A Consuming Controversy

As part of our daily diet, most of us unwittingly consume a cornucopia of endocrine disrupting chemicals (EDCs). These compounds-you've likely heard of bisphenol A (BPA) for example-interfere with normal hormone function. They are in many fertilizers and pesticides and often in the linings of cans, on the nonstick surfaces of pots and pans, and in beverage bottles.

No problem, says Julie Goodman-at least not with BPA. Not even for infants or pregnant moms.

Goodman, PhD '02, ScM '00, represents one side of a debate about whether EDCs are contributing to obesity, heart disease, cancer and other public health problems. Her systematic reviews of published research-she works full time as an industry consultant evaluating health risks from chemicals in consumer products and the environment-indicate that low exposures to BPA are a nonissue.

She has testified to that fact before state legislative committees considering potential restrictions on BPA. And, to address any suspicions of bias, consider that as a new mother she sought out and used baby bottles made of polycarbonate (which contains BPA, a substance that manufacturers voluntarily stopped using even prior to a government ban).

"I need to walk the walk," Goodman explains, "if I believe in my own scientific conclusions."

Other scientists hold different conclusions. Investigated for decades by researchers focused on reproductive and developmental effects, BPA is one of about 800 chemicals known or suspected to be capable of interfering with hormone function. Endocrine disruption, a mounting concern since the 1980s, has been blamed for declining fertility rates as well for increasing rates of the endocrine-associated cancers, namely breast and prostate.

"The multiplicative effects of many chemicals on the endocrine system are difficult to predict," says prostate cancer researcher Terry Brown, PhD, a professor in Biochemistry and Molecular Biology.

Brown represents that camp of scientists who contend that "dose" doesn't matter because hormone receptors are exquisitely sensitive at critical times of human development.

Goodman's not buying it. She attributes the BPA fervor to scientific cherry picking. What's missing, she contends, are consistent, replicable results that indicate evidence of adverse effects on human health. People are exposed to much lower levels than are used in most experimental studies, she points out.

"One study looks at the effect of BPA on 30 things in live animals, and finds an effect on prostate weight but no effect on anything else," Goodman says. "Another study looks at 30 things in live animals and doesn't find an effect on the prostate, but finds an effect on mammary glands. The media interprets this as: Bisphenol A causes effects on prostate and mammary glands. That's not solid science. That's a whole bunch of studies that find one effect here, one effect there. But are the effects because of bisphenol or statistical anomaly, or poor methodology or something else? You can't ignore that question."

The human body naturally has high levels of hormones, she reasons. If you compare the potency of bisphenol exposure from water bottles or canned tomatoes, versus natural estrogen in a person, "it's like nothing," she says. "It's like a grain of sand on a beach."

Goodman's former PhD advisor, James D. Yager, PhD, the Edyth H. Schoenrich Professor in Preventive Medicine, describes her as "brilliant" and her analyses as sophisticated. Meanwhile, he is collaborating on research to determine the effect of endocrine disruptors-beginning with BPA-on signaling and metabolic pathways. Yager, director of the Molecular and Translational Toxicology Program, is working with Thomas Hartung, MD, PhD, the Doerenkamp-Zbinden Endowed Chair for Evidence-Based Toxicology. Using a human cell culture model, they are employing mass spectrometry to detect cellular metabolites whose levels are altered by low concentrations of BPA and other EDC chemicals.

Hartung aligns with the faction that doubts the relevance of EDC contamination on human health. But it's an exceedingly complex issue, concedes the director of the Center for Alternatives to Animal Testing. It requires a whole new method of investigation.

"In a situation of controversy, we need data," Hartung says. He's developing a new endocrine disruptor screening paradigm because, he says, the current toolbox (which relies largely on animal testing) is too costly, time-consuming and crude.

His strategy is to use emerging technologies to better understand the mechanism. This involves developing high-throughput human cell-based assays that show not just what binds to what receptor but also the results of that binding, the so-called downstream effects.

When we rush to get rid of substances like BPA, they are likely to be replaced with new compounds that have not been tested as much, or at all, Hartung cautions. Case in point: One replacement for BPA is BPS, another bisphenol compound. Some think it's not a great choice given its tendency to leach out of the plastic (though less than BPA) and its staying power (greater than BPA). A recent Environmental Health Perspectives study showed that very low levels of BPS interfere with normal hormone activity in animal cells.

In addition to his work with Hartung, Yager is collaborating on a grant for a BPA project with DeLisa Fairweather, PhD, associate professor, Environmental Health Sciences. An immunologist and expert in the emerging science of sex differences, Fairweather is looking at EDCs through a new prism that's decidedly different from any that toxicologists traditionally use. She's exploring the effects of BPA in a mouse model of myocarditis (inflammation of the heart), a male-dominant disease that's driven by sex hormones. Females are protected against heart disease by estrogen. Fairweather's female mice are protected too-unless they sip water treated with low doses of BPA, which renders them male-like, immunologically speaking.

When exposed to coxsackievirus (the most common agent for myocarditis in the U.S.), they developed severe heart disease much more frequently than females who weren't ingesting levels of BPA equal to "high human-relevant" doses.

A bit of BPA alone doesn't cause heart inflammation in mice. But in tandem with a common virus, it alters a once-protective signal and leads more often to a worse disease state.

"BPA can act as a co-factor; alone it would probably never do this," Fairweather says, crediting PhD candidate Katelyn Ann Stafford with that finding. "Receptors activated by the virus and sex hormone receptors work together to drive inflammation in the heart. BPA alters that process, allowing a heightened inflammatory response."

Fairweather, like Brown, argues that any interference with hormones is disruption, and that's likely to have negative consequences, if not right away, then sometime in the future. Meanwhile, toxicologists like Goodman and Hartung bristle at what they see as an inherent inaccuracy in the popular moniker "endocrine disrupting chemical," preferring instead the more neutral endocrine-active chemical. These substances might act like hormones without actually disrupting or interfering with anything, they say.

Goodman says she will change her mind if persuasive data emerges. "But," she adds, "that hasn't happened yet."