. 2002. Clinical trial results support a preference for using CLA preparations enriched with two isomers rather than four isomers in human studies. Lipids. 37:1019-1025.

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Footnote 11

Harper, C.R. and Jacobson, T.A. 2001. The fats of life. Arch Intern Med; 161. 2185 - 2192.

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Footnote 12

Leaf, A., Weber, P.C. 1988. Cardiovascular effects of n - 3 fatty acids. N Engl J Med; 318: 549-557; Lanzmann-Petithory, D. 2001. Alpha Linolenic Acid and Cardiovascular Diseases. J Nutr, Health & Aging; 5(3): 179-183.

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Footnote 13

Kris-Etherton P, Harris WS, Appel LJ. Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease. Am Heart Assoc Sci Statement. 2002; 2747-2757.

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Footnote 14

Harris WS, Isley WL. Clinical trial evidence for the cardioprotective effects of omega-3 acids. Curr Atheroscler Rep. 2001; 3(2): 174-179.

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Footnote 15

Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction. Circulation. 2002; 105:1897-1903; De Lorgeril M, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction. Circulation. 1999; 99:779-785.

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Footnote 16

Kris-Etherton, P.M., et.al. 2002. Ibid; Simopoulos, A.P., Leaf, A., Salem , N. Workshop on the essentiality of and recommended dietary intakes for n-6 and n-3 fatty acids. Bethesda , MD : National Institutes of Health. 1999.

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Footnote 17

Fan YF, Chapkin RS. . 1998. Importance of dietary Gamma Linolenic Acid in human health and nutrition. J. Nutr. 128: 1411-1414; Horrobin DF. 1990. Gamma- linolenic acid. Rev. Contemp. Physiol. 1:1-41.

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Footnote 18

Kamlage B, Hartmann L, Grugl B and Blaut M. 2000. Linoleic acid conjugation by human intestinal microorganisms is inhibited by glucose and other substrates in vitro and in gnotobiotic rats. J Nutr. 130:2036-2039.

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Footnote 19

Belury , MA , Mahon A and Banni S. 2003. The conjugated linoleic acid (CLA) isomer, t10c12 - CLA, is inversely associated with changes in body weight and serum leptin and subjects with type 2 diabetes mellitus. J Nutr. 133:257S-260S.

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Footnote 20

McLeod RS, LeBlanc A, Langille M and Currie D. 2003. Effects of CLA on hepatic very low density lipoprotein metabolism. In: Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg , MB . p. 13.

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Footnote 21

Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Institute of Medicine. 2002.

Return to footnote 21 referrer

Footnote 22

Kris-Etherton, P.M., Harris WS, Appel LJ. Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease. Am Heart Assoc Sci Statement. 2002; 2747-2757.

Return to footnote 22 referrer

Footnote 23

U.S. Department of Agriculture, Agriculture Research Service, Food Surveys Research Group. 1997. Data tables: Intakes of 19 individual fatty acids: Results from 1994-1996 Continuing Survey of Food Intakes by Individuals. www.barc.usda.gov/bhnrc/foodsurvey/home.htm.

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Footnote 24

Scope of the Natural Health Products Regulations. 2004. Natural Health Products Directorate. www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/overview_nhp_regs_e.html#1

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Footnote 25

Harper, C.R. and Jacobson, T.A. 2001. The fats of life. Arch Intern Med; 161. 2185 - 2192.

Return to footnote 25 referrer