Animal Study Sheds Light on Link Between Cancer and High Doses of Beta Carotene Supplements

By Judy McBride

BOSTON, Mass., Jan. 5--Researchers explain in tomorrow's Journal of the National Cancer Institute how high-dose beta carotene supplements may have increased lung cancer rates among smokers in two large intervention trials reported in 1994 and 1996.

"The findings emphasize the advantage of getting important nutrients through foods rather than supplements," says Floyd Horn, administrator of the U.S. Department of Agriculture’s Agricultural Research Service

A study of ferrets--which metabolize beta carotene very much like humans--shows that excess beta carotene stored in the lungs becomes oxidized into products that turn the normal control of cell division upside down.

"These oxidized metabolites decreased a tumor suppressor and increased a tumor promoter in the animals' lungs," says lead researcher Xiang-Dong Wang, a physician and nutritional biochemist. An associate professor with Tufts University School of Medicine, he conducts research at USDA’s Human Nutrition Research Center on Aging at Tufts in Boston.

"Beta carotene gotten from fruits and vegetables is completely safe. There are no reports of harmful effects,” said Horn.

In fact, notes Wang, populations that eat more fruits and vegetables rich in beta carotene and other carotenoids have a lower incidence of cancer, particularly lung cancer.

Wang says the ferrets got the human equivalent of 30 milligrams of beta carotene daily--the dose given in the large intervention trials. By contrast, the average beta carotene intake from U.S. diets is 2 to 5 milligrams (mg) a day. "We're trying to encourage Americans to reach 8 to 10 mg a day through their diets," he says, noting that this dose in supplements should also be safe.

That means eating at least five servings of fruits and vegetables daily and including carrots, dark green vegetables, cantaloupe, sweetpotatoes, pumpkin and other squashes, peaches and mangos or other foods rich in beta carotene and other carotenoids.

Wang explains that body cells convert some of this beta carotene into a vitamin A-like compound, retinoic acid. This compound is reported to dampen cell division and is currently being used to treat skin cancer and leukemia. But an excess of beta carotene exposed to the high oxygen levels in lung cells--along with the oxidizing effects of cigarette smoke--apparently wreaks havoc with this fine-tuned system.

The oxidized beta carotene metabolites destroy retinoic acid, thereby decreasing its tumor suppressing activity. At the same time, they turn up the volume on a protein that activates cell division.

"These metabolites are actually biologically active. They promote cell multiplication and precancerous lesions," says Robert Russell, who oversees this research at the center. The findings "point out the importance of understanding how the body handles these trendy nutrients before we start recommending high doses," he adds. "It's a bit of a warning."

Wang used ferrets to study the effects of high-dose beta carotene combined with cigarette smoke because, in earlier research, he found that the animals handle beta carotene much the same as humans. One group was given the beta carotene supplements and exposed to cigarette smoke--equivalent to a person smoking 1.5 packs a day--daily for six months. Two other groups got either the supplement or smoke exposure for the same length of time, while a control group got neither.

The group getting both treatments had the strongest precancerous changes, Wang says. The products of genes that promote cell division were three- to fourfold higher in these animals than in the control group.

The findings help to explain why smokers in two large studies--the National Cancer Institute's CARET study reported in 1996 and an earlier Finnish study reported in 1994 and 1996--who took 30 milligrams of beta carotene showed an increase in lung cancer rates, prompting the CARET study to be cut short.

Scientific contact: Robert Russell, M.D., or Xiang-Dong Wang, M.D., Ph.D., Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts, Boston, Mass., phone (617) 556-3335 [Russell], (617) 556-3130 [Wang]; fax (617) 556-3344; e-mail addresses: wang_cn@hnrc.tufts.edu; russell@hnrc.tufts.edu.