Published in medi.philica.com
Increasingly, evidence is being accumulated that points out the ineffectiveness and the dangers of antioxidant vitamins, such as vitamins A, C and E. Since there is such widespread use of these vitamins, we can no longer ignore these warnings or attempt to explain them away as paradoxes. Large randomized, controlled trials (RCTs) are clearly showing significant antioxidant harm, particularly for beta carotene and vitamin E. Because of the large volume of data available, there is likely a developing legal liability associated with the unrestrained use of antioxidant vitamins. Intense marketing has promoted the concepts advocated by the flawed free radical theory, which, through testing, has been effectively falsified by scientific evidence demonstrating its lack of predicted efficacy for the antioxidant vitamins. Because of the cumulative data, one can now conclude that antioxidant vitamins are harmful, they should be regulated and the public should be informed of such actions. Addition or fortification of these agents to foods should be avoided or prohibited until appropriate safety measures are instituted. A paradigm shift is occurring away from the alleged damaging character of oxidants and away from the overly hyped benefits of the antioxidant vitamins. Global orthodoxy is gradually turning towards an appreciation of prooxidant protection against pathogens and neoplasia. I propose an explanation for the ill effects of antioxidant vitamins, in that they help create an electronically modified oxygen derivative insufficiency state, which allows for the manifestation of a variety of diseases and a shortened life span.
Antioxidants and empty promises
More than 25 million Americans, or 12 percent, are diagnosed with heart disease, according to the U.S. Centers for Disease Control and Prevention's (CDC) National Center for Health Statistics. It is the No. 1 killer in the United States of America.
The promises antioxidant vitamins held for the control or even elimination of a wide variety of diseases have come up empty due to the fact that their anticipated benefits were based on the erroneous free radical theory. 1-8 This issue is discussed in detail and is available in "The Howes Selective World Library of Oxygen Metabolism at the www.thepundit.com website.
Overly exuberant and exaggerated past expectations and claims of the free radical theory have been quieted by extensive randomized, double-blind, controlled human studies (RCTs). The free radical theory 1 is a testable theory. A half century of data has demonstrated its lack of predictability. Thus, it has been discredited by the scientific method. 2 Widespread use of antioxidants has failed to quell the current pandemic of cancer, diabetes, and cardiovascular disease or to stop or reverse the aging process. 8
On February 15, 2007, I had posted on the Philica.com website an article entitled, "Antioxidant vitamins A, C and E: Assessing potential for harm" 46 in which I discussed these very issues. A review by Bjelakovic et al.was published on Feb. 28, 2007 and it has provided significant additional information upon which to base conclusions regarding the harmful nature of antioxidant vitamins. 10 This additional data has solidified my position, based on years of research, that antioxidant vitamins are, indeed, harmful and should be regulated.
Antioxidant vitamins increase mortality and fail to decrease aging
Antioxidant supplements have failed to decrease cardiovascular risk in extensive human clinical trials to date. Paradoxically, many well-established components of the heart-healthy lifestyle are prooxidant, including polyunsaturated fat, exercise and moderate alcohol consumption. Oxidation includes distinct and specific biochemical reactions, and it is overly simplistic and incorrect to gather them into a unitary process that affects all cell types and metabolic pathways adversely. Guidelines for diet should emphasize safety and adhere closely to what has been clinically proved, and by this standard there is no basis to recommend antioxidant use, beyond what is inherent to the 'heart healthy' diet in order to benefit cardiovascular health. 9
Danish researchers have warned that consumers should be cautious about taking supplements containing nutrients. Supplements that millions of North Americans take to stave off disease and slow the aging process do not boost longevity and appear to actually increase the risk of dying. Bjelakovic's analysis, which pooled data from 68 studies involving more than 232,000 people, found no evidence that taking beta-carotene, vitamin A or vitamin E extends life span. 10
In fact, Bjelakovic's analysis found that beta carotene, vitamin A and vitamin E, taken singly or combined with other antioxidant supplements, were associated with increased all-cause mortality. Conservatively, the supplements increase the likelihood of dying by about 5 percent. Vitamin C and selenium appeared to have no impact on longevity.
According to Bjelakovic's study, vitamin supplements taken by millions of people every day for their health are increasing their risk of death. The international research team, led by Dr. Goran Bjelakovic, reviewed the published evidence on beta carotene, vitamin A, vitamin E, Vitamin C and selenium. These dietary supplements are marketed as antioxidants and people take them in the hope they will improve health and guard against diseases like cancer and heart disease by eliminating the oxgen free radicals that cause so-called "oxidative stress" and allegedly damage and/or kill cells. Antioxidants are also marketed as anti-aging products because they were thought to slow down the aging process but this is not supported by current scientific studies in man. To the contrary, antioxidant vitamins have proven to have undesirable effects.
In this study, 10 Dr. Bjelakovic and colleagues did a meta-analysis on research published before October 2005. The researchers followed a method established by the Cochrane Collaboration, a group of 6,000 health care specialists who review biomedical trials and other research projects. They started with 815 clinical trials of which 68 passed the first level of quality standard (68 randomized trials with 232,606 participants (385 publications). At this level the results were inconclusive. The supplements were found to have no effect on death risk one way or the other. They then went back and eliminated 21 of the trials, leaving only the "low-bias" ones. This was the next level of quality standard.
When looked at separately, they found that Vitamin A increased death risk by 16 per cent, beta carotene by 7 per cent and Vitamin E by 4 per cent. The results for vitamin C were somewhat unclear, but by looking at the best quality trials there was a suggestion that it increased death risk by 6 per cent, either on its own or in combination with other supplements. Duration of supplementation differed among the trials but duration had no significant effect on their results.
However, the figures from the best quality trials on selenium showed that it might reduce death risk by 10 per cent, either on its own or in combination with other supplements, but this was not found to be statistically significant. Selenium can be a prooxidant. The overall conclusion of the study was that on balance, the best quality research shows that beta carotene, vitamin A and vitamin E may increase mortality risk, but vitamin C and selenium need further study. Vitamin C can act as a prooxidant or an antioxidant in vivo. 11, 12
The researchers speculate that there are several potential reasons for these results. One is that the free radicals that are thought to cause the oxidative stress are the byproduct rather than the cause of disease. Another is that they may play an important role in the immune system and eliminating them could be counterproductive. I believe that the antioxidant vitamins interfere with prooxiant protection. 2-8, 41, 46 They added that this study is important for public health reasons because between 10 and 20 per cent of people in Europe and North America take dietary supplements.
Bjelakovic's findings contradicts the older findings of observational studies, which claimed that antioxidants improved health. 13-16 Some prior studies have resulted in no beneficial or harmful effect of the antioxidant supplements. 17-21
Whereas, other studies reported that antioxidant supplements significantly increased mortality and these findings bolster prior reports, which also showed increased mortality from antioxidants. 22-24 Bjelakovic stated that even though anitoxidants have been widely studied, only a few trials used adequate methodologies of analysis. 25, 26 Bjelakovic felt that there may be many unpublished trials but that their results were more likely to have been either neutral or negative than to have shown beneficial effects. 27
Relative to these studies, a co-author with Bjelakovic, Dr. Gluud, said these observations were "a huge disappointment," but added that at least it has been discovered. "We must see the positives in this. The question has been thoroughly addressed and we now know the answer - these agents (i.e., antioxidant vitamins) are harmful. The companies selling these anti-oxidant vitamins have been able to dodge the issue for a long time, saying that any negative data has not been comprehensive. They cannot do this any longer. There are lessons to be learnt here, for example, the importance of conducting trials with these agents and publishing the results."
Dr. Gluud added that food supplements should be regulated in the same way as medical products. "The governments of the world now have the responsibility to inform people of these results. They have been too slow in the past in requesting that health supplements are properly evaluated, and allowing these products to be added to foods. People have been buying these supplements and foods advertised as having these supplements added under the impression that they are good for them, when in actual fact they are harmful. Any potential health supplements should not be allowed to be added to foods unless they have been shown to be beneficial, or at least proven not to be harmful."
In 1956, Dr. Denham Harman proposed the free radical theory, whereby oxygen free radicals were eventually proposed to be the cause for over 100 human diseases including cancer, heart disease and aging. The free radical theory of aging, elaborated and first investigated mainly by Harman and later by many others, taught that oxygen free radicals are harmful byproducts of aerobic life and as such represent the basic cause of aging and numerous, if not all, human diseases. 29-35
Antioxidants were touted as the savior from the alleged damaging effects of electronically modified oxygen derivatives (EMODs) and were quickly called to the rescue. Antioxidants are chemicals which were believed to nullify, scavenge or eliminate free radicals and were predicted to be the answer to so-called "free radical induced diseases" in man. Scientists readily assumed three things: 1) that the free radical theory was correct, 2) that oxygen free radicals were always deleterious and 3) that antioxidants would successfully counteract the damaging effects of oxygen free radicals. They now appear to have been wrong on all three points.
In vitro studies have shown that cells can be damaged by reactions with free radicals. Thus, it was assumed that living/breathing cells would respond in a similar fashion and that free radicals were the causative factor for over 100 pathophysiologies, including cancer, cardiovascular disease and aging. Dr. Denham Harman 36 had planted the seed of confusion, which led to the growth of a sprawling tree of erroneous free radical hypotheses, over shadowing the real truth in regards to oxygen free radicals and human disease causation. 3, 8, 41, 46
Despite the widely held enthusiasm for the free radical theory, I am not aware of the perfection of a single proven medical application or clinical breakthrough, which has been based on the free radical theory (see "The Howes Selective World Library of Oxygen Metabolism, available at www.thepundit.com).
Tens of thousands of scientific papers have been published on this subject and most of those published in the later half of the 20th century were interpreted as being supportive of the free radical theory. Yet, the literature was filled with "paradoxes" and inconsistencies. RCTs subsequent to this have not only demonstrated that antioxidants are frequently ineffective in the prevention of the alleged "free radical caused diseases" but that they were also the source of harm or death. When confronted with non-supportive evidence, the medico-scientific establishment did what any purveyor of profitable misinformation would do, i.e., they either ignored it or called it a paradox and moved on. Interestingly, they simultaneously sought out supportive evidence, no matter how flimsy, and then embarked on an aggressive propaganda campaign to 'indoctrinate' or persuade as many people as possible to accept this allegedly supportive evidence. The end result was that the supplement industry grew to a $23 billion industry and that the general public received a highly distorted interpretation of the data that had little resemblance to the truth. This has been the biased situation with the free radical theory for the last fifty years.
In RCTs, antioxidant vitamins as food supplements have no beneficial effects in the primary prevention of myocardial infarction and stroke. Serious adverse events have been reported. After an initial enthusiasm for antioxidants in the secondary prevention of cardiovascular disease, recent reports from several large randomized trials have failed to show any beneficial effects. Antioxidant vitamins as food supplements cannot be recommended in the primary or secondary prevention against cardiovascular disease. 37
In the last several years, the long-awaited reliable scientific studies (RCTs) were finally performed to test whether antioxidant supplements really protect the heart. Heart protective effects of antioxidant supplements have been tested on about 1,000,000 people in recent well-designed trials. Trials have been completed for vitamin E (5 large trials), beta-carotene (3 large trials), and antioxidant mixtures (2 large trials). Each of these trials showed no effect of antioxidant supplements on cardiovascular disease occurrence. Only a few controlled clinical studies showed beneficial effect for vitamin E (with or without vitamin C), and those studies were performed in people who already had heart disease, or were at high risk of heart disease. As a result, the American Heart Association released a "Science Advisory" regarding antioxidant vitamin supplements and cardiovascular disease. The statement concluded that scientific data does not justify the use of antioxidant vitamin supplements for reducing cardiovascular risk. The American Heart Association (AHA) recommends avoiding antioxidant supplements and rather suggests a variety of fruits, vegetables, whole grains, and vegetable oils as the preferred source of these compounds. 38
The American Diabetes Association (ADA) reports no clear evidence of benefit from vitamin or mineral supplementation in people with diabetes without underlying deficiencies; routine supplementation with antioxidants is not advised because of lack of evidence of efficacy and concern related to long-term safety. 39
Similarly, the U.S. Preventive Services Task Force (USPSTF), which constructs guidelines that doctors use in clinical practice based on strict scientific review of clinical research, reviewed all the clinical research regarding the role of antioxidants in cancer and heart disease. The USPSTF concluded that there is insufficient evidence to recommend either for or against the use of supplements of vitamins A, C, E, or antioxidant combinations for the prevention of cancer or cardiovascular disease. Furthermore, because some studies actually proved harm resulting from particular antioxidant supplements, USPSTF specifically recommends against the use of beta-carotene supplements, either alone or in combination for prevention of cancer or cardiovascular disease.
Any way you look at it, antioxidants fail to protect, reverse or stop atherosclerotic plaque development in humans. 40
In 2005, Johns Hopkins expert, Simeon Margolis, M.D., Ph.D, posted the following cautions on Wed, Aug 24, 2005: "I urge you not to be taken in by unproven claims that a dietary supplement can treat diabetes — or any other disorder, for that matter."
The Mayo Clinic website (http://www.mayoclinic.com/health/anti-aging/HQ00233) states that, "Many ads sound too good to be true: All you have to do is take a pill, and you'll suddenly find yourself muscle-bound and full of youthful energy. What those ads don't tell you is you'll also empty out your wallet and possibly harm your body using an unproven therapy. Proponents believe that antioxidants can prevent chronic diseases, such as heart disease and diabetes but experimental data has failed to confirm this. There's no proof that antioxidants in pill form can improve your general health or extend your life. In fact, they can have the opposite effect."
The National Cancer Institute states that, "Considerable laboratory evidence from chemical, cell culture, and animal studies indicates that antioxidants may slow or possibly prevent the development of cancer. However, information from recent clinical trials is less clear. In recent years, large-scale, randomized clinical trials reached inconsistent conclusions."
The Heart and Vascular Institute of the Cleveland Clinic states the following:
"Natural products, herbal supplements, alternative dietary therapies, antioxidants, micronutrients or plain old vitamin pills…No matter what you call them, if you take these products prior to a heart operation, they can cause real problems during or after your surgery. Previous studies of these and other natural or alternative therapies such as ginger, coenzyme Q-10, and vitamin E, have found that side effects from natural agents can be as serious as a heart attack, stroke or excess internal bleeding."
Further, studies repeatedly demonstrate the ability of antioxidants to block electronically modified oxygen derivative (EMOD)-activated apoptosis of neoplastic cells. 41 This is especially concerning for individuals predisposed to malignancies, those exposed to carcinogenic agents, those with established cancer or those who may be undergoing chemical or radiation treatment for cancer. Before recommending that individuals take antioxidants for chemoprevention, a better understanding of free radical-mediated biochemistry must be considered. 42 Over supplementation with antioxidants may actually produce an environment that is beneficial to the tumor and allow it to survive.
Investigators have recently shown that efficient apoptotic signaling is a function of a permissive intracellular milieu created by a decrease in the ratio of superoxide to hydrogen peroxide and cytosolic acidification. Resveratrol, a phytoalexin found in grapes and wines, triggers apoptosis in some systems and inhibits the death signal in others. In this regard, the reported inhibitory effect on hydrogen peroxide-induced apoptosis has been attributed to its antioxidant property. 43 This emphasizes the point that EMODs are primary signaling agents in apoptosis and that this can be blocked by antioxidants. It also shows that resveratrol can have prooxidant activity.
Antioxidant vitamins are unregulated
The field of antioxidant research is controversial and confusing to many clinicians because the results of some studies conflict with others, making simple conclusions as to efficacy and safety difficult. Supplements fall under regulatory guidelines similar to those for foods and supplements but cannot be marketed for disease treatment or disease prevention. Health promotion is the primary mode of marketing for dietary supplements, although such use transcends some of the regulatory barriers. 44
The Food and Drug Administration's oversight of vitamins and other dietary supplements was side stepped in 1994. Unlike most medications, most supplements sold today never had to be proven safe, much less proven to bring any health benefit.
On 5/17/06, specialists were worried about supplement bottles and labeling that promise 53 times the recommended daily consumption of certain nutrients and they were convened by the National Institutes of Health and called for strengthened federal oversight of the $23 billion dietary supplement industry, especially efforts to document side effects. Dr. J. Michael McGinnis of the Institute of Medicine, led an NIH panel review urging more FDA authority over supplements, urging the agency to, among other things, mandate that manufacturers report customer side effects as is required for drug manufacturers. Legislation to that effect has languished in Congress since 2004; the industry's Council for Responsible Nutrition said on 5/17/06 that it supported that call.
Over half of U.S. adults use multivitamins, most of whom are the health conscious people who also eat nutrient-fortified foods. Though the data are incomplete, up to 30 percent of Americans are taking some form of antioxidant supplement (data accessed 2/17/07 americanheart.org).
Yet, there has been little evidence that most of the antioxidant vitamins do any good at all, other than some nonrandomized, uncontrolled reports by those who are selling promoting or benefiting tangentially from these supplements. There is an additional growing concern that some people may get a risky or harmful vitamin overload. Yet, in health oriented individuals, use of vitamin supplements and foods fortified with vitamins has recently skyrocketed as erroneous speculative reports suggested that high doses of certain nutrients would help prevent cancer and many other serious diseases. That's where safety questions arise, because it has been known that too much of certain nutrients or hypervitaminosis can be bad.
Many of the nonrandomized and uncontrolled studies, that suggested a beneficial effect of antioxidant vitamins, also showed that people who take vitamins tend to take better care of their health in other ways, such as eating plenty of fruits and vegetables, exercising and not smoking and it therefore was difficult to determine whether the vitamins were responsible for any health benefits.
According to Patsy Brannon, a Cornell University nutritionist, concern especially arises with super doses that exceed the government's "recommended daily amount," or RDA. Between 1 percent and 11 percent of supplement users may be exceeding the upper limits set for certain nutrients, if they add together their doses from vitamin pills and their vitamin fortified diets. Too much vitamin A can cause birth defects, and too much vitamin E can cause bleeding problems. Too much vitamin C causes diarrhea and increases oxalate excretion, which may cause kidney stones.
Many people may assume that because vitamins and minerals are vital for health that more is better. But some are toxic at high levels, including vitamin A and iron, and others are simply excreted in the urine.
The antioxidant myth: a medical fantasy
According to Lisa Melton, if popping pills to stave off the ravages of aging sounds too good to be true, that's because it is. 45 Melton said that, "if it is an antioxidant, such as cranberry capsules, green tea extract, effervescent vitamin C, pomegranate concentrate, beta carotene, selenium, grape seed extract, high-dose vitamin E, pine bark extract or bee spit, we will swallow it by the bucket-load."
According to some estimates around half the adults in the US take antioxidant pills daily in the belief they promote good health and stave off disease. We have become antioxidant devotees. But are they doing us any good? Evidence gathered over the past few years shows that at best, antioxidant supplements do little or nothing to benefit our health. At worst, they now appear to have the opposite effect, promoting the very problems they were supposed to stamp out.
It's little surprise that antioxidants have acquired a reputation as miracle health supplements. As long ago as the 1950s, scientists discovered that many diseases, including heart disease, strokes, cancer, diabetes, cataracts, arthritis and neurodegenerative disorders, were attributed to free radicals of oxygen but that theory has been nullified. 46
A glimpse at the ineffectiveness and dangers of antioxidant vitamins
The ineffectiveness of antioxidants in reducing cardiovascular death and morbidity in clinical trials has led many investigators to question the importance of so-called oxidative stress in human atherosclerosis. 2-4, 6, 8, 46, 47 Even the concept of so-called oxidative stress has helped bias global orthodoxy against the beneficial aspects of electronically modified oxygen derivatives (EMODs).
Adverse events from multivitamin/mineral supplements (MVMs) appear with some frequency in both the reports of the American Association of Poison Control Centers and the FDA's MedWatch system. There is evidence that certain ingredients in MVM supplements can produce adverse effects. 48
Vitamin C supplementation exerted prooxidant as well as antioxidant effects in healthy volunteers; however, high doses of this antioxidant increased DNA damage. 12 It was hypothesized that transition metal ions, released from metalloproteins after initial oxidative stress, act as catalysts in the presence of antioxidants to exacerbate the free radical-induced damage. 49
Antioxidant cocktails have no benefit in the prevention of cardiovascular disease. 50-52
The results of large prospective RCTs, mostly involving vitamin E in patients at increased risk of cardiovascular disease (CVD), have been disappointing and have failed to demonstrate the anticipated benefits. 53
The antioxidant beta carotene has been shown to increase lung cancer and CVD mortality and, in the ATBC study, appeared to attenuate the benefit of alpha tocopherol. 54
The finding of the ATBC study of a significant increase in hemorrhagic strokes in male smokers with alpha tocopherol (all-rac-AT) is alarming and of major concern. 55
Prescribing antioxidants such as alpha tocopherol and ascorbic acid as an adjunctive therapy in primary prevention must await the results of ongoing clinical trials with these agents. 56
Four ß-carotene trials also evaluated cardiovascular disease and found no benefits. 57-60 In healthy women, there was a suggestion of increased stroke risk in 1 study 61 and an increased risk for CVD in women smokers in the Carotene and Retinol Efficacy Trial (CARET). 62 When vitamin A was paired with ß-carotene in 1 trial, lung cancer and CVD deaths were increased. 57
Esophageal cancer excess was found with long-term follow-up of older Chinese patients treated with selenium, ß-carotene, and vitamin E supplements. 63
Antioxidants do not promote healthy hearts in animal studies
Past randomized clinical studies failed to demonstrate a protective effect of antioxidant vitamins on coronary and carotid atherosclerotic lesions. 64-66
In fact, long-term experimental antioxidant vitamin (C & E) supplementation in normal pigs impairs myocardial perfusion and coronary endothelial function. 67 These data suggest that antioxidant vitamins may have a detrimental effect on the cardiovascular system in healthy subjects through the imbalance of the endogenous redox equilibrium. I have been arguing this point for years. 3-8
There have also been attempts to prevent myocardial injury during coronary by-pass operations by pretreatment with high doses of antioxidant vitamins. In an RCT, pretreatment with α-tocopherol and ascorbic acid did not affect various indicators of myocardial damage. 68
Most of the major trials evaluating the effect of antioxidant vitamin supplementation on clinical events were inconclusive. 51, 69, 70 All of these studies emphasize the fact that the free radical theory lacks predictive value and that it is not validated by the scientific method. Predictive validity is required for substantiation by the scientific method.
These findings reflect the failure of the free radical theory as it relates to the vascular pathophysiology of atherosclerosis and associations with cardiovascular disease. Stocker and Keaney highlighted the point that the process of lipoprotein lipid peroxidation can be dissociated from atherosclerosis, and studies that do demonstrate an association have, been unable to demonstrate causation. 40
For the most part, human antioxidant clinical trials have failed to demonstrate any improvement in cardiovascular outcomes. 19, 71
In the Women's Health Study conducted between 1992 and 2004, 39,876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo and were followed up for an average of 10.1 years. They received administration of 600 IU of natural-source vitamin E on alternate days. Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer.
During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction. There were no significant effects on the incidences of myocardial infarction, as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction. There was no significant effect on the incidences of total cancer or breast, lung, or colon cancers. Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality.
The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. Lee et al. suggest that these data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women. 71
Antioxidants do not cure or improve cardiovascular disease
Antioxidants, such as beta-carotene and vitamin E, have been touted for their ability to protect against heart disease. This protective effect is attributed to their alleged ability to prevent the oxidation of bad cholesterol by free radicals, which is a process thought to contribute to the build-up of disease-causing fatty deposits on artery walls. But a new study, published online on April 10, 2006, in The Journal of Experimental Medicine, suggests that the heart-healthy effect of one antioxidant has little to do with cholesterol oxidation.
A group of researchers at the University of New South Wales in Australia, led by Roland Stocker, studied a cholesterol-lowering drug called Probucol (Lorelco) in laboratory rodents with vascular disease. Probucol reduces the risk of heart disease in humans, but is no longer prescribed in the US and Australia because of adverse side effects: a tendency to lower good cholesterol along with the bad and the potential to induce an irregular heartbeat. Probucol is still available in Canada and Europe.
In their new study, Stocker and his colleagues show that the protective effect of probucol has nothing to do with its ability to scavenge oxygen free radicals, as the free radical-scavenging part of the drug alone was ineffective in protecting animals against heart disease. Instead, a different part of the probucol molecule was doing the beneficial work.
In fact, contrary to widely accepted opinion, the group found no relationship between the levels of oxidized cholesterol in blood vessels and the severity of heart disease. This might help explain the disappointing results of clinical trials with other free radical-scavenging antioxidants, such as vitamin E, which have shown no protective effect against heart disease in humans. 40, 72
Stocker and Keaney state that the causative relationship between oxidative events and atherosclerosis in general and the pathophysiological importance of LDL oxidation in particular have been challenged by the overall poor performance of antioxidant strategies in limiting atherosclerosis and its cardiovascular events, the overall lack of clear disease stage dependency in the vessel wall contents of oxidized molecules and antioxidants, and by the reported dissociation of atherosclerosis and lipoprotein oxidation in the vessel wall of animals. 40
I concur. 2-8, 46
Concentrations of antioxidants and oxidant markers do not correlate with the extent of atherosclerosis. 73 Consistent with the notion that vitamin E remains essentially intact during atherosclerosis, available data from gas chromatography-mass spectrometry analysis of atherosclerotic plaque shows that only a fraction of the vitamin is oxidized. 74 Homogenates of advanced human plaque also contain ascorbate, uric acid, and α -TOH in quantities comparable to human plasma, sufficient to efficiently block LDL oxidation in vitro.
Considerations of the antioxidant, uric acid, may lend insight into the role of antioxidants and atherosclerosis. Compared with human plasma, healthy arteries contain significantly less urate. In contrast, the concentrations of urate in advanced human lesions are comparable to those in plasma and in some lesions approach if not exceed the limit of its solubility in aqueous solution. 75 Thus, like with ascorbate, currently available evidence suggests that urate levels in the vessel wall do not become decreased during atherosclerosis.
Thus, 2 antioxidants, ascorbate and uric acid are present in atherosclerotic vessel walls and could help decrease EMOD levels. It remains to be established whether uric acid provides antioxidant protection in vivo, and the role of uric acid in cardiovascular disease is still unclear, despite a long-standing association between hyperuricemia and atherosclerosis. I believe that this relationship is contrary to the free radical theory and supports my Unified theory. 3
Some but not all studies have reported a direct association between uric acid concentrations and atherosclerosis, hypertension, and cardiovascular mortality. 76
There is evidence that in human lesions that oxidized lipids associated with LDL accumulate substantially only late in disease development, after accumulation of unoxidized cholesterol and cholesterol esters. 77 Furthermore, lipoprotein lipid oxidation can be dissociated from disease in animal models of atherosclerosis.
The overall marginal impact of α-TOH on lesion formation is perhaps not so surprising given the lack of evidence for a deficiency in this antioxidant. 78 Similar to the situation with vitamin E, vitamin C supplements do not offer consistent benefit against atherosclerosis in animals. It is interesting to note that individuals with a genetically determined tocopherol deficiency do not have increased LDL oxidation. 79
Stocker and Keaney state that the overall outcomes, particularly the results of the RCTs of antioxidant vitamins, have failed and arguably provide the strongest evidence against the oxidative modification hypothesis of atherosclerosis.
In human aortic lesions nonoxidized lipids accumulate before oxidized lipids as disease progresses. 80 Thus, as is indicated by this study, I believe that oxidation is not the initiating or causative event. Additionally, I believe that oxidation of plaque microaggregates makes them suitable for excretion.
Similar to the situation with vitamin E, the evidence linking cardiovascular disease and vitamin C is inconsistent, as reviewed by Carr and Frei. 81 Different studies reported an association (n = 8) or no significant association (n = 8) of dietary vitamin C with cardiovascular disease incidence. Just as with other antioxidant vitamins, this lack of consistency has led to unsubstantiated and confusing claims for vitamin C.
EMODs are ubiquitous and essential to normal physiological functioning
Redox-dependent mechanisms (especially with hydrogen peroxide) have been shown to regulate a wide variety of cellular functions and responses. 82
The exposure of human tissues to hydrogen peroxide (H2O2) may be greater than is commonly supposed, which has implications in relation to the proposed role of this EMOD species in cell signaling. H2O2 is poorly reactive in the absence of transition metal ions. Substantial amounts of H2O2 can be present in beverages commonly drunk (especially instant coffee), in freshly voided human urine, and in exhaled air. 83 Some or all of the reported effects of ascorbic acid and polyphenolic compounds (e.g., quercetin, catechin, epigallocatechin, epigallocatechin gallate) on cells in culture may be due to H2O2 generation by interaction of these compounds with cell culture media. 84
Electronically modified oxygen derivatives (EMODs) are produced as by-products of oxidative metabolism. A major function for EMODs is immunological host defense. Recent evidence indicates that EMODs also function as signaling molecules. 85
Restoration of blood flow after ischemia results in generation of reactive oxygen species (EMODs), which are commonly considered a main contributor to cell death by lipid peroxidation, oxidative modification of proteins, and DNA. However, recent investigations in signal transduction demonstrate that EMODs at a low concentration may also serve as an intracellular messenger to induce "defensive" or "repair" mechanisms against tissue injury. For example, EMOD generation during ischemic preconditioning 86 or anesthetic preconditioning 87 mediate the protection against prolonged ischemia.
The role of EMODs in angiogenesis has recently been shown to involve growth factors such as vascular endothelial growth factor (VEGF), EGF, PDGF, and FGF require EMODs activation and down-stream signaling participation to exert action. Depletion of EMODs impairs cell responses to mitogenic stimulation. 88 EMODs have been demonstrated to enhance proliferation of vascular smooth muscle (VSMC) and endothelial cells (EC), which are primary features in the process of coronary collateralization. Thus, EMODs are involved in varying crucial biochemical processes in extremely complex biochemical networks and antioxidants theoretically interfere with EMOD modulation of these processes.
Further, phagocytic killing of bacteria and viruses is, at least in part, effectuated via EMODs and all antibody reactions involve EMODs, such as singlet oxygen, hydrogen peroxide and possibly ozone. 3, 4
Prospective, RCTs and meta analysis of various trials, (such as Vivekananthan's meta-study 19, Miller's meta-study, 24 ATBC 50, Brown's study 52, Omenn's study 57, Hennekens study, 58 GISSI 69, HOPE 70, MRC/BHF 89), evaluating the effect of vitamin E and other antioxidant vitamins or their combinations on clinical manifestations of cardiovascular disease, cancer and diabetes, have consistently shown that commonly used antioxidant vitamin regimens (vitamins E, C, beta carotene, or a combination thereof) do not significantly reduce overall cardiovascular events, diabetes or cancer.
By extending HOPE and adding to the growing list of neutral prospective vitamin E trials (HOPE, GISSI-IV, ATBC, HPS, and HATS), this report effectively eliminates the prospect of a major protective effect of long-term exposure to vitamin E, taken in moderately high dosage, against complications of atherosclerosis and overall cancer incidence.
In 2005, the Heart Outcomes Prevention Evaluation (HOPE) investigators report an extension of the 9,541-patient HOPE Vitamin E trial roughly 2.5 years beyond its previously reported 4.5-year mean follow-up. In the 2.5-year extension of HOPE (HOPE-TOO), 90 174 of the original 267 centers continued an extended follow-up. From these centers, 3,994 of the 7,030 original study enrollees who were still alive elected to continue the randomized vitamin E/placebo drug assignment. After a mean of 7.2 years of follow-up, vitamin E did not significantly reduce the relative risk (RR) of total cancer incidence, of cancer death, of a composite of cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and stroke, or of individual components of this composite end point.
These findings of lack of benefit from vitamin E (natural source, 400 IU -tocopheryl acetate) during the extended study are also consistent with the original HOPE report and with recent meta-analyses. 19, 24 Vivekananthan studied 81,178 subjects and Miller studied over 135,000. 19, 24
The compelling message of this important study within its limits of confidence and over a 7-year exposure is that moderately high-dose vitamin E does not reduce overall risk of cardiovascular disease or cancer for 50- to 75-year-old men and women with established cardiovascular disease or diabetes, to whom the findings of this trial directly apply. 91
Of greater concern, another subgroup finding in HOPE-TOO was a vitamin E-associated increased risk of heart failure incidence that appeared in a secondary end point analysis in the 4.5-year report and persisted in the 7-year extended follow-up, as did the risk of hospitalization for heart failure.
HOPE-TOO reemphasizes the importance of controlled clinical trials for testing important hypotheses deriving from basic biological findings or from epidemiological observations, neither of which translates directly to in vivo situations. Epidemiological and observational studies have been and can be seriously misleading; well-designed clinical trials are much more reliable and accurate. HOPE-TOO allows physicians to educate their patients as with the following response to inquiries about vitamin E, "In nearly 68,000 patients studied to date, there is no compelling evidence that higher doses of vitamin E reduce cardiovascular risk or cancer; there are studies which indicate that vitamin E, in excess of normal daily intake, slightly increases the risk of ischemic events or of heart failure. You may hear that vitamin E is a ‘natural,' yet effective, way to prevent heart disease or cancer, but this has proven to be a false hope. You should not be misled into neglecting other (possible) methods of prevention."
Legal liability: My opinion
Use of the scientific method is designed to establish scientific fact and accordingly, the free radical theory, which lacks predictive value, has repeatedly been shown to be a non-viable scientific theory.
Had the free radical theory been correct, common diseases would be on the downslide, arterioscloerosis would be blocked, cancer would be stopped, diabetes would be declining, and aging would be conquered. None of that has happened with the use of antioxidants and to the contrary, these diseases are nationally and globally at pandemic levels.
If the free radical theory is wrong, then the antioxidants would not be expected to prevent common diseases or to stop aging. That is essentially what has been found to be the case. Also, according to the free radical theory, if these damaging radicals were removed from the body, overall health would improve, mortality would decrease and life span would increase. In contrast to the failed predictions of the now discredited free radical theory, antioxidants are either without effect on disease occurrence or progression or they cause harmful adverse reactions and increase mortality by a conservative estimate of up to five percent. 10 This is a threatening and dangerous scenario due to the unjustified, widespread global use of antioxidants. Additionally, manufacturers are not adequately informing a confused and misled public about the potential dangers and increased mortality of antioxiant vitamins. This lack of concern for public safety incriminates those who sell these products, which are known to increase mortality. The populus has been and continues to be "radically misled" and the use of antioxidants is still the current rage.
Apparently, few scientists have the courage to speak out against the prevailing sentiment, which supports the free radical theory. This must be due to personal reasons because the free radical theory has been scientifically debunked. I know of no other situation in which drugs or agents are freely marketed and sold, which have been proven to be ineffective and harmful and in which no lawful restraints or challenges have been filed with the legal system. Much of the data, which demystifies the free radical theory and points out the harmful aspects of antioxidants, has been available for over a decade but there is no uprising against the $23 billion supplement industry. Obviously, profit is more important than consumer safety.
Since supplement manufacturers have not provided the public with adequate safety information, I believe that it is time for a class action law suit to control and regulate the supplement industry, as it relates to antioxidants. Adequate scienfitic data is in, the conclusions are becoming clear and it is time to act on behalf of the people. Marketing has placed antioxidants in products ranging from pizza dough to cake mix, from water to energy drinks, from doughnuts to dog food and from bread to bubble gum. Genetic engineers are mutating foods to create fruits and vegetables which contain mega-loads of antioxidants, effectively bringing us into the age of "fortified Franken-foods." These antioxidants have been and will be incorportated into the general food supply, even though individuals may not want to ingest higher levels of these questionable and potentially dangerous antioxidants.
Antioxidant supplements are sold in combination with other supplements. 92, 93 Because of the widespread use of antioxidant supplements by 10% to 30% of the adult population (80-160 million people) in North America and Europe, 10 this is a serious public health issue and the potential for harm or increased mortality is highly significant. It now appears that antioxidant vitamins may be agents of "death in small doses" and it seems likely that this implies an associated legal liability and a significant public health safety issue.
Antioxidants can block crucial EMOD functions, including sperm and ova function, apoptosis, the respiratory burst, protein translation, phagocytosis and detoxification. 94-96 Excessive antioxidants could dangerously interfere with these protective functions, while temporary depletion of antioxidants can enhance anti-cancer effects of apoptosis.
I believe that EMODs are of low toxicity and are essential secondary cellular messengers. We must endeavor to maintain adequate levels of prooxidant protection from pathogens and neoplasia.
The lofty predictions of the discredited free radical theory, as regards the ability of antioxidants to prevent, nullify or reverse mankind's common diseases and aging have fallen woefully short. To the contrary, the antioxidant vitamins actually increase the risk of the diseases they were supposed to cure or prevent and they increase mortality. At this point in time, randomized controlled trials have accumulated convincing data showing the ineffectiveness and dangers of common antioxidants, such as vitamins beta carotene, A, C and E. These same vitamins are promoted and marketed with near reckless abandon regarding consumer safety. Because of the quantity and quality of the scientific data, there is now a legal and moral liability issue associated with their unrestrained use. We must make patient and consumer safety our number one priority.
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Adjunct Assistant Professor of Plastic Surgery, The Johns Hopkins Hospital, Baltimore, Md., U.S.A. and Espaldon Professor of Plastic and Reconstructive Surgery, University of Santo Tomas, Manila, Philippines.
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Howes M.D., PhD., R. (2007). Antioxidant Vitamins A, C & E; Death in Small Doses and Legal Liability?. PHILICA.COM Article number 89.
1 Peer review [reviewer #47336] added 20th August, 2011 at 20:22:39
This is one of the better articles of the author in his Nature Proceeds series on similar subjects. I really enjoyed the author’s comments on ‘Franken-foods’, i.e., “monster- foods”, or “Dr. Frankenstein-foods” that are somewhat realistic, in spite of the fact that the author included only very few scary examples; one such example that could be given but was not provided is that of the *Dream Soy Milk*—“trademarked by FrankenFoods Company”; that product was/is supplemented with high concentrations of soybean isoflavones that act-it seems - as weak estrogens at certain high doses that are present in the ‘health-food’ called ‘Dream Soy Milk’— which really fits the unorthodox description of ‘Franken-foods’, especially for its suspected effects of speeding up the growth of human breast tumors at the higher doses of isoflavones, and at concentrations also naturally present only in certain Peking soybean cultivars, as found by my research team and I in my laboratory. On a different note, the term ‘Franken-foods’ has been widely used for quite different types of foods—those that are made from crops that were genetically engineered. In that context, the term is a total misnomer because such foods do not seem to have any particular or demonstrable adversary health effects, and therefore I should like to recommend that the term should be used much more carefully and with proper caution in medically or health related articles for those engaged in the medical profession or biomedical research.
Originality: 2, Importance: 5, Overall quality: 5