University of Missouri biology professor Frederick vom Saal has been sounding the alarm about bisphenol A for a decade. Has he got your attention?

Rob Krebs

On a spring day one year ago, scientists in life vests and blue jeans invaded the bucolic slice of nature where Perche Creek empties into the Missouri River. The scientists, representing the U.S. Geological Survey and a lab from the University of Missouri-Columbia, suspended mesh cages in the river's current and filled them with fathead minnows — the white rat of the aquatic world, ideal for biological testing. Meanwhile, from the river's edge, National Geographic cameras took in the scene.

The TV crew was filming a special about bisphenol A, a synthetic material commonly used to make plastic. When it's formed into a polymer, bisphenol A makes a hard, clear plastic that isn't brittle, which is why nearly all water bottles are made from it, as well as eyeglass lenses and the linings of aluminum food cans.

Chemists know that bisphenol A has characteristics of estrogen, a hormone that determines sexual traits and is key in the development of brain function and nerve cells. Though toxicologists long ago deemed bisphenol A to be safe at high quantities, recent studies have linked it to several human epidemics, including breast and prostate cancer, enlargement of the prostate, early onset of puberty, hyperactivity in children and obesity.

National Geographic was invited on the river to record two days of fieldwork by Don Tillitt, a biochemist with the Geological Survey. Joining Tillitt was Frederick vom Saal, a biology professor at the University of Missouri and a leading expert on the harmful biological effects of bisphenol A.

Vom Saal is a controversial figure in his area of expertise — at least where the manufacturers of bisphenol A are concerned. His willingness to speak frankly about his findings is alarming to the top five makers of bisphenol A: Dow Chemical, Bayer Material Science, Sunoco Chemicals, SABIC Innovative Plastics and Hexion Specialty Chemicals.

More than 6 billion pounds of bisphenol A are produced every year.

"If I were to say to you, 'Oh, here's a pack of birth control pills. I'm going to extract out the hormone and make plastic out of them,' you'd think I was crazy," vom Saal says. "And indeed, the idea that you're using sex hormones to make plastic is just totally insane."

For a decade, vom Saal has seen the chemical industry distort his research and government regulators ignore it.

But after years of quietly publishing studies in scientific journals and presenting papers at toxicological conventions, vom Saal is starting to be heard. Since the first study of bisphenol A came out of his lab in 1997, he has been interviewed about the chemical for PBS' Frontline series and by ABC's 20/20. For FOX News, he has measured the amounts of bisphenol A that leach out of plastic baby bottles, and he has even been quoted in subculture-celebrating Vice magazine regarding the Texas-sized island of discarded plastic floating in a remote part of the Pacific Ocean. Recently, he has flown around the country to testify in front of state legislators writing measures against the use of bisphenol A.

Vom Saal was on the river with Tillitt a year ago because his measurements picked up meaningful quantities of bisphenol A in the waterways around Columbia that feed into the Missouri River. Tillitt's lab at the Columbia Environmental Research Center will spend the rest of this year trying to determine whether the quantities of bisphenol A in the water are causing measurable changes — what Tillitt calls a "fingerprint" — in the genes of the fathead minnows swimming in the cages set up on Perche Creek.

Bisphenol A is only one of several chemicals being scrutinized by the U.S. Geological Survey, and for Tillitt, the research holds special significance. Scientists who study Missouri wildlife have come across unusually high instances of hermaphrodism — when an individual displays both male and female sex organs — in the endangered pallid sturgeon. Hermaphrodism occurs normally in certain species of fish, but sturgeon isn't one of them. It could be caused by a multitude of different environmental pollutants.

"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 as 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 non-toxic 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.

To his students, Welshons explains low-dose hormonal effects this way: A cubic millimeter of a chemical is a milligram, which is a relatively large amount. If you take one thousandth of that, you have a microgram, which is visible to someone with excellent eyesight. (It's the smallest particle a human eye can resolve.) If you take one of those microgram particles, waft it onto the floor, step on it and grind it into a thousand more particles, you have nanogram particles, which are invisible to the naked eye. If one of those nanogram particles floats into the air and lands in a 1-liter container of liquid and dissolves there, it creates a solution that, in the case of bisphenol A, will stimulate human breast-cancer cells in a cell culture, causing the cancer cells to proliferate.

Nagel's first study showed that low doses of bisphenol A could have effects; further research indicated that bisphenol A enlarged the prostates of laboratory mice. She demonstrated that the effects in mice occurred at doses close to what humans are exposed to each day from sources such as food packaging. Her study was published in the January 1997 issue of Environmental Health Perspectives, a journal put out by the National Institute of Environmental Health Sciences.

A second publication of Nagel's findings — this time noting that bisphenol A lowered sperm counts in mice — was approaching when, in late 1997, vom Saal received a visit from John Waechter, a scientist with Dow Chemical. Waechter introduced himself as a representative of a group then called the Chemical Manufacturers Association.

The meeting took place in a conference room in the biology department. Vom Saal and Welshons were there, as were the chairman of MU's biology department and a visiting professor from the University of Illinois. Welshons remembers that Waechter seemed nervous during the meeting.

"He gave all the signs of feeling like he'd been asked to do something which was wrong," Welshons says.

Waechter told the group that the Chemical Manufacturers Association was surprised at the findings in vom Saal's lab and that the association wanted to try to replicate the bisphenol A findings in a larger, industry-funded study.

"They offered a very large, very expensive study," Welshons says. "Obviously a lot of money to the University of Missouri, that's what those things mean. Not money for us personally, but as research support."

Vom Saal says he'll never forget Waechter's words: "Can we arrive at a mutually beneficial outcome where you withhold publishing this paper until authorized to do so by the Chemical Manufacturers Association?"

The scientists felt they were being offered a bribe.

Mark Walton, the lead spokesman for Dow Chemical, has been asked about Waechter's visit by media outlets before — Frontline, specifically. He says that what felt to the scientists like bribery was "simply an enormous misunderstanding between what Dr. Waechter attempted to communicate and what was heard by Dr. vom Saal. And there was no intent or effort in any way, shape or form to do anything that would cause Dr. vom Saal to do anything other than to publish science that was accurate."

Vom Saal says he told Waechter, in no uncertain terms, what he could do with his offer.

It was the MU scientists' first glimpse of industry backlash.

In 1998, not long after Waechter visited MU, the American Plastics Council, a trade association that represented industry giants such as Exxon Mobil, DuPont and Dow Chemical, hired an advertising agency. The Washington, D.C.-based Bivings Group (then named Bivings Woodell), created a multitiered campaign to convince Americans to buy plastic — which they were already doing.

Vom Saal was aware of the campaign before the first "Plastics Makes It Possible" commercial aired on television. He says a friend of his who worked for the Environmental Protection Agency called to say he'd heard from a well-connected source that the chemical industry was unveiling a massive public-relations project.

"They knew [our studies] were going to be the end of the world for them," vom Saal says. "And they were going to have to spend millions."

"Preemptively," Nagel adds. "Really, because at the time, who needed to be convinced that plastics were good?"

The commercials showed images of children riding bikes — protected by plastic bike helmets — and premature babies being placed into clear plastic incubators.

"The really sick part of this is that they targeted the ads toward babies," vom Saal says. "And what her [Nagel's] data was so clear on was — "

" — That babies are the most sensitive to [bisphenol A]," Welshons finishes.

Rob Krebs, a spokesman with the American Chemistry Council, which merged with the American Plastics Council last year, remembers when the "Plastics Makes It Possible" campaign was in full swing. He denies that the industry group was motivated by Nagel's paper; versions of the campaign were in development as early as 1992, Krebs writes in an e-mail. At the time, he explains, plastic fast-food clamshells and disposable baby diapers were a new solid-waste concern, and people were fearful that the waste would clog landfills.

Krebs says the first wave of plastics commercials focused on educating the public that plastic could be recycled. Later, he says, "We found that benefits messages about plastics preserving health in child safety, medical safety and automobile safety were more appealing to the public at large and scored higher positive impressions with audiences and viewers."

The industry response didn't end with PR.

In science, a controversial finding gains credibility when other scientists can replicate the same experiment with the same results. Vom Saal was expecting other labs to eventually confirm his findings. The plastics industry threw money behind a few corporate laboratories, asking them to try Nagel's experiments. But because they weren't endocrinologists, they needed some help. When representatives from the hired laboratories contacted vom Saal, he didn't mind sending one of his students to AstraZeneca's lab (now Syngenta) in England to teach his methods to their scientists. He also filmed his procedures for the scientists hired by Dow Chemical.

None of those studies found that bisphenol A harmed the developing prostate in low doses.

Meanwhile, Nagel was getting phone calls from the media regarding her paper.

"It was strangely nerve-racking," she says, "because I had no experience whatsoever in talking with the press. At the time, I had limited experience presenting my data in general, even to other scientists."

But Nagel wasn't alone much longer in talking about her findings. In 1999 Chhanda Gupta, a professor then in the pharmacology department of the school of medicine at the University of Pittsburgh, replicated Nagel's study and found that bisphenol A permanently enlarged the prostate size of male mice that had been exposed to the chemical as fetuses.

Nagel finished her Ph.D. in reproductive and environmental endocrinology at MU in 1998 and went on to do a postdoctoral fellowship at Duke University from 1998 to 2001.

The first seminar she attended was taught by Frank Welsch, a scientist who'd tried to repeat Nagel's study and found no effect of bisphenol A.

Welsch, who worked for the Chemical Industry Institute of Toxicology (which is funded by the American Chemistry Council), presented his analysis showing that he couldn't find any effect of bisphenol A in a developmental study.

"Here I am, sitting there, and all he [Welsch] is doing is presenting a study showing that he couldn't find any effect," Nagel says. "It's highly unusual. My work was the entire focus of the seminar."

Welsch's 2000 publication on bisphenol A's effect on the weight of developing mouse prostates was later the subject of a peer review at the National Institutes of Health; the authors of the peer review called Welsch's work on bisphenol A "seriously flawed" and "misleading."

"It took a couple of years," vom Saal says of the follow-up studies. "By 2000, there were five or six papers published [on low-dose effects of bisphenol A]. By 2001, there were a few more, and there were 30 the next year, 50 the year after that."

"And 150 by 2006," Welshons adds. "It's one of the most studied chemicals now."

But industry-funded studies kept insisting that bisphenol A was safe.

In 2003, Welshons and vom Saal traveled to an international toxicology symposium in Germany, at the University of Berlin, where scientists from around the world were presenting papers on their research. Many of the papers presented were on bisphenol A.

A scientist named Jörg Oehlmann showed how bisphenol A in snails caused such an overgrowth in ovarian cells that the animals exploded and died.

A study by Gilbert Schönfelder found amounts of bisphenol A in human blood, specifically in the blood of pregnant mothers and in the placenta and umbilical-cord blood of their babies.

Then Waechter, the scientist with Dow Chemical who had visited vom Saal's lab at MU, stood up and read the results of a study he'd co-written. The study, which contradicted Schönfelder's, insisted that humans aren't exposed to bisphenol A because they metabolize it completely in the liver. His findings had come from cultures he'd done with liver cells in petri dishes, not living animals.

"It was at that point that you went a little ballistic," vom Saal says with a giggle, looking at Welshons.

Welshons says he stood up in the auditorium in Berlin and challenged Waechter's facts.

"I was civil," Welshons says. "I asked questions like: 'On what basis do you accept this C-R-A-P instead of actual measurements from animals and people? What basis is there for that?' And he ran away."

"Waechter literally stopped taking questions and ran out of the room," vom Saal says. "We're in this big corridor, and Wade jumps up and runs after him, and he's yelling, 'Come back here! Come back here and answer this question!' And Waechter ran out of the building with everybody in the audience sitting there."

Other scientists at the meeting don't remember it this way. Oehlmann, the scientist who did the snail study, writes in an e-mail, "I attended that meeting in Berlin in 2003 but do not remember a person leaving the room after being asked a particular question." Ellen Silbergeld, a professor of environmental health sciences at Johns Hopkins University who attended the Berlin symposium, says via e-mail: "There were several heated discussions at the meeting, but I do not recall anything like this."

Waechter wasn't available for comment. But Walton, Dow Chemical's spokesman, explains Waechter's behavior in an e-mail: Walton says that, according to Waechter, the confrontation happened on a stairway outside the meeting hall. "Dr. Waechter said that he told Dr. Welshons that he had a telephone call he needed to make at that moment and that he would not be able to have that discussion then, and that he then proceeded to his hotel room to make his telephone call. Dr. Waechter said the entire discussion took only a few seconds," Walton writes.

In 2004, vom Saal and another endocrinologist, Claude Hughes, conducted a review of the 115 published studies on bisphenol A and concluded that 90 percent of government studies found adverse low-dose effects, but not a single industry-funded study found any effect.

"Honesty in industry is not a requirement," vom Saal says. "As a matter of fact, the willingness to be dishonest seems to be the criterion for these people being hired and representing the chemical industry. We're playing on a very uneven playing field when we talk to them."

Welshons nods. "They can lie, and we can't."

Concern over chemicals such as bisphenol A eventually came to the attention of the government agencies charged with protecting public health. However, vom Saal and his fellow researchers have watched in disgust as federal agencies repeatedly fumble their responses.

The Environmental Protection Agency was supposed to be doing something about bisphenol A more than ten years ago.

In 1996, Congress passed the Food Quality Protection Act and the Safe Drinking Water Act, mandating that by 2000 the EPA was to begin protecting consumers from endocrine-disrupting chemicals such as those used in pesticides and plastics.

Scientists don't know how many of the 80,000 federally registered chemicals act as hormone disruptors. This year, the EPA was to have begun screening the first round of 50 to 100 chemicals. The tests haven't started yet.

The delay is partly because the EPA rounded up panels of experts to evaluate the process. Scientists were invited, but so were representatives of the chemical industry. Not surprisingly, consensus was hard to come by.

Five EPA panels have met to advise the EPA on chemical screening. Nagel was invited to be part of the second EPA panel for the Endocrine Disruptor Screening Program from 2001-03. She listened in frustration as fellow panelists dismissed the importance of measuring low-dose effects of hormones such as bisphenol A and failed to recognize the distinction between testing the chemicals on fetal animals versus adult animals.

Nagel says that on such panels, industry representatives are able to dilute the process because of their tenacity in insisting that there is controversy in science where none really exists. The panels also try not to include particularly outspoken scientists. "They deselect people like Fred and me," she says. "They want people who are trying to bend over backwards not to have an opinion. But industry is never not trying to further their cause."

Nagel was not invited to join later panels. The screening program's participants have since decided to conduct hormone testing on a breed of rat that many endocrinologists consider a bad candidate for such study. The panelists also chose to feed the rats a type of chow that is high in soy, which contains enough natural estrogens to disrupt the study findings. Perhaps worst of all, the panel concluded that it was open to allowing chemical companies to tailor the tests to their liking.

"That's not uncommon at all," Nagel says. "Traditionally, these panels will say, 'Here's the guidelines for the tests, but you can choose one of these four ways [to carry them out].'"

The flaws in this effort were widely reported. For instance, The Dallas Morning News revealed that the EPA had solicited advice on what breed of rat to use from a toxicologist who works for a company contracted by the chemical industry.

Last month, a House committee opened an investigation on rumored conflicts of interest in the scientific panels that advise the EPA.

But the EPA isn't the only federal agency battling conflict-of-interest accusations. Another federal agency, the Center for the Evaluation of Risks to Human Reproduction, which is part of the U.S. National Toxicology Program, convened an expert panel on bisphenol A in 1997. Naturally, vom Saal wanted to be part of the process, but he was barred. No scientists were allowed to be part of the CERHR panel if they'd published a study on bisphenol A.

The American Chemistry Council, on its Web site, explains why it agrees with this decision: "Scientists who have conducted significant amounts of research or have otherwise taken a position on the chemical of interest, either favorable or unfavorable, are generally excluded from participation on the panel to avoid conflicts of interest or bias."

Vom Saal calls this position "absolutely based on complete ignorance of the way science works. What we love about what we do is it's absolutely self-correcting. Unlike practically any other field, if you publish something important and it's wrong.... It's critical that other scientists point that out."

Because more than 200 studies have confirmed vom Saal's initial hypothesis on bisphenol A, "it's not a debated hypothesis anymore," he says. "And the idea that we proposed that and published that makes us biased — when 200 independent groups have confirmed it — there's something very, very seriously wrong with that message."

So vom Saal flew to Virginia on his own dime to attend March 2007 meetings of the CERHR panel on bisphenol A, joining other scientists and members of the press in the audience. Like Nagel, he was disgusted by the basic scientific misunderstandings he was hearing from members of the appointed panel.

"It was like listening to a high school debate or something," vom Saal says of the panel's arguments. "All of the critical issues that Wade, Susan and I and other scientists working in the field have been raising ... they weren't discussing that. They were saying, 'Humans are exposed to bisphenol A orally, and it's completely metabolized.' What they were sitting there saying is completely contradicted by a large scientific literature."

The panel threw out studies by vom Saal and many others because of vom Saal's methodology. Panelists disagreed with any study that used injection as a method to introduce bisphenol A to mice, claiming that because humans absorb bisphenol A through drinking water and food, the only acceptable test method was to feed it to mice. But bisphenol A is most dangerous to fetuses, which absorb the chemical through their mothers' bodies rather than by eating it, vom Saal and other scientists argued in letters they submitted as public comments on the process. And because bisphenol A is present in air and water, digestion isn't the only means by which people come into contact with it. Bisphenol A can enter through the lungs and even through the skin (the same way that birth control does in patch form).

The CERHR panel was ultimately discredited, though not by vom Saal. In a March 7, 2007, Los Angeles Times story, reporter Marla Cone revealed that Sciences International, the company contracted to write the CERHR's reports, had been funded by more than 50 chemical companies, including Dow Chemical. The firm had drafted reports analyzing seventeen chemicals, including bisphenol A. The conflict of interest had gone under the radar since 1998, when Virginia-based Sciences International first landed the $4.3 million contract to help manage the CERHR.

The Los Angeles Times story was published the same day that one of the CERHR's panel meetings was taking place. Vom Saal says he was in the room when the director of the CERHR, Mike Shelby, walked in and dismissed the meeting.

"He said, 'Basically, the panel meeting's over,'" vom Saal remembers with a laugh. "Yeah, the Los Angeles Times article came out basically saying that this is a completely corrupt process."

Congress is starting to notice industry science-for-sale schemes. John Dingell, a Democratic representative from Michigan and chairman of the Energy and Commerce Committee, just launched an investigation into the Weinberg Group Inc., a Washington, D.C. firm hired by the American Chemistry Council and other industry groups to come up with scientific findings in their favor. Among the documents uncovered in the congressional probe was a 2003 memo from the Weinberg Group to the chemical manufacturer DuPont that read, in part, "We will harness ... the scientific and intellectual capital of our company with one goal in mind — creating the outcome our client desires."

Also under scrutiny is the Food and Drug Administration. In March, a congressional inquiry into the FDA's conflicts of interest with the chemical industry found that the FDA's conclusion that bisphenol A is safe was based on only two studies — both funded by the chemical industry. The FDA's Stephen Mason admitted in a letter that the studies were sponsored by the Society of the Plastics Industry.

All of this vindication should be gratifying to vom Saal and his Endocrine Disruptors team, but there's no time to celebrate. Vom Saal is up to his ears in teaching classes and in his latest studies, which focus on the link between bisphenol A and obesity.

"We're working on the interaction of natural nutrients and fetal growth, and how these chemicals alter fetal growth and program fat cells to then accumulate abnormal amounts of fat," he explains.

On MU's campus, in the basement of Lefevre Hall, one dishwasher is constantly running. It's full of plastic baby bottles — all different brands. Some start leaching bisphenol A after the first 10 washes, vom Saal says. Others take more than 100, but at some point, they all start breaking down. Fill them with juice, and acids from the fruit strip the bisphenol A from the plastic faster. Fill them with milk or formula, which contain lipids, and the bisphenol A links to the fat molecules in the milk.

Vom Saal is also swamped with media requests.

Last month, he helped PBS film a "house audit" in which he went to a home with small children and pointed out all of the products containing bisphenol A. This was the second house audit he'd done, and it went considerably better than the first one, when the team found so many offending products that the mother burst into tears.

You won't find any plastic bottles in vom Saal's home. He rolls his eyes at the perceived safety of water filtered through Brita brand pitchers — charcoal-filtered water is great, but not when it empties into a polycarbonate jug.

"Stay away from food packaging in plastic. Put no plastic in any kind of heat, specifically in the microwave," he offers. "Virtually anyone we know who knows about this has really changed their lifestyle. And these are very simple things to do. It's not a crisis, not using canned products," he says of the fact that bisphenol A is also used in the lining of aluminum cans. "If you drink beer, drink it out of a glass bottle instead of out of a can."

As for Welshons and Nagel, they're married with six-year-old twins. Even they haven't been able to follow the no-plastic rule perfectly. They used glass baby bottles, but recently they discovered that the detachable nipples contained traces of bisphenol A.

Nadia Pflaum is a staff writer at the Pitch, Riverfront Times' sister paper, in Kansas City.
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