Positive Health Online

A Tide of Evidence Washes Away Flawed Fish Oil Prostate Cancer Study[1]

Alliance for Natural Health Europe - www.anh-europe.org

Any health conscious consumer would have had to work hard to avoid hearing about the latest media scare story that’s linked fish oil supplements with increased prostate cancer risk.[2]

The study that has precipitated these concerns about fish oils was led by Theodore Brasky, PhD of the Fred Hutchinson Cancer Research Center in Seattle, USA and published in the Journal of the National Cancer Institute.

The study was a prospective case-control study that involved comparing the blood levels of various fatty acids, including the long-chain omega-3 fatty acids, in a group of 834 men who developed prostate cancer (156 the high grade, aggressive form), against 1393 who did not. The subjects were all part of the SELECT (Selenium and Vitamin E Cancer Prevention) trial that aimed to evaluate the effects of vitamin E and selenium supplements on prostate cancer. As an aside, but because it evaluated the effects of supplements — and being in mind the fish oils study most certainly didn't involved studying supplements —  it’s of interest that the SELECT trial found that those who took selenium supplements alone experienced a 20% reduction in absolute risk of prostate cancer, while those who took both selenium and vitamin E benefited even more, with a 60% risk reduction. Somewhat predictably, high dose vitamin E (alpha-tocopherol) on it own, exposed study subjects to a 160% increase in absolute risk. 

Ever wondered why combinations of nutrients as provided for in a healthy natural diet or in concentrated forms in supplements might be better for us than taking single, isolated nutrients — as if they were drugs?

Prostate cancer

While prostate cancer is the most prevalent cancer in men, it is essentially a disease of older men, with around 8% of American men developing it between their 50th and 70th birthdays.

In the USA, based on National Cancer Institute figures, 125 men out of each 100,000 will develop prostate cancer at some stage in their lives, with diagnosis on average occurring at age 66. Death occurs in only 23 out of 100,000 and the average age of death is 80.

For more information on prostate cancer, and the opinion of leading doctors advocating non-surgical, chemo- or radio-therapy approaches, see Peter Starr’s information-packed documentary Surviving Prostate Cancer Without Surgery, Drugs or Radiation, which we think should be essential viewing for any man over the age of 40.

Key findings of study

Firstly, the investigators did not evaluate diets or record or have any data on fish oil supplement intake. They evaluated blood levels of various fatty acids, including the omega-3s eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), among those that didn’t get cancer, and compared these with those who developed low-grade and high-grade prostate cancers, respectively. They assumed that subjects with the highest blood levels were taking high dose fish oil supplements or consuming very large amounts of oily fish.

The researchers reported that men with the highest blood levels of omega-3 fatty acids had an overall 43% increase in risk for all prostate cancer, compared with men with the lowest blood levels of omega-3s. But what really made news headlines was the researchers’ finding that the risk for high-grade, aggressive prostate cancer was 71% greater, and that for low-grade, non-aggressive prostate cancer 44% greater, than among those with low blood levels of omega-3s.

The authors indicate that data on the subject of omega-3s is conflicting, but they assert that this prospective trial now provides stronger evidence that high intakes of omega-3s might be have the capacity to promote prostate cancer, especially if taken in supplemental form, where the DHA and EPA in particular are concentrated.

ANH-USA report on study

Our colleagues at ANH-USA released an important appraisal of the study yesterday, and in particular highlighted its weaknesses and the difficulties associated with drawing the conclusions made by the authors and those subsequently published in the media.

Read ANH-USA report.

Take home points about the study

No causal relationship between high omega-3 intake and prostate cancer was demonstrated, simply an apparent association.

Major weaknesses in the investigators' interpretation of their findings were apparent, including:

• The study only measured fatty acids in blood (plasma) at baseline and then annually. This does not give any measure of long-term omega-3 fatty acid intake (mroe accurately measured in red blood cells).
• No account was taken of the oxidation state of the omega-3 fatty acids measured. Fish oils can be ingested in their native or oxidised states. Cheap fish oil supplements (as frequently sold in pharmacies and supermarkets) are often oxidised (rancid to a grrester or lesser degree) and these can produce free radicals and elevated oxidative stress, which is associated with increased cancer risk. Another source of highly oxidised omega-3 fatty acids is oily fish subjected to high-termperature cooking.
• Owing to the link between inflammation and cancer, subjects who developed cancer would be suffering significant inflammation, and inflammatory processes were probably elevated well before tumorigenesis occurred. Higher intakes of fish oils under such conditions could induce a pro-oxidant, rather than an antioxidant, effect.
• The so-called ‘high levels’ of Omega-3 in the study are not actually typical of high plasma (blood) levels when compared with those taking high dosages of high quality fish oil supplements, containing highly concentrated EPA and/or DHA.
• No account was taken of factors that are known or emerging predictors of prostate cancer, such as hormonal markers (e.g. testosterone, insulin growth factor 1 (IGF-1), PSA glycosylation).
• The process of tumour initiation (tumorigenesis) in patients who were found to have high blood levels of omega-3 fatty acids and subsequently went on to develop prostate cancer could well have already been firmly initiated before intake levels were increased.
• Those with high levels of circulating omega-3 fatty acids may have had genetic defects (polymorphisms) that affected fatty acid metabolism or oxidation. 
• There is strong evidence from a recently published systematic review of evidence that high levels, relatively, of one of the omega-3 fatty acids, DPA, is associated with a reduced risk of prostate cancer. There are also plausible mechanisms for this, associated with DPAs effect on inhibiting the COX pathway of inflammatory. DPA is found in marine oily fish, along with EPA and DHA, but typically in smaller amounts.
• For most human populations, and certainly Western ones, there has been a decline in the amount of long-chain omega-3 fatty acids consumed, and, in addition, the ratio of short-chain omega-6 fatty acids has increased (from approximately 1:1 to 10:1). These changing ratios are likely to interfere with the health protective effects of omega-3 fatty acids.

These and other weaknesses aside, there are potentially some plausible mechanisms by which low quality, oxidised fish oil supplements, or fish oils oxidised by high-temperature cooking, may yield increased cancer risk. Most importantly, these oxidised oils may generate higher levels of free radicals, causing increased oxidative stress, this process having been associated with greater cancer risk.

Prostate cancer expert Anthony Victor D’Amico, MD, PhD, points out that the authors failed to adjust for main risk factors of prostate cancer when they did the calculations for the study. They excluded key risk factor predictors such as ethnicity, age, BMI, and PSA level, despite the fact that these appeared in Table 1. If taken into account, as they should have been, these alone could have significantly altered the study conclusion. D’Amico has commented: "The study really cannot make the conclusion that it’s trying to. These types of studies are not cause and effect. These studies are simply associations…. They didn't account for the known predictors of prostate cancer when they were making the calculation. You're left with a weak association”.

The contamination issue

Marine fish contaminated with environmental toxins, such as polychlorinated biphenyls or methyl mercury compounds, as found in fish and in cheap, unpurified fish oil supplements, can disrupt androgen and estrogen balance. This in itself could potentially lead to high-grade cancers, prostate cancer included. In addition, omega-3 fats can become damaged in an oxidizing environment such as that where there is chronic inflammation. The derivative products could then ultimately cause DNA damage leading to cancer.

Prostate cancer: changes in the metabolism of fats

Some studies have shown that prostate cancer can bring about changes in fatty acid metabolism. Fatty acid beta-oxidation appears to become a more dominant energy pathway, due to the alteration of several enzymes. Glycolysis, the glucose metabolic pathway, usually increases with most malignancies, but with prostate cancer, it appears to slow down.

A new meta-analysis by Michael E Chua, MD explains: “the presence of long chain n-3 PUFA (DHA and EPA) in the prostate cell’s beta-oxidative metabolic process leads to the formation of lipid hydroperoxides in the microenvironment of the cell; this can generate reactive species. With chronic exposure to these reactive molecules, the prostate cell can become dysplastic and develop into an aggressive cell”. Chua found that that only high serum levels of long-chain omega-3 PUFAs are associated with reduced prostate cancer risk, whilst the possible role of both EPA and DHA needs to be examined further.

Part of an orchestrated attack on natural healthcare?

Negative findings linked to the Brasky et al study have been widely reported in the media. It's been a chance to pour cold water on the public enthusiasm over supplements, in the hope the public won't even realise fish oil supplements were not even evaluated in the study.

The paper’s senior author, Dr Alan Kristal, was reported to say: “We’ve shown once again that use of nutritional supplements may be harmful”. Kristal has also drawn attention to a recent (2012) review published in the Journal of the American Medical Association, showing an association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events.

This attack is on a key food with which the human race has evolved, and its benefits are backed up solidly by evidence. There's been no discussion about prostate cancers among indigenous peoples whose long-chain omega-3 fatty acid consumption is at the top end of the spectrum, such as the Inuit Nunangat population of Canada.  This population's prostate cancer levels were significantly lower than the average for Canada.  

One of the key aspects of fish eating that has changed during evolutionary history relates to the nature and ratio of polyunsturated oils in fish (e.g. differences between farmed and wild fish) and, especially, the presence of contaminants.  These factors vary not only between species, but according to the aquaculture system, or whether the fish are wild caught.  On top of this, you have the issue of the 10-fold increase in the ratio of omega-6 to omega-3 fatty acids that's occurred since the industrialisation of food production.

Presented along with the very negative media attention, and coming in the wake of the transatlantic attacks on supplements by Dr Paul Offit, we have to ask: is this yet another study designed to fail?

Footnote about the Fred Hutchinson Cancer Research Center
Spare the following a thought. The Hutchinson Center is a leading recipient of National Cancer Institute funding among academic and research institutions. It is ranked in the top two in National Institutes of Health funding among independent research institutions in the US. In addition, it receives funding through licensing and partnership agreements facilitated by pharmaceutical companies e.g. Actinium Pharmaceuticals Inc. and GlaxoSmithKline. Funding is also enabled indirectly, as a result of the centre's membership of the National Comprehensive Cancer Network.

Could this have anything to do with the anti-supplement bias we've witnessed?

References and Further Information

1. A Tide of Evidence Washes Away Flawed Fish Oil Prostate Cancer Study

http://anh-europe.org/news/a-tide-of-evidence-washes-away-flawed-fish-oil-prostate-cancer-study?utm_source=The+Alliance+for+Natural+Health&utm_campaign=b5bfe590f7-130717_ANH_Intl_eAlert_No_1577_17_2013&utm_medium=email&utm_term=0_aea8a87544-b5bfe590f7-84938700

Alliance for Natural Health Europe  www.anh-europe.org  info@anhinternational.org

2. Theodore M. Brasky,Amy K. Darke, Xiaoling Song, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson, Frank L. Meyskens Jr,  Gary E. Goodman, Lori M. Minasian,  Howard L. Parnes,  Eric A. Klein and Alan R. Kristal. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial. http://jnci.oxfordjournals.org/content/early/2013/07/09/jnci.djt174.abstract

Essential Benefits Of Vitamins And Minerals

The Health Supplements Information Service (HSIS)

In response to an article in the Daily Mail on Thursday July 25th posing the question as to whether vitamins can take years off your life, the Health Supplements Information Service (HSIS) is reminding the nation about the many benefits behind vitamins and minerals that are needed daily to fuel our bodies and keep us healthy.

Sorting Out The Real Facts

Vitamins and minerals perform a variety of vital functions in the body, mainly due to their participation in biochemical processes including:

• Working with enzymes to help in the release of energy from food
• Helping to maintain the health of body systems and organs such as the brain, heart, blood vessels and nervous system.

Vitamins and minerals work together to maintain our health and the body cannot function without them. They are essential nutrients and a lack of such vitamins and minerals can lead to poor health. Vitamins and minerals can be obtained from food, but modern diets are often lacking in these nutrients due to poor food choice. This is amply demonstrated by the findings from the large UK Diet and Nutrition Surveys, which methodologically are among the most robust surveys in the world.

These surveys continue to show a lack of essential nutrients to some extent across population groups but particularly in young women whose mineral intakes may be severely compromised and in children and older people where vitamin D intakes fail to match recommendations.[1]

The most recent data from this survey[2] shows that mean intakes fell below the Reference Nutrient Intake (RNI) for a number of minerals, in particular iron, magnesium, potassium and selenium. This was particularly the case for boys and girls aged 11 to 18 years. Mean iron intake was 58% of the reference nutrient intake (RNI), the same proportion as in the previous survey of this age group. Mean intakes of magnesium and potassium also fell below the RNI for both boys and girls aged 11-18 years, as did zinc, calcium and iodine for girls.

Substantial proportions of older girls had mineral intakes below the Lower Reference Nutrient Intake (LRNI; a level at which deficiency is likely); 46% of girls aged 11-18 years had intakes of iron and magnesium below the LRNI; the equivalent figure for potassium was 30% and for zinc 15%. Among boys of this age group, 26% failed to achieve the LRNI for magnesium.

Intakes of calcium were of particular concern in 11-18 year old girls, an age at which calcium is particularly important for bone development. More than one in 10 girls in this age group failed to achieve the LRNI for calcium. Significant numbers of adults also had low intakes. One fifth of adult women failed to achieve the LRNI for iron, while one in 10 men and one in 10 women failed to achieve the LRNI for magnesium.

Intakes of selenium fell below the RNI in both older children and adults. Adult women overall achieved 72% of the RNI while adult men achieved 74% of the RNI. Around half of adult women and older girls and a fifth of men and older boys had intakes below the LRNI.

It is clear that UK dietary surveys continue to show that significant numbers of the population do not achieve recommended intakes of essential nutrients. In the light of this continuing dietary gap, it is misleading to imply that vitamin pills are unnecessary.

A 2010 report entitled Towards a Healthier Britain[3] found evidence that vitamin and mineral supplements boost intakes and increase blood levels of these essential nutrients with fewer people taking multivitamin and mineral supplements having intakes below recommendations.

Nutrient Spotlight

Vitamin E

Vitamin E is the collective name for a group of fat-soluble compounds that exhibit antioxidant activity. Antioxidants protect the body cells from the damaging effects of free radicals, which are molecules that contain an unshared electron. Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species (ROS). The body forms ROS when it converts food to energy. The body is also exposed to free radicals from environmental factors such as cigarette smoke, air pollution and UV radiation. Free radicals damage cells and may contribute to the development of body organ damage.  

In addition to its activities as an antioxidant, vitamin E is involved in other essential functions such as immune function, chemical messaging between cells, regulation of gene expression, and other metabolic processes.[4] Vitamin E inhibits the activity of protein kinase C, an enzyme involved in cell proliferation. Vitamin-E–replete blood vessels have been shown to be better able to resist blood cell components adhering to the blood vessel surface so helping to maintain the health of the blood vessels. Vitamin E also increases the activity of two enzymes that influence fatty acid metabolism, which again helps to maintain the health of the blood circulation.[5]

Vitamin E is one of the essential nutrients for health. Several studies, including the two studies mentioned in the Daily Mail article have evaluated the role of vitamin E in large doses, often 40 times and more greater than the RDA. These studies have involved methods similar to those used in drug trials to see if vitamin E and other essential nutrients can prevent or treat disease.

However, vitamin E, like all essential nutrients is essential for the maintenance of health and prevention of deficiency. Such drug-like trials may be of interest to researchers looking for mechanisms of action but are of no relevance for the daily health maintenance of the UK population where intake of vitamin E should follow recommended amounts. Recommended daily amounts of vitamin E have not been associated with adverse effects in healthy populations. Anyone taking medication or with any disease should ask for the advice of their health care professional about their nutrient intake.

Vitamin C

Vitamin C (ascorbic acid) is an essential vitamin required for the formation of collagen in bone, teeth and blood vessels. It also helps to maintain the optimal activity of several enzymes and is involved in the synthesis of several physiological compounds in the body such as carnitine and noradrenaline. Vitamin C acts as an antioxidant and helps in the absorption of non-haem iron (iron from plant sources).

Low vitamin C intake has been associated with conditions such as stroke[6] and periodontal disease.[7] Studies in which people have taken vitamin C supplements on a regular basis indicate that vitamin C may reduce the duration of colds.[8] Vitamin C may be useful for reducing the development of colds in people exposed to brief periods of severe physical exercise.[9]

Calcium

Calcium is an essential nutrient that plays a whole host of vital roles for health in the skeleton, blood and neuromuscular system. The essentiality of calcium for bone health is indisputable and as many as one in 10 young women in the UK have an intake which falls below the Lower Reference Nutrient Intake (LRNI),[10] an intake at which deficiency is likely with consequences for bone health throughout life.

The Journal of the American Medical Association [JAMA] study[11] mentioned in the Daily Mail article in which calcium was linked with cardiovascular disease (CVD) was not a randomized controlled trial (RCT) but a prospective study from which a cause and effect cannot be established with certainty. There was also no information in the JAMA paper on the duration of supplement use and a lack of information on family history of CVD.  Calcium intake was self-reported by the study participants and therefore subject to error. In addition, calcium intake was only measured at baseline; so change in dietary or supplemental calcium intake could not be assessed during follow-up.

Selenium

Selenium is an essential trace mineral which functions as a part of several seleno-proteins and enzymes involved in essential metabolic processes. However, in the UK, intakes of selenium are low. Data from the 2006 UK Total Diet Study showed that the mean intake of selenium is 48-58 micrograms a day which is below the UK reference nutrient intake of 75 micrograms a day for men and 60 micrograms a day for women.[12] Similar findings emerged from the latest UK National Diet and Nutrition Survey (NDNS) [13] in which intakes of selenium fell below the Reference Nutrient Intake (RNI) in both adults and older children. Adult women overall achieved 72% of the RNI while adult men achieved 74% of the RNI. Around half of adult women and older girls and a fifth of men and older boys had intakes below the Lower Reference Intake (LRNI). Such low intakes are associated with reduced blood levels of selenium and significantly increased risk of mortality in both Europe and the US.[14, 15]

Summary

Overall, there is ample evidence to suggest that many people in the UK have a poor diet with below recommended intakes of essential nutrients. Although these nutrients should ideally be obtained from the diet, it is clear that this is not happening. A multivitamin and mineral supplement in recommended amounts represents a useful means of helping to bridge this dietary gap.

References

1. Bates B, Lennox A, Prentice A et al. National Diet and Nutrition Survey. Headline Results from Year 1, Year 2 and Year 3 (combined) of the Rolling Programme (2008/2009-2010/2011). Department of Health. 2012.

2. Ibid.

3. Mason P, Ruxton C. Towards a Healthier Britain. Proprietary Association of Great Britain (PAGB). 2010 .

4. Traber MG. Vitamin E. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins R, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore, MD: Lippincott Williams & Wilkins. 396-411. 2006.

5. Ibid.

6. Myint P, Luben R, Welch A et al. Am J Clin Nutr 87 :64-69. 2008.

7. Leggott P, Robertson P, Rothman D et al. J Periodontol 57 :480-485. 1986.

8. Hemila H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 1:CD000980. Jan 31 2013.

9. Ibid.

10. Bates B, Lennox A, Prentice A et al. National Diet and Nutrition Survey. Headline Results from Year 1, Year 2 and Year 3 (combined) of the Rolling Programme (2008/2009-2010/2011). Department of Health. 2012.

11. Xiao Q, Murphy R, Houston D,  et al. Dietary and Supplemental Calcium Intake and Cardiovascular Disease Mortality. The National Institutes of Health–AARP Diet and Health Stud. JAMA Intern Med. Published online February 4 2013. doi:10.1001/jamainternmed.2013.3283

12. Food Standards Agency. Survey on measurement of the concentrations of metals and other elements from the 2006 UK total diet study. Food Survey Information Sheet 01/09. London: UK. FSA:16-17, 37-45. 2009.

13. Bates B, Lennox A, Prentice A et al. National Diet and Nutrition Survey. Headline Results from Year 1, Year 2 and Year 3 (combined) of the Rolling Programme (2008/2009-2010/2011). Department of Health. 2012.

14. Bleys J, Navas-Acien A, Guallar E. Serum selenium levels and all-cause cancer and cardiovascular mortality among US adults. Arch Intern Med 168:404-10. 2008.

15. Akbaraly NT, Arnaud J, Hiniger-Favier I et al. Selenium and mortality in the elderly: results from the EVA study. Clin Chem 51:2117-23. 2005.

Note

All supplement claims are approved by the European Food Safety Authority  (EFSA). Vitamins and Minerals supplement the diet where there are dietary shortfalls; they are not intended to work like medicines.

Jonathan Falcone

Senior Account Executive

Jonathan Falcone <Jonathan.Falcone@nexuspr.com>

Further Information

The Health Supplements Information Service (HSIS) is an independent information body, set up to provide balanced information on vitamins and minerals. It is supported by a restricted educational grant from the Proprietary Association of Great Britain (PAGB). HSIS may be contacted on Tel: 020 7052 8955; www.hsis.org.uk.