The Experiment That Could Clobber Ex Lax

Experts using a new toxicology test say it may cause cancer, but is the method valid?

Ex-Lax has been a fixture in many an American's medicine cabinet for decades. But on June 3, the century-old laxative became the target of an ad campaign that claimed its active ingredient causes cancer. Launched by Schering-Plough Corp., the maker of rival laxative Correctol, the ads followed an Apr. 30 Food & Drug Administration committee meeting at which Ex-Lax' active ingredient--phenolphthalein--was deemed a cancer risk to humans. How did such a trusted consumer product become suspect?

The plight of Ex-Lax is hardly unique. In the 1970s and '80s, every few months another chemical--a pesticide, food dye, or sweetener--was being pilloried as cancerous. Many, like the one in Ex-Lax, were on the market before the government began requiring extensive toxicology testing. Saccharin, grape flavoring, and nitrates are just a few examples.

DNA DAMAGE? In all, the government's cancer testing program, set up 25 years ago to run animal tests on suspicious chemicals, has examined 500 substances. The standard tests involve giving rats and mice very large quantities of a chemical--often 60 or 70 times more than the equivalent maximum dose humans would receive--for two years. Controversy over how to relate data from these overtaxed mice to man has raged ever since.

The phenolphthalein case has intensified the disagreement. Evidence of phenolphthalein's carcinogenicity was uncertain using the standard two-year rodent tests, so researchers tried an experimental test using mice that have been genetically altered to be very susceptible to tumors. Novartis, which markets Ex-Lax, has questioned the validity of the new test and says it believes its products are safe. But John R. Bucher, deputy director of the Environmental Toxicology Program at the National Institute for Environmental Health Sciences in Research Triangle Park, N.C., defends the findings: "A number of different tests pointed to the same thing," he says.

In the 1980s, cell culture tests done at the National Cancer Institute on phenolphthalein raised the red flag, says the cancer institute's Harold Seifried. The tests found that, when broken down by the body, the chemical damages cells and their DNA. Phenolphthalein was placed on a list of suspicious substances. This list was then sent to the National Toxicology Program, part of the National Institute for Environmental Health Sciences.

Faced with a huge backlog of more alarming chemicals, the toxicologists didn't get to phenolphthalein until 1991. They then began conventional two-year rodent studies. When a draft of the results was first released in December, 1995, the FDA and representatives from the toxicology program and industry decided that more testing of phenolphthalein was needed.

Schering-Plough deemed the preliminary data alarming enough. The company began substituting another active ingredient--bisacodyl--for phenolphthalein in its Correctol and Feen-a-mint laxatives. The change also reduced the laxatives' effectiveness, however, and Schering's laxative sales dropped 27% this year, to $33 million.

In April, 1996, the FDA's carcinogenicity assessment committee agreed that there was clear evidence of tumors in rats and mice from phenolphthalein but voted 7 to 5, with one abstention, that the data so far did not indicate a risk to humans. The FDA decided to wait for new mice data before reaching a final conclusion.

The National Toxicology Program presented its final report on Apr. 30 of this year. The clincher was a test on so-called p-53-deficient mice. The p-53 gene is a tumor-suppressor gene that helps keep cancers from forming. Most mice--and humans--carry two copies of this gene, but p-53-deficient mice carry just one, making them more susceptible to tumors. Thus, a lab needs fewer mice and only six months, instead of two years, to get results. That can also cut costs by up to 70%. But the specialized mice have been around for only three years, so the test is not fully validated.

"PUBLIC SCARE." The results of the p-53 test on phenolphthalein seemed convincing to the FDA, though. The committee members voted 15 to 1, with one abstention, that the laxative ingredient posed a "relevant carcinogenic risk for humans." The test also helped convince them that phenolphthalein had a so-called genotoxic mechanism--it damaged DNA.

Novartis officials do not--as yet--plan to drop the chemical. The dosages given the mice "would be similar to a human taking 60 pills of phenolphthalein a day for an entire lifetime of 70 to 75 years," argues Marc B. Gelbert, vice-president for scientific affairs. "This has created more of a public scare than it has an issue of human health."

So what is the final verdict? The cancer institute's Seifried, who stresses that he is not a regulator, says phenolphthalein is "fairly low down on the scale of potency." Its risk depends on who is taking it and how often they take it. The FDA ended a 30-day review and comment period on June 13 but has yet to take action. Since the drug is not medically important--there are alternatives, and constipation is not usually life-threatening--the agency could take a harder line. It could ban phenolphthalein, suggest a voluntary recall, or require label warnings.

The laxative brouhaha is still unfolding. Schering-Plough has pulled its attack ads, under pressure from the FDA. And Bucher says that bisacodyl, the ingredient in Schering's laxatives, is "structurally very similar to phenolphthalein." It is also under review and will undergo similar testing. Meanwhile, the debate over how relevant rodent tests are to humans is reigniting. Ex-Lax, a trusted household name, could be the first to get burned.