Antioxidant Reviews Mired in Controversy

December 3, 2008



If free radicals are the enemy of a healthy body, then what role do anti­oxidants play? A treacherous one, according to a review in the third issue of the Cochrane Database of Systematic Reviews (Oxford, UK) that was quickly denounced as marginal and unbalanced by some scientists.

The review, a revision of previous research with some data errors corrected, was a meta-analysis of 67 randomized trials with antioxidant supplements. The report concluded that beta-carotene and vitamins A and E had the ability to increase mortality risk by up to 16%.

"This report suffers from the same deeply critical flaws as previous reports by the authors," says Jeffrey Blumberg, PhD, director of the Antioxidants Research Laboratory at the USDA Human Nutrition Research Center on Aging (Boston).

Other critics agree. "As in previous studies by this group, there appears to be an inherent bias to tell a story that supports their agenda," according to the Natural Products Association (NPA; Washington, DC).

The Council for Responsible Nutrition (CRN; Washington, DC) is also skeptical and questions the exclusion of some mortality data from the study's data pool.

A Closer Look

The research published in the Cochrane Reviews was based on 67 randomized trials with 232,550 participants. Of those trials, 47 studies including 180,938 participants had a "low risk of bias" and 21 trials included 164,439 healthy participants. The 47 trials included 68,111 participants with various gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, and endocrinological problems.

"TROJAN HORSE" MOLECULE MAY IMPROVE ANTIOXIDANT VIABILITY

ACCORDING TO A RECENT JOHNS HOPKINS UNIVERSITY NEWSLETTER, supplements like IP6, antioxidants, vitamins, minerals, and essential fatty acids have the ability to build up the immune system. Other supplements like vitamin E promote apoptosis, a self-destructive form of cell death.

Though the average person should be able to produce enough endogenous antioxidants, during times of stress additional antioxidants may be needed. However, the actual amount of antioxidants necessary has not been determined.

In August, scientists from Monash University in Australia found that while enough antioxidants are normally produced in the human body to protect it from free radical damage, those with degenerative conditions or unhealthy diets are not receiving nearly enough from their diet.

For instance, only between 0.1 and 1.1% of catechins, which are among the most potent dietary antioxidants, make it into the bloodstream, notes Monash researcher Ken Ng, PhD. "If we can improve that rate," he says, "the benefits are enormous."

In order to do this, Ng and his partner, Ian Larson, PhD, developed a sponge-like chitosan biopolymeric nanoparticle made from the shells of crustaceans such as shrimp and crabs that is one-thousandth the thickness of a human hair. The nanoparticle functions as a shielding vehicle for the antioxidants.

"Antioxidants sit within this tiny 'Trojan horse,' protecting it from attack from digestive juices in the stomach," Larson says. "Once in the small intestine, the nanoparticle gets sticky and bonds to the intestinal wall. It then leaks its contents directly into the intestinal cells, allowing them to be absorbed directly into the bloodstream."

Ray A. Matulka, PhD, assistant director of toxicology at the Burdock Group (Orlando, FL), says the idea may be ingenious.

"This is a novel delivery system that may provide a greater concentration of antioxidants to reach the small intestine, where most are typically absorbed into the bloodstream," Matulka says.

Matulka adds that companies need to learn more about how to shield antioxidants from degradation during the manufacturing process, storage, and during transit through the stomach.

In essence, additional research should go into novel storage systems that may enhance antioxidant functionality in order to make antioxidant absorption more effective in their food, Matulka says. Companies must keep in mind that every product has different, proprietary levels of antioxidants during the formulation process and should be marketed as such.

On the whole, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis, but significantly increased mortality in a fixed-effect model, the study concluded. When the various antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A, beta-carotene, and vitamin E, but no significant detrimental effect of vitamin C. Low-bias risk trials on selenium found no significant effect on mortality.

Blumberg offers several explanations why the study may be flawed. "By use of their own selective-and far from widely agreed upon-criteria of randomized clinical trials to include in their analyses, they effectively exclude most of the published studies on dietary antioxidant supplements," he says.

He notes that the study's conclusions are based on less than 9%, or 67 of 748 studies, of the totality of available clinical trial evidence. Another problem with Cochrane's approach, he says, is the exclusion of any studies in which no deaths were reported. In essence, Blumberg asks, "How can the safety of these supplements be evaluated when studies demonstrating no harm are systematically excluded?"

Blumberg adds that the meta-analysis considers as "comparable" very different populations, such as the young and old, the healthy and sick, those taking various medications, institutionalized and free-living patients, and people following a range of diets. Yet the study attrib­utes the differences in all-cause mortality only to the antioxidant supplements, ignoring all other potential contributing factors.

The study also treats as similar clinical trials that range in duration and use markedly different doses of the same nutrients. Interestingly, he says, the authors claim to have found "no significant differences between the effects of antioxidant supplements in healthy participants (primary prevention trials) or participants with various diseases (secondary prevention trials), in contrast to the established principle of toxicology that vulnerable individuals are more susceptible to harm from any insult."

In addition, one of the study's authors defines retinol as an antioxidant, even though it does not act as an antioxidant and is not defined as such by experts, standard nutrition textbooks, and the dietary reference intakes, he says.

"Despite the effort apparently invested in their original meta-analyses and in this report as well, the study's authors never address the cause of death presumably induced by these different nutrients," he continues, adding that the analyses offers no biological plausibility for its conclusions.

The number of deaths included in the study that were due to cardiovascular and infectious disease; cancer; and pulmonary, renal, hepatic or neurological conditions, etc., were never specified. It is difficult to presume then, says Blumberg, that one or more of these nutrients could "kill" through any and all possible mechanisms of action-including accidental death, homicide, and suicide, which were included in the study's analysis of all-cause mortality.

The study's reviewers called for more oversight on the nutraceuticals industry in their conclusion, to a degree that perhaps they could not justify in their report.

BLUEBERRIES TAKE TOP SPOT IN ANTIOXIDANT RESEARCH STUDY

PORTLAND, MAINE-Blueberries surpassed more than 25 other fruits such as apples, bananas, red grapes, and strawberries for antioxidant activity in new research published in the current issue of the Journal of Agricultural and Food Chemistry. Blueberries were shown to have the highest cellular antioxidant activity of the over two dozen fruits tested, as well as the highest total phenolic content and oxygen radical absorbance capacity (ORAC), according to lead scientist Rui Hai Liu, PhD.

Liu used the cellular antioxidant activity (CAA) assessment developed by Cornell University (Ithaca, NY) to determine the level of antioxidant activity in foods and dietary supplements.

"In expanding the test to include more fruits, we found that blueberries had the highest antioxidant activity, with other berries and pomegranates also showing strong performance. While further testing is needed to confirm how dietary antioxidants are absorbed by and go to work in the human body to prevent cancer and other chronic diseases, we're encouraged by the response in this initial screening measure," says Liu.

According to Liu, using human liver cancer cells as the testing model, the CAA assessment was developed to investigate how antioxidant compounds in foods react inside cells. The CAA test is a more biologically relevant method than the chemistry antioxidant activity assays since it accounts for uptake, meta­bolism, distribution, and activity of antioxidant compounds within cells versus solely looking at antioxidant value. The CAA test is the first movement in the antioxidant field away from test-tube chemistry assays and toward cell-based antioxidant activity assays.

Wild Blueberry Association nutrition advisor Susan Davis, MS, RD, advised choosing brightly colored fruits and vegetables with an emphasis on berries for higher antioxidant levels. According to Davis, berries are naturally rich in anthocyanins, and are currently being studied for their possible preventive role in fighting cancer, heart disease, Alzheimer's, and other effects of aging.

"The CAA assay results present more evidence that anti­oxidant-rich foods like (blueberries), when eaten as part of a well-balanced diet, have the potential to reduce chronic disease risk and promote healthy aging," says Davis.

"We should request that the regulatory authorities dare to regulate the industry without being financially dependent on the same industry," wrote the study's authors.

"I find it astonishing that while the stated aim of this work was to assess the effect of antioxidant supplements on overall mortality in primary or secondary prevention randomized clinical trials, the authors conclude that antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing," Blumberg says.

"I could find nowhere in this report any review of regulatory practices and effectiveness or the evaluation of public health policies, procedures, or perspectives," he adds. "Indeed, it is not clear that the authors possess any expertise in these areas."

CRN's critique was more succinct: "It appears to be a systematic attempt by the authors to publish work that supports their own predetermined conclusions about antioxidants and the way they should be regulated."