Time for a Debate on Folate?
Too much of a good thing could turn out to be bad
Six decades ago, Harvard physician Sidney Farber discovered to his disappointment that a synthetic form of the vitamin folate called folic acid, recently shown to prevent cancers in lab animals, actually accelerated the disease in children dying of leukemia. Making good of his inconvenient discovery, Farber went on to develop folate-blocking compounds that became some of the world's first chemotherapies. Separately, other scientists discovered folic acid's tremendous power for good—it prevents birth defects such as spina bifida—and launched a movement to make sure people get enough. But echoes of those early findings have been reverberating of late: New research links widespread use to a surprising rise in colon cancer and perhaps other tumors.
Today, the vitamin is a common food additive throughout North America, and U.S. adults are told to have at least 400 micrograms a day. Since 1998, by government mandate, flour, bread, cereal, pasta, rice, and other grain products have been fortified with folic acid in a campaign to end folate deficiency in childbearing women. Associated birth defects have since fallen by as much as half, from what used to be about 3,000 cases per year in the United States. Folic acid also appears to safeguard some older people against stroke and cognitive decline, and researchers haven't abandoned Farber's original hope that it can stave off cancer. Some manufacturers elect to add it to other foods, too, and many people get an extra dose from a daily vitamin pill.
But some researchers now worry that the vitamin has a dark side. "The [established] benefits are limited to a very specific population—women of childbearing age," says Young-In Kim, a gastroenterologist at the University of Toronto who has studied folate's complex relationship with cancer. "In other groups, it might do more harm than good." Kim and others suspect that folic acid wields "a double-edged sword," as he puts it. Cells use folate to keep their genetic software—their DNA—in good repair and to make copies of DNA when they divide. DNA is less likely to develop the sorts of defects that lead to cancer when it's well maintained, so folate may lower cancer risk in people who are healthy. But once a defect is present, experts theorize, replicating cancer cells hungrily gobble up folate to make new copies of their malevolent DNA. Often, defective cells lurk undetected in outwardly healthy people. "What we've discovered," says Joel Mason, a Tufts University gastroenterologist, "is that folate seems to have a paradoxical effect."
Unintended outcome? The paradox could account for an upward shift in colorectal cancer in both America and Canada in the late '90s. According to Mason's latest research, which appeared in the July issue of Cancer Epidemiology, Biomarkers & Prevention, folic acid fortification may be causing 4 to 6 colorectal cancers annually per 100,000 people—and alternative explanations, such as increasing rates of cancer screening, don't seem to account for the spike. "That works out at 15,000 new cases per year in the U.S.A.," says A. David Smith, a pharmacologist at the University of Oxford in England who advised a British government panel to postpone the country's planned food-fortification policy.
Another worrisome finding comes from a recent cancer-prevention trial in which researchers gave pills containing 1,000 micrograms of folic acid to half of about 1,000 people. Over the next six years, both groups developed precancerous polyps at the same rate—though the people who'd been taking folic acid seemed more prone to particularly dangerous polyps. Moreover, they developed more unrelated cancers—mostly prostate tumors—than did people who received dummy pills.
Folate's effects on the brain, in contrast, appear to be mainly positive. For example, taking folic acid supplements seems to cut stroke risk by about 18 percent in people who are at elevated risk, according to a report in the Lancet in June. High folate levels also appear to preserve seniors' cognitive abilities—usually. Two recent studies, however, suggested that they could have the opposite effect in seniors who have lower-than-average levels of vitamin B12. "These are just the first peeks at potential risks," says Martha Clare Morris, a nutritional epidemiologist at Rush University Medical Center in Chicago, who led one of the studies.
Right dosage. Even in this era of nationwide fortification, intake is largely under a person's control. Fortified foods add 128 micrograms of folic acid, on average, to a woman's daily intake, researchers at the Centers for Disease Control and Prevention recently found. A single daily multivitamin—or a serving of heavily fortified breakfast cereal—can pack 400 micrograms, which by itself is enough to prevent the vast majority of neural tube defects. "I don't know what the cutoff would be, but you don't want to get toward 1,000 [micrograms per day]," says John Baron of Dartmouth, who coauthored the recent cancer-prevention study. One multivitamin "is probably neutral to beneficial. But don't take two." However, Xiaobin Wang of Children's Memorial Hospital in Chicago believes taking 400 to 800 micrograms of folic acid daily is often warranted for preventing stroke.
Toronto's Kim offers different counsel. While women of childbearing age should use multivitamins, he says, "I would definitely advise [other people] against taking supplements with folic acid." In particular, he says, that applies to anyone who has cancer or is at risk of harboring precancerous growths because of family history, genetics, or advanced age.
Nobody is calling for a change to the U.S. fortification policy at this point. Many women still aren't getting enough folate, notes Michael Katz, senior vice president for research at the March of Dimes. But some researchers urge other nations considering fortification, including Britain and Australia, not to adopt a policy just yet. And they're not ruling out a reversal here. Says Baron: "We're exposing a lot of people, and we're in the uncomfortable position of not really knowing what it does."
On the Plus Side
Although some studies hint at potential risks, folate is often beneficial.
Fetal health: Women who may conceive need folic acid to prevent birth defects. Get 600 micrograms daily during pregnancy; 1,000 is considered the upper limit.
Brain: Folic acid may reduce stroke risk and, in people with ample vitamin B12, may guard against cognitive impairment.
Cancer: Folate may ward off cancer in healthy people (but accelerate it in others, such as survivors harboring hidden malignancies).
This story appears in the August 13, 2007 print edition of U.S. News & World Report.