Science news from the Bond LSC



NEW RESEARCH SUGGESTS FLAWS IN CURRENT METHODS OF STUDYING EXPOSURE TO BPA

June 6, 2011
Denise Henderson Vaughn

UIC Scientist Considers Changing Testing Procedure

After reviewing Cheryl Rosenfeld's new manuscript, a peer research scientist in Chicago is considering changing her method of dosing rats with bisphenol A (BPA) in her experiments.

For Gail Prins, a professor in the departments of urology and physiology at the University of Illinois at Chicago, the kicker was the revelation that BPA appears to be more biologically available—it "gets into circulation and is free and available to affect tissues"—when sourced chronically from food rather than from a single oral dose.

Prins conducts research on effects of BPA on the prostate gland. Within the last year, she has published a paper comparing once-time oral dosing of BPA to placing the chemical in subcutaneous tissue.

Upon reading Rosenfeld's study, Prins said, she was quite interested to learn that blood concentrations of the bioavailable form of BPA became higher when daily diet was the source, even though total BPA consumption was a bit lower in the mice chronically dosed in food versus those given a single oral dose.

"I found that to be utterly fascinating," Prins said. The implications are "of great interest... maybe what is bioavailable is (currently) being underestimated." With that realization, Prins said, "that's when I thought... I should be switching over to food."

Bond Life Sciences Center investigator Cheryl Rosenfeld is challenging an accepted method of administering bisphenol A (BPA) in research studies. She says the manner in which many research animals and human research participants have been dosed with BPA does not accurately reflect exposure to BPA in real life situations, and therefore the research results are potentially underestimating the amount of BPA that might accumulate in the body.

Cheryl Rosenfeld

BPA, a chemical used in plastics, is pervasive in the environment and has been found in most water sources worldwide, Rosenfeld said. BPA is a known endocrine system disruptor, and it is suspected of involvement in prostate cancer, breast cancer, and a number of other recent disease trends.

Specifically, Rosenfeld's research is calling into question the dosing method used in a highly-cited 2002 study of BPA exposure and blood concentrations in human subjects. Conducted by Wolfgang Vokel, this study is considered a cornerstone for current U.S. Food and Drug Administration (FDA) guidelines on acceptable BPA exposure for humans. During the 2002 study, research subjects only consumed a one-time dose of BPA, in the form of a hard gelatin capsule taken orally. Vokel concluded that humans rapidly metabolize and excrete BPA; he found that both urine and blood concentrations were cleared below detection levels within six hours.

Other Studies Offer Background on BPA's Properties and Potential Effects

Bond Life Science Center investigator Cheryl Rosenfeld is but one of many researchers conducting tests on the effects of the chemical bisphenol A, or BPA. A mounting pile of scientific studies documents the pervasiveness of BPA in the environment; studies are also demonstrating its effects on humans and animals.

BPA is primarily used to harden plastics, and it can be found in a wide range of consumer products, including eye glasses, gasoline containers, computer CDs, water supply pipes, and a variety of food packaging. It adds durability, clarity, and impact-resistance to plastic products. Recycling symbol "7" indicates BPA content.

Several studies show that BPA easily breaks down when heated, and small quantities are nearly ubiquitous in streams and in drinking water supplies in and near developed areas. Tests by the Centers for Disease Control in 2004 showed traces of BPA in the urine of some 95 percent of Americans. One’s diet is considered a primary source of BPA.

Several billion pounds of BPA are used by manufacturers yearly, but only a small percent is turned into packaging, which includes food and drink containers. These products are under the most scrutiny, such as hard plastic water bottles, baby bottles, and thin plastic film liners for steel food cans and aluminum soda cans. Also considered to be possible sources of human exposure is household dust and cigarette smoke, Rosenfeld said. BPA might also enter the body by way of dental sealants, water supply pipes, liners for water storage tanks, and thermal carbonless paper, which is used for cash register receipts.

Studies have established that BPA mimics the female hormone estrogen, and in so doing it disrupts the body’s endocrine processes. Because estrogen affects many areas of the body, pinpointing the various individual effects of BPA is a daunting task for researchers. Complicating the issue are other dietary sources of estrogen, such as soy products and birth control pills, which could exacerbate or enhance the adverse effects of BPA, Rosenfeld said. Doses of estrogen for the pill are significantly more potent than typical BPA exposure, but unlike the pill, BPA exposure and effects might be insidious and chronic in nature, she added.

In real life, Rosenfeld says, animals and humans are chronically exposed to BPA, which primarily occurs through one's daily diet, consisting of both food and drink ingested throughout the day. Researchers are also exploring other potential routes of exposure.

In her research, Rosenfeld measured BPA blood concentrations in mice exposed with the traditional method, a one-time oral dose. She then compared the blood concentrations of mice which were exposed to BPA continuously through a diet supplemented with this chemical.

Rosenfeld's study is the first to examine concentrations of BPA in the blood of any research animal after being exposed through a daily diet.

The experiment was designed so that both sets of mice would receive the same concentration of BPA per body weight. However, in reality, Rosenfeld said, those exposed to a single oral dose ended up receiving a higher concentration than those exposed through diet.

Researchers checked the animals' blood for the biologically active form of the chemical, known as "unconjugated" BPA, which is the kind that is available to bind to receptors within the body and act as an endocrine disruptor.

Mice were tested at one hour, four hours, six hours, 11 hours, 24 hours and at seven days after beginning to consume the BPA-supplemented diet. For the mice consuming the single oral dose, Rosenfeld's findings were consistent with the 2002 findings and with other studies that have used this method of exposure. By 24 hours, the mice had excreted most of the BPA.

Not so in the case of the mice continuously consuming BPA in their food. At the end of 24 hours, Rosenfeld's results were on par with the 2002 study, with most of the unconjugated BPA being metabolized and excreted. However, seven days later this group of mice had higher unconjugated BPA concentrations than they did at the 24-hour timepoint. This concentration was higher than was found in the mice consuming the single oral dose, even though the oral dose group ended up being exposed to a higher overall concentration per body weight than was the diet-only group.

This finding suggests that continuous and chronic dietary exposure to BPA results in accumulation of unconjugated BPA in the body, Rosenfeld said.

Consequently, the testing method that uses a single oral dose might be underestimating BPA exposure risk, Rosenfeld said. "Exposure via diet is a more natural and less stressful. We believe that exposure of BPA through the diet is the most appropriate measure, and thus the best modeling system for estimating animal and human exposure."

Rosenfeld's research results contradict the 2002 study, and potentially contradict the premise on which the FDA has established current safe levels to BPA exposure, because regulatory agencies might assume that BPA is quickly metabolized and excreted out of the body.

Other MU researchers also question elements of the 2002 study. MU Biological Sciences professors Fred vom Saal and Julia Taylor conducted a study last year on Rhesus monkeys and mice exposed to BPA. They used the single oral dose method of testing, but disputed the 2002 finding that these animals completely eliminated BPA within 24 hours.

Importantly, Taylor and vom Saal also performed side-by-side blood concentration comparisons between mice and monkeys; they showed that the two species have parallel rates of metabolizing and excreting BPA. This finding weakens an argument some scientists had previously made against using mice for BPA research, saying that rodents are so different from humans in the way they take in, metabolize and excrete this chemical that BPA studies with mice should not be considered relevant.

Rosenfeld said this previous research with monkeys and mice provides a firm foundation for her current findings, because it establishes that BPA blood concentration studies using mice are relevant to primates and by extension, to humans.

Vom Saal is one of Rosenfeld’s co-authors on a paper outlining her new study results, which was published June 6 in Environmental Health Perspectives. Additional authors include Paizlee Sieli, Eldin Jašarević, Denise Warzark, Jiude Maos and Mark Ellersieck, all with MU, plus Chunyang Liao and Kurunthachalam Kannan, both with the State University of New York at Albany, and Séverine Collete and Pierre-Louis Toutain, both with the Université de Toulouse in France. Rosenfeld is an associate professor in the Department of Biomedical Sciences at MU.

Scientists, Regulators Disagree on Safe Levels

Establishing BPA toxicity levels has led to contention between scientists and regulators.

In 2007, a panel of 38 scientists sponsored by the National Institute of Environmental Health Sciences and the Environmental Protection Agency issued a consensus statement. These scientists concluded that research has verified a wide range of adverse effects in lab animals from low doses of BPA, at exposure levels typically found in humans. According to the panel’s final report, these findings cause concern for possible similar effects in humans, and may account for recent disease trends, including prostate cancer, breast cancer, abnormal genitals in baby boys, ADHD, lowered sperm counts, early puberty in girls, and obesity.

"It’s hard to dispute the mounting evidence against BPA," said Rosenfeld, referring to the many studies evaluated by this panel.

Despite lobbying by advocacy groups for tighter restrictions, current BPA exposure limits established by the FDA have remained unchanged for several years, including exposure limits for pregnant mothers and infants. The European Food Safety Authority also uses the same standards as the FDA.

But Canada and California have banned BPA in baby products, based on concerns about infants’ abilities to metabolize BPA. Most companies that make baby bottles have voluntarily moved away from using plastics containing BPA, and some retailers have voluntarily removed BPA baby items from their shelves.  Some food companies are in the process of switching to BPA-free steel food cans, while others maintain that BPA in these cans is safe.

Human exposure is not the only concern. Treated wastewater often contains BPA, and studies have indicated effects of BPA on the growth and reproduction of aquatic creatures, including fish, invertebrates, amphibians and reptiles. A 2010 Canadian study compared fish in uncontaminated river segments with areas containing hormone-affecting chemicals, including BPA. Researchers report indications of sex reversals; they identified 85 percent female populations of a certain fish species, compared to 55 percent female in uncontaminated areas.

What To Do? Advice From Researchers

To avoid BPA exposure, researchers recommend not using plastic #7, especially food containers that are scratched or worn. In particular, avoid heating food in plastic containers, placing hot food in plastic containers to cool, heating foods covered in plastic wrap, and washing plastic containers in the dishwasher. Throw away worn baby bottles or water bottles containing BPA, and try to buy only BPA-free food cans and plastic food and water containers, researchers say.

However, these measures are not expected to eliminate all sources of BPA exposure, Rosenfeld said. She encouraged anyone seeking additional information about precautionary measures to get the facts from reputable government sources, including the National Institutes of Heath and the Centers for Disease Control. Websites, such as http://www.bisphenol-a.org/, that are sponsored by the chemical industry or other corporations with a vested interest "should be viewed with some skepticism," Rosenfeld said, as they might not accurately present the various research to date and the current stance of governmental agencies.