ANTIOXIDANTS REPORT SETS CEILINGS.

"It's too early to say." That was the recurring theme of the report on four antioxidants--vitamin C, vitamin E, selenium, and carotenoids--issued in April by the National Academy of Sciences (NAS).(1)

Although the NAS made minor changes in the Recommended Dietary Allowances (RDAs) for vitamins C and E and selenium, most noteworthy was what wasn't said. The scientists set no numbers for carotenoids like lutein, lycopene, and beta-carotene. And they concluded that it's too early to say whether antioxidants could help prevent major threats like cancer, heart disease, diabetes, or Alzheimer's disease.

"Does taking larger doses of dietary antioxidants help limit the gradual buildup of cellular damage that one day may turn into chronic disease?" asked NAS panel chair Norman Krinsky of the Tufts University School of Medicine in Boston.

"After a comprehensive review of the scientific evidence, our panel concluded that too little is known at present to provide a definitive answer."

It's not surprising that the scientists stopped short of more sweeping advice. In fact, the evidence is still in the promising-but-not-conclusive stage--which means that reasonable people could decide to either take or not take high-dose antioxidant supplements (see NAH, April 2000).

The most useful part of the report: The panel set Tolerable Upper Intake Levels (ULs). "ULs are a ceiling," says Krinksky. "They're the largest amount that healthy individuals can take each day, from food and supplements, without risking adverse health effects." Here's the rundown on the NAS's Upper Levels for the four widely consumed antioxidants.

Vitamin C--2,000 mg a day

The panel set an Upper Level for vitamin C based on reports of diarrhea in several small studies. But after two scary headlines the month before the NAS report, the possibility of diarrhea must have sounded downright reassuring to vitamin-C-takers.

Doses of 500 mg a day or more could clog arteries that feed the brain, warned one wave of earlier media reports. But the results of that study, which haven't been published, are too shaky to act on (and are so preliminary that the NAS panel never considered them).

The study measured blockages in the carotid arteries of 570 healthy middle-aged men and women on two occasions, 18 months apart. Arteries clogged faster in those who reported taking 500 mg or more of vitamin C a day than in those who said they took less. The link was even stronger among smokers. But questions remain.

"The blood levels in vitamin-C-takers were lower than they should have been in people taking supplements," says Mark Levine, a vitamin-C expert at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. That suggests that people didn't actually take the amount of vitamin C they said they took.

What's more, in the larger, well-designed Atherosclerosis Risk in Communities study,(2) "researchers saw fewer arterial lesions with increasing intakes of vitamin C," says Iswarlal Jialal, an NAS panel member from the University of Texas Southwestern Medical Center in Dallas.

The bottom line: Sit tight. "We can't review the unpublished data because it's only an abstract," says Levine. "There are offen surprises when a full study is published."

Soon after that alarm died down, another one went off. "High doses of vitamin C may interfere with cancer treatments," cautioned headlines.

The source was David Golde of the Memorial Sloan-Kettering Cancer Center in New York. His conclusion was based on a published study in which mice were injected with human cancer cells from the breast, prostate, and blood. The tumors that later developed readily absorbed vitamin C.(3)

"Now we know exactly how tumors acquire and retain large amounts of vitamin C," said Golde. "It's conceivable that vitamin C might make cancer treatment less effective, and therefore reasonable that cancer patients undergoing chemotherapy should avoid taking large amounts of this vitamin."

But not everyone agrees.

"It's been known for years that tumor tissues accumulate vitamin C, just as healthy tissues do," says Levine. "But we have no data from human studies to say whether or not vitamin C promotes tumor growth or prevents radiation or chemotherapy from working."

Without data, it's impossible to make any recommendations, he adds. "The only way to know is to do a study."

Vitamin E--1,100 IU (synthetic) or 1,500 IU (natural) a day

The NAS panel based its Upper Level for vitamin E on studies showing that very high doses can cause hemorrhages in rats. "But there are no good data to show that vitamin E in high doses is toxic to humans," says Jialal.

The experts did note that a trial on 29,000 Finnish men found a slightly higher risk of hemorrhagic stroke in those who were given 50 IU (International Units) of vitamin E a day. But in three other trials in people with heart disease who were given 300 IU to 800 IU a day, researchers saw no signs of hemorrhage.

"And in two of those trials, some of the participants also got either fish oil or aspirin, which would increase the potential for bleeding," notes Jialal.

He adds that the Finnish men were smokers with high cholesterol, high blood pressure, and "a lousy diet." Indeed, the report called the results "preliminary and provocative, but not convincing...."

The panel did caution that high doses of vitamin E could cause bleeding in people who are deficient in vitamin K or who are taking anti-clotting drugs like coumadin.

"Both E and K are fat-soluble vitamins, so it's possible that they compete for absorption in the gut," explains Jialal. In other words, too much vitamin E may keep vitamin K from entering the bloodstream.

The bottom line: Tell your doctor if you're taking coumadin and vitamin E.

Selenium--400 mcg a day

Lost or brittle hair or nails. The panel picked those signs of selenium toxicity to set an Upper Level for the trace element because those minor problems are more common than gastrointestinal disturbances, fatigue, nervous system abnormalities, or other signs of toxicity.

Unfortunately, the experts had to base most of their calculations on a report of toxicity in only five people who got their selenium from food, not supplements. Fortunately, hair and nail loss aren't terribly severe side effects, and they are usually (though not readily) reversible.

What makes selenium tricky is that different regions of the U.S. have more or less in the soil, which means higher or lower levels in food and water. Though Americans eat less and less locally grown food, selenium intakes still vary widely.

"Typical intakes in the U.S. are about 100 micrograms a day," says panel member Susan Taylor Mayne of the Yale University School of Medicine. "But there are areas, like South Dakota, where people consume much more, and other areas, like the Southeast and parts of Connecticut, where intakes are much lower."

The panel didn't advise the public to take selenium supplements, despite a clinical trial on skin cancer in the Southeast that unexpectedly found a lower risk of lung, prostate, and colon cancers in people who were given 200 micrograms (mcg) of selenium a day (see NAH, April 2000).

"The number of people in the study with cancers of the lung, prostate, or colon was small, and the findings came out of the blue," says Mayne.

A new cancer trial testing selenium (200 mcg a day) and/or vitamin E (400 IU a day) on roughly 32,000 men is about to get under way, she adds.

"The results of the first trial are extremely promising, but they weren't sufficient for us to say that people should take selenium."

Carotenoids--No Upper Levels

"A UL has not been set for beta-carotene or carotenoids," said the NAS panel. For lycopene, lutein, and most other carotenoids, there's no UL because there are no known harmful effects at high doses.

But for beta-carotene, the panel's reasoning was quite different. No UL was set, said the experts, because "based on evidence that beta-carotene supplements have not been shown to confer any benefit for the prevention of the major chronic diseases and may cause harm in certain subgroups ... beta-carotene supplements are not advisable for the general population."

That's a fairly strong statement. But then, lung cancer is a fairly fatal disease.

The evidence that beta-carotene increases the risk of lung cancer comes from two large trials in smokers and asbestos workers, who already were at high risk. Participants were given high doses of beta-carotene (20 to 30 mg--or 33,000 to 50,000 IU--a day) for five to eight years. Instead of cutting the risk of lung cancer, as researchers had expected, beta-carotene raised it by 18 to 28 percent.

"The results were totally unexpected," says Mayne. "All the animal and population data supported a reduction, not an increase, in risk."

In a third trial, 50 mg (83,000 IU) of beta-carotene every other day didn't raise (or lower) lung cancer risk in physicians. One possible explanation: Blood beta-carotene levels didn't rise as high in the physicians' trial.

"Different preparations from different manufacturers differ in how well the body can absorb them," Mayne explains.

While most of the physicians didn't smoke, about ten percent--2,200 of them--did. And although they took the beta-carotene for 12 years, "there was no increase at all in their risk of lung cancer," says Mayne. "So no one can fully explain why we saw an increased risk in two studies but not the third."

That's not to say that people should worry about beta-carotene in their multivitamins.

"The committee wasn't concerned about multivitamins that are designed to provide people with vitamin A," says Mayne. (Beta-carotene is converted into vitamin A in the body.) "It's the high-dose single-nutrient supplements that concerned us."

Nor should people fear that beta-carotene-rich foods like carrots, cantaloupe, and sweet potatoes are dangerous. In one study, getting 30 mg of beta-carotene from a supplement raised blood levels five times higher than getting the same amount from carrots.

"If you look at the literature on people who consume large amounts of beta-carotene from fruits and vegetables, you see a dramatically lower risk of lung cancer than in those who consume less," says Mayne.

(1) "Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids," National Academy of Sciences, National Academy Press, 2000.

(2) Circulation 92: 2142, 1995.

(3) Cancer Research 59: 4555, 1999.

THE ANTIOXIDANT LINE-UP

If you don't know your RDAs from your DVs, you're not alone. The National Academy of Sciences (NAS) sets Recommended Dietary Allowances (RDAs) that vary, depending on gender and age. That's too much information to put on a food or supplement label, so the Food and Drug Administration (FDA) sets Daily Values (DVs) that apply to everyone aged four or older. The NAS has made (usually minor) revisions to the RDAs over the years, but the FDA hasn't changed the DVs since they were set in 1970s. So don't expect the DVs on labels to reflect the new RDAs for some time.

The RDAs and Tolerable Upper Intake Levels (ULs) shown below are daily intakes for adults (both men and women, unless otherwise indicated). The NAS set no numbers for carotenoids like lutein, lycopene, and beta-carotene.

Antioxidant                     Old RDA           New RDA

Selenium                        55 mcg (women)    55 mcg
                                70  mcg (men)

Vitamin C                       60 mg             75 mg (women)
                                                  90 mg (men)

Vitamin E, natural              11 IU (women)     22 IU
  (d-alpha tocopherol)          14 IU (men)

Vitamin E, synthetic            11 IU (women)     33 IU
  (d-alpha tocopherol)          14 IU (men)

Antioxidant                     Daily Value       Upper Level
                                (DV)              (UL)

Selenium                        Nose set          400 mcg

Vitamin C                       60 mg             2,000 mg

Vitamin E, natural              30 IU             1,500 IU
  (d-alpha tocopherol)

Vitamin E, synthetic            33 IU             1,100 IU
  (d-alpha tocopherol)

Source: National Academy of Sciences.