The trials of beta-carotene: Is the verdict in?

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It hasn't been glamorous or provocative, and it may have sounded ultra-conservative. But despite the steady stream of news stories and the constant barrage of advertising touting the magic-bullet benefits of vitamins C and E and beta-carotene, we've urged our readers to think twice before popping antioxidant supplements. The best way to get your antioxidants, we've held firmly, is to eat a diet rich in fruits and vegetables.

Of course, it's easy to see why Americans have been spending $40 million annually on beta-carotene supplements alone. After all, vitamin pills, sold over-the-counter, have seemed so harmless.

Yet the National Cancer Institute recently put the brakes on a long-term, $42 million beta-carotene research trial because of findings that the antioxidant might be harming participants. At the same time, another major study concluded that beta-carotene did not improve the health of more than 22,000 men who had been swallowing supplements for a decade.

Did scientists miss the mark? Have the potential benefits of beta-carotene been overblown? Worse still, have people taking beta-carotene supplements been harming themselves?
Circumstantial evidence

Exactly 15 years ago, in March 1981, a group of internationally renowned cancer researchers published a landmark paper that tossed into the scientific arena a theory fife with possibility. They pointed to a number of studies showing that in populations where consumption of fruits and vegetables rich in beta-carotene runs high, the risk of cancer runs low. These findings suggested that beta-carotene may somehow help stall the development of malignant tumors. Evidence of a link between high blood levels of beta-carotene and low cancer rates lent weight to the theory.

Naturally, the idea that beta-carotene might offer protection against cancer was an enticing one. It had been 10 years since Richard Nixon declared the "war on cancer," yet researchers were making little headway in their search for ways to prevent the disease. If an inexpensive, easy-to-swallow, seemingly harmless substance like beta-carotene could solve the problem, it would be a boon to public health.

So scientists embarked on numerous studies, and the results looked promising, especially for lung cancer. Between 1983 and 1993, more than two dozen studies linking beta-carotene to a reduced incidence of lung cancer were published. Overall, the reports consistently indicated anywhere from a 10 to 70 percent drop in the risk of lung cancer in people whose diets were high in beta-carotene.
Deliberations

While the studies were insightful, their conclusions were far from definitive. They mostly showed loose associations: for example, people with high blood levels of beta-carotene tended to have lower rates of cancer than people with lower beta-carotene blood levels. But that doesn't prove that taking beta-carotene pills will reduce cancer risk.

To learn whether the connection is more than a coincidence, a chemoprevention trial is necessary. In this type of study, people are given the substance in question and then followed to see if they are less likely to develop disease than people not given the test substance.

Because cancer can take decades to develop, chemoprevention trials typically last many years. And they often involve thousands of people. The duration and number of participants make for a very high price tag. But given the enormous potential of beta-carotene, the National Cancer Institute began pouring millions of dollars into a number of beta-carotene chemoprevention trials during the mid-1980s.

In 1994, the results came in for one of the first of these studies, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial--the ATBC Trial, for short. The news was disturbing. After more than 29,000 male smokers in Finland took supplements of either vitamin E, beta-carotene, or a "dummy" placebo pill daily for five to eight years, 18 percent more cases of lung cancer and 8 percent more overall deaths occurred in the beta-carotene group than in the other groups. Because these results countered those of earlier studies, however, scientists chalked them up to a possible statistical fluke and punctuated them with a large question mark.

Then in January of this year, an independent watchdog committee monitoring a similar, ongoing study called the Beta Carotene and Retinol Efficacy Trial (CARET) noticed the same trend. After an average of four years, 28 percent more cases of lung cancer and 17 percent more overall deaths had occurred in the group taking beta-carotene. Because it looked as if beta-carotene wasn't helping and may actually have been harming participants, the trial was halted in January.

Simultaneously, yet another eyebrow-raising announcement was made about the Physicians' Health Study, a 12-year look by Harvard researchers at more than 22,000 male physicians. Again, beta-carotene came up short, apparently conferring no protection against cancer or heart disease.
Rush to judgment?

On the face of it, the newly released results suggest that millions of consumers who have been taking beta-carotene pills may have been hurting themselves--or at least wasting their time. But experts maintain that even in light of the negative findings, the beta-carotene case is not closed.

Consider that the ATBC trial involved only male smokers. And CARET included only smokers, former smokers, and workers exposed to asbestos. Scientists suspect that something about long-term exposure to cigarette smoke or asbestos in combination with beta-carotene supplements may promote lung cancer. It might be that some component of cigarette smoke interacts with beta-carotene to generate particularly harmful by-products in the body, according to Norman Krinsky, PhD, a beta-carotene expert at the Tufts University School of Medicine. But at this point, he says, "We know zilch about what these by-products might be," and more research is required to pinpoint them.

Another unanswered question is why study after study has revealed a significant association between diets rich in beta-carotene and a reduced risk of lung cancer, but the major supplement trials have "failed." Again, possibilities abound. Maybe beta-carotene "works" only in the presence of some other substance in fruits and vegetables, like chlorophyll. Or perhaps it's not beta-carotene at all, but some other substance in produce that confers protection against cancer.

Back in the 1980s, when interest in beta-carotene took off, it was the only member of a group of substances called carotenoids that scientists had singled out as a possible disease tighter. And because beta-carotene was available in pill form, it was a convenient substance to test in large-scale trials. During the past few years, however, scientists have come up with more and more research suggesting that beta-carotene is just one of many members of the carotenoid family that may fight disease.

For example, researchers now suspect that the carotenoids called lutein and zeaxanthin, found in spinach, kale, and broccoli, help protect against an eye condition called age-related macular degeneration, which ranks as the leading cause of irreversible blindness among older adults. And in December, Harvard University researchers published a study linking diets rich in another carotenoid named lycopene, found primarily in tomatoes, with a decreased risk of prostate cancer. Because beta-carotene is found along with other carotenoids in fruits and vegetables, it may serve as a marker of fruit and vegetable consumption but not be the ingredient that is staving off disease (see blue box on page 5).
The trials continue

Another reason experts say the jury is still out on beta-carotene concerns the design of the studies that have been concluded or stopped thus far. The Physicians' Health Study was a primary prevention trial aimed at determining if beta-carotene helps prevent cancer or heart disease in a healthy population. The ATBC trial and CARET were both secondary prevention trials, which were designed to see whether beta-carotene helps prevent cancer in high-risk groups like smokers or people exposed to asbestos. But if beta-carotene supplements were tested in, say, a secondary prevention study of a large group of men at high risk for a disease other than lung cancer, the outcome might be different. What's more, all three trials involved only men; beta-carotene may behave differently in women.

Because so many questions remain, some of the trials on beta-carotene are continuing despite the latest round of negative findings. One is a secondary prevention trial called the Women's Antioxidant and Cardiovascular Study, designed to evaluate the effect of vitamin E, vitamin C, and beta-carotene in some 8,000 women at high risk for heart disease. Besides acting as an antioxidant, beta-carotene is thought to help relax the artery walls, making them more flexible and less likely to become blocked.

"We haven't seen any evidence of harm from beta-carotene in these women, and there's good reason to believe beta-carotene may benefit them," says Jo Ann Manson, MD, a Harvard researcher who is spear-heading the trial. "But we're going to be monitoring the interim results very closely."
Beta-carotene and beyond

Time was when nutritionists viewed beta-carotene and other members of the, carotenoid family as nothing more than vitamin A precursors, that is, substances that were converted into vitamin A in the body. Today we know of more than 500 different carotenoids, many of which appear to function as much more than just vitamin A precursors.

Scientists have only begun to scratch the surface to learn about how these substances work in the body. Preliminary research suggests that two carotenoids--lutein and zeaxanthin--protect the eyes against age-related macular degeneration, which afflicts one in three people over age 75. Another carotenoid, lycopene, may help stave off prostate cancer.

Despite the potential of carotenoids, food composition tables currently used by nutritionists still lump beta-carotene and its relatives together under vitamin A, making it difficult to identify good sources of particular carotenoids. Fortunately, the U.S. Department of Agriculture and the National Cancer Institute have begun putting together the first carotenoid database, from which the following chart is derived.

Note that there is no recommended dietary allowance for the various carotenoids. The table however, highlights good sources of carotenoids and underscores the benefits of eating a wide variety of produce. It also helps you see what you're missing if you rely on supplements alone rather than eating fruits and vegetables.

Legend for Chart:

A - Beta-Carotene (micrograms)[*]
B - Lutein & Zeaxanthin (micrograms)
C - Lycopene (micrograms)

A B C

1/2 cup cooked broccoli 1,014 1,404 0
1/2 cup Brussels sprouts 374 1,014 0
1 medium raw carrot 5,688 187 0
1/2 medium pink grapefruit 1,611 0 4,135
1/2 cup cooked kale 3,055 14,235 0
1 medium peach 86 12 0
1 cup raw spinach 2,296 5,712 0
1 medium tomato 640 123 3,813
3/4 cup tomato juice 1,638 0 15,616

* A microgram is a thousandth of a milligram. Amounts are averages taken from a number of samples and should be viewed as estimates rather than hard-and-fast values.

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