Low Doses of Common Chemical Have Science in a Quandary

A Compound Found in Many Plastic Items Stirs Debate Over Possible Widespread Health Risks

Karen Brandon / Chicago Tribune 26dec00

Frederick vom Saal's famous white mice live in shoebox-like containers shelved in basement closets beneath the flat Missouri plains.

These tiny, elaborately monitored animals have been exposed to a chemical that is ubiquitous in modern life, a building block of the plastic found in food containers, bottles, nail polish, eyeglass lenses and other everyday products.

The doses administered by the University of Missouri professor were small--so small that many researchers dismiss them as harmless and not worth testing.

So when vom Saal's mice developed reproductive abnormalities, they caused a sensation.

In essence, the mice have provoked a debate in science and public policy circles about the health risks of exposure to chemicals at levels commonplace in the environment, even infinitesimal amounts.

And in particular, they have challenged the established methods of assessing potential health hazards posed by a group of substances called endocrine disruptors because of their ability to affect such hormone-driven biological processes as growth and reproduction.

In October, a panel of experts put together by the National Toxicology Program met to review for the first time the scientific merit of what vom Saal and other researchers call the low-dose hypothesis: namely, that minute exposure to endocrine-disrupting chemicals can have significant negative effects.

The experts examined dozens of the studies that have brought attention to this growing controversy, including those conducted by vom Saal, the most vocal of scientists working on the topic.

The results of the review, expected to be compiled into a report early next year, could bring changes to the nation's health and environmental policies and its industrial practices. If significant effects at low doses are found, the U.S. Environmental Protection Agency, for example, would consider changing the way it does its tests.

"If EPA is using standard, traditional tests to do their risk assessments, are they missing something?" asked panelist Ralph Cooper, chief of the EPA's endocrinology branch. "You're always worried about what you're missing."

At the heart of the question are the delicate workings of the body's endocrine system, a network of hormones and glands that governs growth, development and reproduction, intertwining closely with the immune system and the brain.

The precise effect of endocrine-disrupting chemicals on the system is not well known, but they are thought to be dangerous because they closely mimic the action of molecules produced by the body.

"Basically, embryos come with everything they need for normal development. You go beyond that, and you start getting into pathologies and dysfunctions," said David Crews, a zoology and psychology professor at the University of Texas at Austin.

Bisphenol-A, the substance given to vom Saal's mice, is not a household name. But as the chemical building block of polycarbonate plastic, it is in so many commonplace products--from dental fillings to compact discs--that the United States uses nearly 2 billion pounds of it every year.

When vom Saal exposed male mice to a tiny amount of BPA during their fetal development, they grew abnormal prostates and damaged testes and had lower sperm production. Females entered puberty at earlier ages, and both sexes showed an abnormal increase in their growth rate.

Vom Saal, a 55-year-old biological sciences professor, likens the interaction between small doses of BPA and the endocrine system to the workings of a stereo.

"Cells in the body are like stereo amplifiers," he said. "The cell has systems that take little signals and put out a huge blast of information."

Scientists had discovered in 1936 that BPA, an organic compound synthesized in 1905, could act as a weak estrogen. But its principal use came in 1953, when researchers found they could transform BPA with heat and pressure from a clear liquid at room temperature into a clear, hard and useful plastic.

The chemical's old reputation as an estrogen re-emerged seven years ago, when scientists at Stanford University's medical school reported their experiments had been tainted by BPA leaching from plastic flasks they were using. The cells reacted even though the amounts were too small to be detected by the maker's safety testing procedures.

About the same time, other researchers reported similar contamination from another type of plastic. Since then, consumer protection and environmental groups have asked that some of these chemicals be removed, mainly from use in baby bottles and toys, and some companies voluntarily complied.

But the U.S. Food and Drug Administration steadfastly has said the amount leaching out is quite small, especially under normal conditions of use, and is safe.

What was so startling about vom Saal's research is that his mice showed effects after receiving an extraordinarily minute quantity of BPA--about 100,000 times smaller than commonly tested in standard methods and 1,000 times lower than anyone had tested previously.

Those levels have been pronounced safe by government regulations and are said to be the equivalent of the exposure people receive in the course of everyday life.

In some of vom Saal's experiments, the characteristics that appeared as the result of very low doses of BPA showed the opposite effect brought on by high doses. A very small dose led to an abnormally large prostate, while a large dose led to an abnormally small prostate, for instance.

Such results raise questions about a standard assumption of toxicology--specifically that by testing at higher doses, scientists generally can predict the potential effects and safety of much lower ones. Advocates of the low-dose theory essentially argue science is failing to assess the potential effects from exposure to endocrine-disrupting substances because it asks the wrong questions.

The FDA has dismissed vom Saal's results, saying any human exposure to BPA is so minimal that it presents no harm. But the National Toxicology Panel's entry into the fray signals the debate over the low-dose theory is far from over.

"This raises a public policy nightmare because of the way it undermines the standing and assurances of tests that have been done," said John Peterson Myers, co-author of the book "Our Stolen Future," which argues that hormone "impostors" are threatening mankind. "It dramatically compounds the hurdles that have to be passed to reach some assurances of safety. Those hurdles have implications in time and money."

To explain the difference in the traditional and new approaches to hazardous substances, Myers offered this analogy:

"Imagine your goal is to make sure a ship doesn't reach port," he said. "Under the old toxicology model, you have to bomb it. But suppose you can get one terrorist on board who substitutes for the pilot, and he can change the ship's course by a degree or two right when they take off. The ship will end up somewhere on a reef instead of in port. ... The new paradigm is saying you can hijack a cell's mechanisms."

Some researchers contend there is no dose of endocrine-disrupting chemicals small enough to be safe. Detractors say this view is alarmist, absent compelling evidence of human harm and dependent on limited and flawed animal studies.

Stephen Safe, a toxicology professor at Texas A&M University, is perhaps the most outspoken scientist who dismisses the low-dose premise. Although he does not take issue with the merits of vom Saal's science, as others have done, he questions its broader significance.

"There's one problem with the low-dose effect theory," he said. "The human data suggest there isn't any effect of these things at all. We see wildlife effects, but the human effects, as far as I can see, don't exist."

In animals, endocrine disruptors have been linked to eggshell thinning, altered sex ratios and creatures that show signs of both sexes. But in humans, they are a suspected, but not proven, cause of a variety of ailments, including cancers and reproductive problems.

Differences of opinion over the substances' effects occur in part because it would be unethical to test them on humans. Most studies use animal subjects--and animals are an imperfect substitute.

The public health dilemma, then, is what policy to pursue in the face of incomplete information. Industry argues it can never absolutely prove the safety of chemicals, but others argue the policy is skewed in favor of industry at the expense of potential health effects.

"When you get to industrial chemicals, things that are in products, the theory there of our regulation is `innocent until proven guilty,'" said Sheldon Krimsky, a Tufts University professor of urban and environmental policy and author of "Hormonal Chaos," a book on the endocrine-disruptor debate. "It's very difficult to prove that a chemical is a public health threat because we just can't do the experiments on humans. Every experiment you do is an approximation."

Richard Jackson, the physician director of the National Center for Environmental Health at the Centers for Disease Control and Prevention, said: "I would argue for caution. There is a long history of examples where chemical exposures that were thought to be harmless have turned out to be major problems--lead, DDT, PCBs. I think the goal should be that no child should be exposed until we know it's safe."

The A&M professor also argues for caution, but of a different sort.

"We'd better be very careful about banning compound X before allowing compound Y that may have an effect," Safe said. "Chemicals make the world go 'round. We could go back to the Stone Age."

Industry representatives argue that current testing for Bisphenol-A are more than adequate. The industry's Web site, www.bisphenol-a.org, calls the substance "one of the most extensively tested materials in use today," citing 40 years of studies that support its safety.

The bulk of tests has focused on how much of it leaches into food and drink, and the results vary widely. Some studies indicate no measurable leaching, and in others, industry and regulators dismiss the amount of BPA migration as minimal under normal use.

The concern over endocrine disruptors stems in part from the cautionary tale of DES, a potent estrogen given to millions of pregnant women beginning in the late 1930s. The drug was prescribed to them because it was falsely thought that boosting estrogen levels would reduce the chance of miscarriage.

Decades later, in the 1970s, science began to tie cancers and other medical problems appearing in young men and women whose moms had taken DES in pregnancy.

And though BPA is a much less potent chemical than DES, the reaction of vom Saal's mice to BPA was strikingly similar to that produced by the stronger drug.

Citing such findings, advocates of the low-dose theory say endocrine-disrupting substances require a rethinking of traditional ways of assessing risk, recognizing the significance of subtle yet harmful bodily changes, the particular vulnerability of fetuses to chemicals, and the potential delay between exposure and health effects.

Vom Saal is not alone in advocating these points, but he is at the center of the storm.

Environmentalists have championed him as the successor to University of Pittsburgh researcher Herbert Needleman, who was put on trial for scientific misconduct over his studies documenting human harm from lead. Those studies were later validated, and at levels much lower than anyone previously considered harmful.

Industry officials deride vom Saal because three studies they funded have failed to replicate his findings. Vom Saal counters that the industry studies are flawed.

Until recently, the industry also was able to say that no one else had replicated the University of Missouri findings, but a study corroborating vom Saal's results was published in a respected peer-reviewed journal in June.

"I found the same effect," said Chhanda Gupta, an associate professor in the pharmacology department at the University of Pittsburgh medical school. "I don't know how much you can equate it to the human, but this tells me we should be careful."

Tribune environment writer Jeff Long contributed to this report.