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"We're a little bit concerned about that," Tillitt says. "We want to know: Is this the canary in the coal mine?"
Vom Saal saw his canary in the coal mine in the early 1990s.
He was testing dozens of natural estrogens — the estrogen found in soy, for instance — to observe their interactions with cells. He decided to test some synthetic estrogens as well, including bisphenol A. In the experiment, vom Saal noted that, unlike natural estrogens, bisphenol A molecules did not bind to blood proteins, which normally act like barriers, keeping the estrogens from entering cells.
"Since this barrier system was failing for this chemical, it means that the majority of this chemical that would get into your blood would go into your cells and potentially cause harm," vom Saal says. "So we did some very simple biochemical calculations. We gave a dose 25,000 times lower than any toxicologist had ever studied, and it wreaked havoc with the developing reproductive organs."
Vom Saal is speaking from his office at MU's Lefevre Hall, a two-story, white-stone building where biology classes are held, including vom Saal's popular graduate class on mammalian reproduction. Several framed photographs of vom Saal's wife, their daughter and his single-engine Cessna 210 (he's a pilot) sit atop file cabinets, but the rest of the office is dominated by shelves of document-stuffed accordion folders and thick academic texts.
Soon, he's joined by Wade Welshons, a professor of biomedical sciences, and Susan Nagel, a professor of obstetrics, gynecology and women's health. They are two of vom Saal's research partners who, along with four other professors, make up the Endocrine Disruptors Group. It's a new field of study that vom Saal, Welshons and Nagel helped establish.
Nagel has a cheerful voice and an infectious laugh; she pulls up a chair in vom Saal's office. She came to vom Saal's lab as a grad student in 1993, working with breast-cancer cells. Not long after vom Saal had made his first observations using bisphenol A, he suggested to Nagel that she take up the work.
Nagel recalls, "He said, 'I have this project that's just guaranteed to be a short study, and you'll get a publication out of it. You already know how to do the techniques, so all you have to do is go over to his [Welshon's] lab and just turn this out.'"
The "short study" ended up taking her more than two years, but Nagel did come out of it with a publication — a landmark. Toxicologists' tests on bisphenol A claimed that it was nontoxic at extremely high doses, but Nagel's study showed that bisphenol A was hormonally "active" — meaning it caused an effect — in cells at levels thousands of times lower than toxicologists had previously deemed to be safe.
These "low-level effects," as Nagel's findings came to be called, represented a whole new way of thinking about chemicals and human safety. Toxicologists look at high doses of chemicals to find out how much is necessary to cause serious harm — birth defects or death. But endocrinologists know that the amounts of a substance necessary to cause harm on a hormonal level are tiny and can pack profound consequences. Exposing a developing fetus to additional estrogen, for example, can permanently alter crucial phases of development, irreversibly altering systems that are designed to react to the most miniscule changes in hormone levels.