The Facts About Omega-3 Fatty Acids and Increased Prostate Cancer Risk

A study released this week, “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial,” published in the Journal of the National Cancer Institute (JNCI)) suggests that the omega-3 essential fatty acids EPA, DPA, and DHA - but not the omega-3 fatty acid ALA, found in flax, chia, hemp seeds, and nuts that have repeatedly been shown to lower prostate cancer rates - are somehow associated with increased risks of high-grade prostate cancer. At the same time, higher amounts of normally harmful trans fats in these subjects were associated with lower rates of advanced prostate cancer. [1] Because of the known limitations of this particular kind of study, all of these reported results were completely unproven, highly questionable, and highly unlikely to be true.

What kind of study was this? It is data mining of a previously published population study in which important variables and endpoints for fish oil's relationship to prostate cancer were not controlled, nor any cause and effect demonstrated. Because it is a secondary analysis of a largely epidemiological (population) study, it represents the lowest level of evidence in human studies because most relevant variables, confounding factors, and clinical endpoints are not systematically collected for proper analysis as they would be in an actual controlled clinical trial. Instead, the limited goal was to look for possible associations that were admittedly not rigorous enough to be considered as actual evidence of a causal relationship. As a preliminary study, it was consciously designed only to raise questions, rather than to provide answers, and it did accomplish that goal but also created a messy splash of misleading and over-emphatic headlines inaccurately suggesting that this one study somehow trumps many more robust clinical trials. So much for the media knowing of and respecting the Scientific Method. [2]

Dr Marilyn Glenville PhD, the UK’s leading nutritionist specializing in women’s health and former President of the Food and Health Forum at the Royal Society of Medicine, has noted some deficiencies in the current JNCI report; some examples: [3]

• “This is not a randomised controlled trial but a trial comparing Omega 3 levels in men with prostate cancer with healthy men. The men with prostate cancer had higher levels of Omega 3. But you cannot extrapolate cause and effect from this finding. It is like saying that if the majority of men with prostate cancer played tennis compared to healthy controls then tennis could trigger prostate cancer.”
• In 2009 the Harvard School of Public Health reported that “Omega 3 deficient diets cause up to 96,000 preventable deaths a year in the US. The researchers estimated the number of deaths resulting from 12 preventable causes and Omega 3 deficiency ranked as the sixth highest killer of Americans. A deficiency in these fats was classed as a bigger killer than high intake of trans fats.” [4]
• “…there are many cultures such as the Japanese who eat high amounts of oily fish containing Omega 3 fatty acids and yet have one of the lowest prostate cancer death rates in the world.”

Duffy MacKay, N.D., vice president, scientific and regulatory affairs of the Council for Responsible Nutrition, also noted some concerns with the report: [5]

• “Hundreds of studies over the past two decades have shown omega-3 fatty acids to have positive effects associated with cardiovascular health, perinatal health, inflammation, cognitive function, or cancer. Collectively, this body of research serves as the basis for numerous recommendations from respected organizations, scientific boards and healthcare practitioners that Americans get omega-3 fatty acids in their diets.”
• “While we encourage researchers to continue to study omega-3 fatty acids with an open mind, it is counterproductive when studying nutrition for researchers to promote their study as if it were the only piece of research that counts. In this case in particular, it is especially disingenuous for the researchers to make the kinds of assertions we've seen in the press, given their results are in stark contrast to previous epidemiologic studies that not only demonstrate no correlation between omega-3 consumption through fish and/or supplementation and the risk of prostate cancer, but in many cases also showed a protective effect against prostate cancer.”
• “One should also consider whether this study could have simply been measuring a biomarker reflecting recent intake of fish or fish oil supplements in a group of high risk cancer patients that had been told to increase their EPA and DHA levels, as compared to a group of non-cancer patients that had not been told to consume more EPA and DHA. Plasma levels of EPA and DHA reflect very recent intake and are considered a poor biomarker of long term omega-3 intake especially when compared to red blood cell levels, which reflect medium term intake. A single fish oil dose (or hearty serving of fish at lunch) results in >100 percent increase in plasma omega-3 levels. So looking at plasma levels in healthy and sick people may only provide insight into the recent habits of these individuals.”
• “The American Heart Association, the World Health Organization (WHO), the U.S. Institute of Medicine’s Food Nutrition Board (IOM FNB) and the 2010 Dietary Guidelines all have current policies advising Americans to eat more fatty fish to get the benefits of omega-3 fish oils. It is highly unlikely this one study will change that advice. Omega-3s can also be obtained by taking one of the many supplement products on the market. For those consumers who have concerns about prostate cancer or other questions about omega-3 fatty acids, we recommend speaking with your doctor or other healthcare practitioner.”

If you are a man and believe this report, then you’ll probably want to eat partially hydrogenated artificial trans fats instead of omega-3 fats for prostate health; though that change would greatly increase your risk of suffering far deadlier cardiovascular diseases, based on evidence from many clinical trials. But that would be ridiculous. In fact, many cultures around the world consume far more fish oil than Americans without having increased risks of aggressive prostate cancer; these include the Inuit people ("Eskimos"), Scandinavians, Southeast Asians, Pacific Islanders, Japanese, Filipinos, and others. 

In any case, in the absence of proper controls or any evidence of causation, we actually can’t know what these study results really mean. For example:

• Were DHA levels related to diet, supplementation, or both?
• Were fish and/or fish oils perhaps consumed as a deliberate health choice because of prior knowledge of prostate issues, rather than actually causing or aggravating those issues? In other words, could the consumption represent an attempt to improve a pre-existing condition by improving one’s nutritional status and be unrelated to the disease itself? Perhaps even suggested by medical teams as potentially helpful for patients' diet?
• If they had been collected, what would key inflammatory and oxidative markers, that are much likelier to be related to prostate health problems than long-chain omega-3 fatty acids such as DHA, have told us about these men’s state of health and disease?
• Where is the biochemical evidence that DHA itself may negatively contribute to prostate concerns? None is presented, even theoretically.

The Global Organization for EPA and DHA Omega-3s (GOED) also criticized these and numerous other some aspects of the JNCI report, among them these important points: [6]

• “The difference in mean blood plasma phospholipid fatty acids blood level for omega-3s was 4.66% in the combined cancer group versus 4.48% in the control. They are basing their results on just ca. 0.2% difference in omega-3 levels.”
• “Plasma phospholipid fatty acids as measured in this study are not a good index of long term intake and are influenced dramatically by a single meal, or even timing of a fish oil dose. A single fish oil dose massively increases LC omega 3 (typically increasing levels by 100% or more) in about 4-12 hours and then washes out around 48 hours.”
• “The study was not designed to look at omega-3 and confounded with selenium and Vitamin E used in the treatment arms.”
• “The test cohort included sick and healthy people. It is possible that sick people were taking fish oil supplements at a higher rate than the healthy individuals.”
• “A recent meta-analysis of fish consumption and prostate cancer by Szymanski et al. (2010) reported a large reduction in late stage or fatal prostate cancer among cohort studies." [7]
• "Several population based studies have shown a benefit of increased omega-3 fatty acid intakes to reducing prostate cancer risk.” [8]^, [9]

As I said earlier, this type of study raises questions about possible associations; but due to its built-in limitations, and results conflicting with most other related studies, provides no real answers.  Unfortunately, its counter-intuitive results generate sensational press coverage rarely accompanied by any true perspective on what this new study really means (not much).

In real life, most Americans and others in Western societies no longer consume the ideal amount or ratio of omega-3 fatty acids in their diet as our ancestors did a century or two ago. This reduction reportedly contributes to the large increase in chronic health problems that plague these societies. It is a public disservice to inappropriately scare people away from healthy foods and supplements, which help balance the diet in these many cases where the lack of essential nutrients is actually causing harm, based solely on such flimsy “evidence”. 

After reviewing this study I, a vegetarian, will continue to take my vegan DHA supplement twice a day with absolutely no concerns that it will negatively affect my own prostate health. Why am I not at all concerned? Because there is still no hard evidence explaining how long-chain omega-3 fatty acids like EPA and DHA may promote prostate cancer. There is still no demonstrated mode of action for this concern, and there are still no plausible explanations of any biological mechanisms that could justify the theory that long-chain omega-3 fatty acids may promote prostate cancer. My lack of concern is evidence based, after carefully reviewing the studies in question. Contrast this with the fear-mongering about fish, fish oil, and omega-3 fatty acids in foods and supplements that is overwhelmingly based on speculation, flimsy data, ignorance (on several levels), and maybe even some bias.

By Neil E. Levin, CCN, DANLA

REFERENCES:

[1] http://www.newswise.com/articles/view/605211/?sc=rssn&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+NewswiseScinews+%28Newswise%3A+SciNews%29

[2] http://teacher.nsrl.rochester.edu/phy_labs/appendixe/appendixe.html

[3] http://www.hfma.co.uk/docs/Omega_3_and_Prostate_Risk-July2013.pdf

[4] The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors" study, April 2009, PLoS Medicine

[5] http://www.crnusa.org/CRNPR13-Omega3071113.html

[6] http://us1.campaign-archive1.com/?u=4ae075406cd789efec4e9ff09&id=6f3dc7a018&e=1704ffc192

[7] Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92(5):1223–1233

[8] Terry P, Lichtenstein P, Feychting M, et al. Fatty fish consumption and risk or prostate cancer. Lancet, 2001,357:1764-6.

[9] Lietzman MF, Stampfer MJ, Michaud DS, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr 2004;80:204-216.

Prenatal vitamins lower autism risk in children

Taking prenatal vitamins lowers the risk of having an autistic child by 700% for genetically susceptible mothers. http://www.sciencedaily.com/releases/2011/05/110525112109.htm

Calcium & Cardiovascular Health: My review of the latest meta-analysis

At the end of July (2010) there was another nasty swipe at dietary supplements (Natural Health Products, for our Canadian friends). Again, the negative report came not from a single study, but from a particularly troubling type of report called a meta-analysis. Rising like a spider on a lethal web, this type of report keeps popping out of nowhere, attempting to make connections between studies where none may have been found before. In fact, we rarely see a competently designed meta-analysis on nutrients because there are many variables that come into play that simply don’t exist for isolated pharmaceutical drugs that aren’t (or at least aren’t supposed to be) present in our normal food supply. The interplay of nutrients affects each others’ metabolism, serum levels, and activities in a live human body. So when I see yet another meta-analysis getting major press coverage based on fairly flimsy evidence, I cringe and wonder why researchers and journalists fail to see the obvious flaws in their big story. Perhaps drug researchers are trying to branch out into nutrient research and just get in over their heads because they fail to see the complexity of nutrient research design.

The alleged danger this time: supplemental calcium was associated with a 30% increased risk of myocardial infarction, so the risks now outweigh the benefits. But was this proven? NO! Absolutely not. Nada. Zilch. Even the authors of this analysis know better than to claim that their report was definitive proof of these alleged dangers.

First of all, there was no increase in deaths in the groups given supplemental calcium. There was an increase in non-fatal heart attacks; but only in people who had already high calcium intake from their diets and also took high doses of supplemental calcium that they apparently didn’t need. And there was no problem demonstrated when calcium was given along with supplemental vitamin D, so maybe the problem was really that some folks had inadequate levels of that essential vitamin to deal with a high calcium intake.

But since vitamin D is both in the diet (as is calcium) and made from sunshine under the right conditions, these meta-analysis authors don’t really know how much vitamin D these people actually had, confounding their data. They don’t know because it would have required a rigorous study design that looked at all three intakes: food, supplements, and sunlight exposure at the times of day and year where vitamin D could be internally produced. Or at least measuring the serum before treatment to detect vitamin D levels and eliminate that as a variable. But that wasn’t done, perhaps because these researchers only looked at other people’s studies rather than running a human clinical trial themselves.

This points out perhaps the major problem with this type of study: since a meta-analysis is only a statistical model that cannibalizes previously published work to “mine” data in ways that were not planned by the original study designers, it has many built-in limitations. For example, cardiovascular outcomes were admittedly not intended as the primary endpoints in any of the 15 studies ‘Mixmastered’ together to make up this meta-analysis, so data on cardiovascular events were not gathered in the usual standardized manner. In plain English: the few cherry-picked studies included in this report had not done the type of standardization and control of variables needed to properly design a robust cardiovascular study because the original studies actually were looking at calcium’s effects on bone health, not heart health. This was, in fact, an admitted limitation of the current meta-analysis.

A good meta-analysis tries to pick the largest possible number of studies with similar designs to pool their results and in effect try to get a larger, hopefully more significant number of virtual test subjects. The farther from that model the meta-analysis gets, the more variables get introduced to confound the researchers. And since control of variables is the essential competence of the scientific method, we unfortunately find that an inexpertly executed meta-analysis is a misleading and erroneous scientific tool; like a ruler that has not been calibrated correctly and implies that our measurements are accurate when they may be way off the mark.

Researchers utilizing the imprecise tool of meta-analysis should not delude themselves that their work is definitive, because it almost never is. Nor should they become media darlings because they have espoused new theories - based on an unproven brew of mathematical models - that usually are already contradicted by a lot of better designed primary science. Nor should their attempts to re-examine previously published studies for results which were never intended to be measured scare us away from taking essential nutrients, which are commonly more healthful than harmful. As the current meta-analysis reported, the problem was that people who ate a lot of calcium who also took a lot of supplemental calcium without the benefits of taking vitamin D or other bone-forming cofactors had more non-fatal heart attacks. No one died. This implies that, at the most, one should not take a single nutrient in excess as if it were a magic drug, especially when they probably already get plenty in the diet. Don’t most of us know that already?

Nutrients are synergistic; therefore an imbalanced diet, including unneeded supplements that may tilt one even more into imbalance, may not properly support good health. Heck, I could have told you that before all this media fuss. But, with enough vitamin D the problem magically disappeared!. Supplementation of vitamin D apparently re-established good calcium metabolism, even at high levels of intake. The true issue then isn’t so much related to variations in calcium and vitamin D supplies, not to mention the unknown availability of other essential bone nutrients. It’s the misapplication of a drug model to a nutrient while ignoring known variables that affect the body’s proper use of that nutrient. One shouldn’t give a lot of calcium to those with adequate dietary intake, nor to those with insufficient vitamin D (and K, magnesium, et al) intake. This type of thought process is elementary to a nutritionist, of course, but apparently not to the well credentialed authors of many flawed drug model meta-analyses and their often overreaching conclusions.

You may be interested to know that a world-class researcher who has been working on calcium metabolism and osteoporosis for more than 50 years, the respected scientist who drafted the World Health Organization’s dietary calcium recommendations, strongly opposed the conclusions of the current calcium meta-analysis. Professor Chris Nordin from the Royal Adelaide Hospital in Australia was interviewed by ABC News. This news report cited Professor Nordin as saying that the meta-analysis was misleading because it improperly included studies involving a mixture of men and women, and the findings were not statistically significant. "Men are much more liable to heart attacks than women but women need calcium far more than men, so it is absurd to publish a study of the effect of calcium on the heart without separating men from women," he was quoted. Professor Nordin noted the fact that calcium supplements are predominantly recommended for and used by postmenopausal women because their bone loss is due to an increase in bone breakdown, which responds well to calcium supplementation (and vitamin D, if necessary). But he reports that calcium is seldom recommended for elderly men because their bone loss has a different cause, which is seldom caused by a need for more of that mineral. "Concluding that calcium supplements can lead to a 30 per cent increase in heart attack risk is quite premature and alarmist and can only set back the cause of osteoporosis prevention which should be our primary objective," he said.

According to ABC News, Osteoporosis Australia has also questioned the findings of the meta-analysis because many long-term studies have shown calcium supplements are safe and effective. In a statement posted on its website, Osteoporosis Australia says the weight of evidence to date indicates no increased risk of heart attacks from taking calcium supplements, which it says are an effective way of reducing fracture risk and bone loss in older men and women who have diets low in calcium.

This should point out the folly of well-meaning researchers who design studies to investigate topics that they don’t properly understand. In those cases, they simply don’t realize that there are other essential factors that can change everything and require a completely different and more comprehensive study design. That’s par for the course when meta-analyses are used to sort through previously published nutrient studies. Basic design flaws often make meta-analyses fatally flawed, despite the apparently sophisticated mathematical models and methods that researchers incorrectly try to apply to the data. Is it any wonder that we’re so confused about nutrition when researchers gain worldwide prominence for issuing highly questionable sensational reports that contradict the scientific consensus - but never have to say they’re sorry?

Calcium does not cause more heart attacks in well-designed primary human clinical studies. Healthy people should not be concerned about taking essential nutrients just because certain studies were flawed or performed on sick or at-risk populations and may have had negative results. Many of those negative reports have been challenged and may not have been verified and replicated in well designed clinical trails. The conclusions of such reports are sensational and well publicized precisely because they seem to negate our previous scientific consensus; which should make them more, not less, suspect. But the modern news cycle seems to thrive on such controversy, without caring how confused we get about what’s healthy and what’s not. But don’t worry; you have Honest Nutrition to help you sort it all out!

REFERENCES:

Bolland MJ, Avenell A, Baron JA, Grey A, Maclennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691. doi: 10.1136/bmj.c3691. PubMed PMID: 20671013.

http://www.bmj.com/cgi/content/full/341/jul29_1/c3691?view=long&pmid=20671013

http://www.abc.net.au/news/stories/2010/08/03/2972399.htm?section=justin

Risk factors in developing Type 2 (adult-onset) diabetes

Improper diet and lack of exercise are major risk factors in developing Type 2 (adult-onset) diabetes. Prolonged stress and too high proportions of carbohydrates (carbs) in the diet also contribute to blood sugar problems. The problem carbs are excess levels of sugars – especially simple sugars - and starches. Complex carbs from vegetables, whole fruits, whole grains and beans are used to fuel brain activity and other body functions without excessively elevating our blood sugar. Fiber content will also help the ability of food to make us feel full. Fiber also helps to slow the introduction of other carbohydrates into the bloodstream, reducing blood sugar “peaks” after a meal. Another bonus of whole foods is that fiber can absorb cholesterol-containing bile salts, a key way to dump excess cholesterol from the body.

Eating a diet composed largely of processed/refined foods means that the carb level is probably too high while nutrients that help us to deal with blood sugar (B vitamins, fiber, chromium, etc.) are stripped from our food supply. This leaves us defenseless against weight gain, abdominal obesity, high blood pressure, high blood sugar and elevated stress hormones.

Many of us are literally drowning in excess empty calories that affect our metabolism. But skipping meals doesn’t help, nor does eating meals that lack adequate protein. Both habits discourage calorie burning.

Spikes in blood sugar are the main enemy of dieters and those with blood sugar control issues. Elevated blood sugar triggers the release of the hormone insulin, which can cause low blood sugar (hypoglycemia), which makes us fatigued after a meal. If this happens too often it can create insulin resistance, eventually causing a loss of blood sugar control that can result in Metabolic Syndrome. This is a pre-diabetes condition defined as a combination of two or more of these symptoms: insulin resistance, glucose intolerance, abnormally high insulin levels, high triglycerides, low high-density lipoprotein (the "good" cholesterol), and hypertension (high blood pressure). Metabolic Syndrome increases belly fat and is a step towards developing adult-onset diabetes.

Your options are greatest when you first discover that your blood sugar has gone out of balance. If you wait until after you're on insulin or other medications, any natural means for improvement in blood sugar control could cause a dose of medicine to become an overdose. It is very important that your physician knows if you are going to try to control your blood sugar naturally, and that you test your blood sugar levels every time before taking medication in order to avoid dangerous interactions.

Going on a low-carbohydrate (low-carb) diet is the next step. The worst carbs are the simple sugars, found in processed foods, sweets, table sugar and soda pop. Processed grains and starchy vegetables are sometimes a problem, especially in excess. Flours (especially white flour) are more of a problem than whole cooked or sprouted grains. Even carrot juice is high in sugar!

If you tend to have weight gain and blood sugar problems in middle age, the good news is that you are genetically programmed to survive a famine. The bad news is that it's a prolonged feast which can kill you! Portion control and exercise are important for your health. Controlling stress will also help your sugar balance.

The balance of nutritional components within a meal regulates fat storage and fat burning. Try to balance each meal using the ZONE diet, where at least 30% of the calories in every meal are from protein, about 30% from healthy fats and about 40% from complex carbohydrates such as whole grains, fruits or vegetables. This balance will minimize blood sugar increases. Blood sugar spikes can lead to more fat storage and less fat burning, especially without enough protein to start the calorie burning cycle after a meal.

To improve the insulin response that moves sugar out of the blood and into cells for fuel instead of turning into fat, supplements of Omega-3 fish oil (or flax oil for vegetarians), Alpha Lipoic Acid and Chromium may be helpful. Phase 2®, from a white kidney bean extract, will block some digestion of starches to sugar and therefore effectively lower your carb and calorie intake. Antioxidants of all kinds are very protective for people having blood sugar issues.

Take a good multiple vitamin with a fat-containing meal to enhance absorption of the fat-soluble nutrients. If you take green foods or other nutritionally dense dietary supplements, also take them with a meal to help increase the total nutritional value of that meal.

Beta-carotene risks over-stated

Beta-carotene risks over-stated By Neil E. Levin, CCN, DANLA A recent journal article pointed out the widely-reported danger of smokers using beta-carotene, a natural source (provitamin) of vitamin A, as part of their multivitamins. 1 In this meta-analysis the researchers have neglected to consider pre-existing dietary and serum levels of this nutrient, making their claim to control by placebo inadequate to properly isolate this variable. In fact, this failure to determine the effects of beta-carotene at a dose-dependent plasma level – and by neglecting to measure total beta-carotene intake along with the relevant synergistic antioxidants associated with it, as opposed to simply measuring supplemental intake - raises serious questions about the validity of these results. 2 There is also legitimate scientific debate over the use of trans versus cis forms of this provitamin that may affect the way it is used in vivo that dispute whether all forms are equal, which most studies simply do not address (including this meta-analysis). 3 Regarding beta-carotene safety little has been satisfactorily resolved, and the negative studies have been vigorously disputed for these and other reasons. For example, researchers have previously noted in the Journal of the National Cancer Institute that beta-carotene has been shown to not affect the risk of oxidative DNA damage in male smokers, despite its reputation as an antioxidant. But neither did the provitamin A prove to cause oxidative DNA damage. 4 It has become apparent to numerous observers that simply measuring supplementation of beta-carotene is not a good predictor of serum levels or of risk, and that a low level of total antioxidant intake may be a more valid marker in this regard. In fact, the dietary level of several antioxidants has been shown to be an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A recent study reports, “This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.” 2 As the authors (Tanvetyanon, et al) of this current analysis have themselves noted, the Physicians Health Study compared the effects of taking 50 mg of supplemental beta-carotene (over 83,000 IU) every other day to a placebo in 22,071 US male physicians aged 40-84 and found no adverse health effects over a 12-year study period. 5 Likewise, the Women’s Health Study of 39,876 health professionals found no significant difference on lung cancer rates when looking at the effects of 50 mg of beta-carotene administered on alternate days over 2+ years plus a 4 year follow up period, using forms and dosing similar to the Physician’s Health Study to achieve very high serum levels of beta-carotene. 6 In a third study used in the current meta-analysis, The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (ATBC), an antioxidant study in Finland was halted early because of a widely reported small increase in cancer rates among male smokers taking beta-carotene that were only possibly linked to that nutrient. 7 Headlines associated this supplement with cancer risk. Despite objections that the study was flawed, beta-carotene use dropped. This study continues to be widely cited and believed, despite the researchers’ own statements that the results were most likely due to chance. A later analysis published in July 2004 took another look at that same Finnish smokers study’s data, but now taking into account total antioxidant intake, which should have cleared away some of the scientific controversy over beta-carotene. The smokers’ risk of getting lung cancer was inversely associated with total antioxidants in the diet, with more total antioxidants resulting in fewer cancers. 8 In this study a composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: a combination of antioxidants lowered lung cancer risk in male smokers. Properly reviewed, beta-carotene was not the culprit; low antioxidant status was the more relevant factor affecting cancer rates, and supplementation with a single antioxidant supplement simply failed to create enough improvement to avert deaths related to oxidative factors. Perhaps the supplementation with beta-carotene was simply a case of “too little, too late”, rather than a root cause of a slightly higher lung cancer rate in those smokers. It is notable that Tanvetyanon et al included the ATBC study but failed to even reference the later Wright et al study that largely refuted the alleged harms of beta-carotene shown in ATBC, which were shown to be more likely due to low levels of total antioxidant intake than to excessive beta-carotene intake. This later review of ATBC should be a cautionary tale concerning the lack of proper controls in nutrient studies, especially as compounded by the use of meta-analysis, and should have alerted the current authors to that all-too-common mistake in nutrient study design. Indeed, another large study has noted that high carotenoid intake, confirmed by measures of plasma, was associated with lower mortality rates among the elderly over a ten year period. 9 This model measured results of consuming both supplements and foods, not solely supplement input, and when combined with plasma levels should therefore be regarded as a far more robust type of science for measuring vitamin effects than a meta-analysis of simply supplementation. As in the long-term Physicians Health Study, there was no observable risk of lung cancer noted in this report. The fourth study used in the current meta-analysis used very high doses of both beta-carotene (30 mg, equal to 50,000 IU) plus 25,000 IU of pre-formed vitamin A. 10 These amounts are extremely high; the Upper Limit for vitamin A is 10,000 IU, though there is none for beta-carotene because of its historic safety record. The amount of beta-carotene used in the eye vitamins were high only because the authors selected solely formulas designed for eye health that typically provide more beta-carotene than ordinary multivitamins. This distinction is not clear in their calling such formulas “multivitamins”, because that name is typically given to full-spectrum formulas containing a full range of the essential vitamins with minerals, not system-specific formulas like those sold for eye health. Such formulas have proved to be beneficial in maintaining eye health and the combination of antioxidants have been stronger antioxidants than beta-carotene, which is potentially a pro-oxidant at times and could thus be used more safely – and effectively - in combination with other antioxidants. 11 Most importantly, the authors have not shown why they assume that “multivitamin” use would be associated with the supposed risks of beta-carotene used singly, even if those risks for the solo provitamin are assumed to be true. Nor have they adequately demonstrated the alleged dangers of taking eye formula supplements, or even the danger of lung cancer rates increasing in those taking mixtures of beta-carotene combined with other antioxidant nutrients. In the case of multivitamins most studies have shown overwhelmingly positive effects, such as one report evidencing reduced infections in nursing homes with vitamins over placebo (73% vs. 43%; P < 0.001). Intervention was with a multivitamin containing beta-carotene. Infection-related absenteeism was higher in the placebo group than in the treatment group (57% vs. 21%; P < 0.001). Perhaps most importantly, 93% of participants with diabetes mellitus reported an infection versus only 17% of those receiving supplements (P < 0.001). 12 These huge reductions in potentially serious infections among our elderly citizens should be measured against the relatively slight and mostly theoretical risk of increased lung cancer rates associated with beta-carotene supplementation. A study reported in the Journal of the National Cancer Institute looked at death rates in a population given multivitamins or other nutrients. 13 After supplements were given for 5.25 years in the general population trial of 30,000 people, significant reductions in total [relative risk (RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium combined. The same researchers reported on a subgroup of 3,318 persons with esophageal Dysplasia (a precursor to esophageal cancer) that was given either a multiple vitamin-and-mineral supplement or a placebo for 6 years. In this portion of the trial, small reductions in total (RR 0.93) and cancer (RR = 0.96) mortality were observed but were not significant. In any case, no increase in cancer rates was noted in the group taking multivitamins; there was actually a possible small benefit in terms of reducing this risk. The participants getting the multivitamin took a daily beta-carotene capsule along with two multivitamin tablets. This was a group of subjects at high risk of getting throat cancer. 14-15 It is a leap of faith to assume that a single nutrient would have identical effects to a combination of nutrients without substantial supporting evidence, which is still lacking; confounded by conflicting evidence and multiplying variables in meta-analyses. Since nutrients are both synergistic and present in the diet, it is important to factor those known variables into a proper study design. All too often, researchers do not consider this fundamental difference between drug and nutrient research and unwittingly introduce extra variables that undermine their conclusions. 16 This current meta-analysis of 4 studies - only one of which unquestionably shows a slight increase in lung cancer risk but does not actually measure isolated beta-carotene risk; two others are well-designed and robust studies looking at serum levels of those taking a high dose of beta-carotene but show no increased risk in lung cancer rates, and the fourth has been largely shown to be moot by a later and more complete re-analysis of the data - does not support the hypothesis that beta-carotene increases rates of lung cancer and that multivitamins are therefore dangerous. Thus, there is no sound basis in the current review for suggesting that warning labels may be needed for multivitamins or eye health supplements containing beta-carotene along with other nutrients that have been shown in well-designed studies to help protect the eyesight – and independence - of our aging population. REFERENCES: Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer. 2008 Jul 1;113(1):150-7. PMID: 18429004 Valtueña S, et al. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. Eur J Clin Nutr. 2007 Jan;61(1):69-76. Epub 2006 Jul 12. PMID: 16835597 [Supported by the European Community IST-2001–33204 'Healthy Market', the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.] Andreas Schieber, Reinhold Carle. Occurrence of carotenoid cis-isomers in food: Technological, analytical, and nutritional implications. Trends in Food Science & Technology, Volume 16, Issue 9, September 2005, Pages 416-422 van Poppel G, Poulsen H, Loft S, Verhagen H. No influence of beta carotene on oxidative DNA damage in male smokers. J Natl Cancer Inst. 1995 Feb 15;87(4):310-1. PMID: 7707423 Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1145-9. PMID: 8602179 Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999 Dec 15;91(24):2102-6. PMID: 10601381 The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994 Apr 14;330(15):1029-35. PMID: 8127329 Wright ME, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004 Jul 1;160(1):68-76. PMID: 15229119 Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr. 2005 Oct;82(4):879-86. PMID: 16210720 Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155. Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt. 2003 Sep;23(5):383-99. Review. PMID: 12950886 Liu BA, et al. Effect of multivitamin and mineral supplementation on episodes of infection in nursing home residents: a randomized, placebo-controlled study. J Am Geriatr Soc. 2007 Jan;55(1):35-42. Erratum in: J Am Geriatr Soc. 2007 Mar;55(3):478. PMID: 17233683 Blot WI, Li IY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993:8ı:1483-92 Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993 Sep 15;85(18):1492-8. PMID: 8360932 Blot WI, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995 Dec;62(6 Suppl):1424S-1426S. PMID: 7495242

A Tale of Two Studies: Vitamin E - Food vs Supplements

Vitamin E: Food vs Supplements Here is an illustration of the apparent contradiction between whether food sources of vitamin E are better to prevent prostate cancer than supplemental vitamin E sources: Two large studies, both published in the same technical journal at the same time, seem to reach contradictory results as to whether supplemental vitamin E is valuable in relation to prostate cancer. But are they both equal and contradictory? Actually, one is far more rigorous, and thus presumably more valid, than the other. In the first one (Serum and Dietary Vitamin E in Relation to Prostate Cancer Risk <1>), definite and large benefits were shown for supplemental alpha-tocopherol vitamin E, but not for food sources (containing mostly gamma-tocopherol). In the second one (Supplemental and Dietary Vitamin E Intakes and Risk of Prostate Cancer in a Large Prospective Study <2>), only food sources containing gamma-tocopherol were effective, but not supplemental vitamin E as alpha-tocopherol. A closer look reveals that the first study responsibly looked at serum levels and food plus supplemental vitamin E intake, then related that data to prostate cancer rates over up to 19 years afterward. This study's conclusion was that, "In summary, higher prediagnostic serum concentrations of alpha-tocopherol, but not dietary vitamin E, was associated with lower risk of developing prostate cancer, particularly advanced prostate cancer." The second study looked only at questionnaires related to subjects' intake of vitamin E from food and supplements at the start of the 5-year study, then compared the number of cancers over a 5-year period to data obtained from that questionnaire. The incubation period for cancers is estimated to be in the decades, rarely a period of 5 years or less. That, along with the lack of any data on serum antioxidant status and the use of a questionably reliable survey to determine intake of vitamin E from food or supplements, makes the second report far less meaningful than the first one. Don’t get me wrong, I am not against food sources of nutrients and routinely recommend vitamin E sources containing gamma-tocopherol, along with the full range of tocopherols and tocotrienols. But when preliminary or sketchy science is all-too-often reported as if it’s definitive when it’s really not, and when it is contradicted by better science, I am compelled to put things into a more realistic perspective. The measurement of serum levels in the body, along with careful reporting of a nutrient’s intake from various sources, is much more compelling than relying on a questionnaire that may be done by memory. It is well-known among nutritionists that daily food diaries are notoriously different than weekly food surveys done by memory recall, which almost always seem to conveniently forget the junk food, snacks and extra calories. A cancer study lasting nearly 4 times as long is also far more compelling than a shorter one because it will be more likely to encompass the cancer’s incubation period and allow for the development of symptoms that will allow detection. As the National Cancer Institute reports: “Prostate cancer often does not cause symptoms for many years.” <3> The use of supplemental alpha-tocopherol is supported by other reputable studies. For example, The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study demonstrated a 32% reduction in prostate cancer incidence in response to daily alpha-tocopherol supplementation. <4> Levels of Vitamin E above 100 IU daily are associated with decreased risk of coronary heart disease and certain types of cancer, as well as enhancement of immune function. These increased vitamin E intakes (100 I.U. and above) are considerably above levels obtainable from diet alone. <5-7> In the case of supplemental vitamin E, the results for prostate cancer in the more rigorous, better designed and better implemented study shows that it is more beneficial for prostate health than only food sources of vitamin E, which also tend to be much weaker amounts (often far below 100 IU daily, with Americans’ typical intake being only around 9.5 IU (6.4 mg) of alpha-tocopherol, below the RDA of 22.5 IU (15 mg). <8-9> This indicates our general need for supplemental vitamin E, unless by some miracle we all suddenly decide to eat wholesome natural foods containing a lot more vitamin E. But in the meantime, it would be nice if these studies were put into perspective so we could accurately assess their value to our health habits. Unfortunately, media coverage of negative reports, especially regarding vitamins, tends to drown out the positive ones, even when the good news is backed by studies with better design and implementation. In this case, supplemental vitamin E was the clear winner over the abysmal amounts in our diet, which ideally should be increased to healthy levels. REFERENCES: 1. Weinstein, SJ, et al. Serum and Dietary Vitamin E in Relation to Prostate Cancer Risk. Cancer Epidemiol Biomarkers Prev 2007 16: p. 1253-1259 http://cebp.aacrjournals.org/cgi/content/abstract/16/6/1253?ct 2. Wright, ME, et al. Supplemental and Dietary Vitamin E Intakes and Risk of Prostate Cancer in a Large Prospective Study. Cancer Epidemiol Biomarkers Prev 2007 16: p. 1128-1135 http://cebp.aacrjournals.org/cgi/content/abstract/16/6/1128?ct 3. National Cancer Institute’s Web site http://www.cancer.gov/cancertopics/factsheet/Detection/early-prostate 4. Weinstein SJ, et al. Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study. J Natl Cancer Inst. 2005 Mar 2;97(5):396-9. PMID: 15741576 5. Bauernfeind, J. Tocopherols in Foods. In: Vitamin E: A Comprehensive Treatise. Marcel Dekker, Inc., New York and Basel, pp. 99-167, 1980 6. Horwitt, M.K. The Promotion of Vitamin E. J. Nutr. 116:1371-1377, 1986 7. Weber, P., Bendich, A. and Machlin, L.J. Vitamin E and Human Health: Rationale for Determining Recommended Intake Levels. Nutrition 13:450-460, 1997 8. Ervin RB, Wright JD, Wang CY, Kennedy-Stephenson J. Dietary intake of selected vitamins for the United States Population: 1999–2000. Advance data from vital and health statistics; no 339. Hyattsville, Maryland: National Center for Health Statistics. 2004 9. Vitamin E, Office of Dietary Supplements • NIH Clinical Center • National Institutes of Health http://ods.od.nih.gov/factsheets/vitamine.asp

Am I biased?

A reader of my nutrition blog wondered if I may be biased. That's a fair question. Actually, I believe that everyone has to deal with the issue of bias, and the Scientific Method is supposed to help us all overcome these biases by focusing on valid, reproduceable data. Unfortunately, some of us seem to be trying harder than others to fairly represent unbiased data. For one example, my letter published by the cancer journal CA, the Journal of the American Cancer Society http://caonline.amcancersoc.org/cgi/eletters/55/5/319#176 rebutted an article positing that antioxidants should be avoided during cancer therapies. However, none of the references provided in that article showed any evidence of risk! In my rebuttal, I catalogued a number of studies that used nutrients with drugs or radiation therapies, which showed no harmful effects and in some cases even enhanced anticancer effects. I also pointed out the 40% of cancer patients who die of malnutrition while under their doctors' care, much of which may be preventable if physicians actually follow evidence-based medicine instead of clinging to conventional therapies and theories. Click on the title of this article to see the original report and my response. I think that you'll find that I presented relevant published scientific reports to counter a biased opinion that was not even supported by the author's references. How did that crappy opinion even get published in a peer-reviewed journal in the first place?