In a recent decision to permit continued use of a chemical in food packaging that research has tied to cancer, diabetes, miscarriages and developmental delays in children, the U.S. Food and Drug Administration has favored two industry-funded studies over more than 1,000 independent analyses finding the chemical poses serious risks to human health.
The FDA’s decision on bisphenol A was not an isolated, or even unusual, call. For more than 30 years, U.S. regulatory agencies have relied on an arcane rule for approving chemicals used in everything from food packaging and drugs to pesticides and electronics, one that favors industry-funded reports over independent academic research.
That process exalts studies that follow design standards known as “Good Laboratory Practice,” and discounts research that may be confirmed through peer review, but do not follow the GLP protocols. Favoring GLP has given a green light to hundreds of chemicals and products from nicotine to atrazine linked to human disease and chronic health conditions.
Critics contend that the protocols, defended by the chemical industry, have become an arbitrary barrier, shutting out important independent research. In the case of BPA, a common chemical used in food packaging, adherence to the protocol largely overrode studies linking BPA to breast cancer, prostate abnormalities, low sperm count, developmental disorders, heart disease, obesity and diabetes.
Good Laboratory Practice standards are used almost exclusively in industry-funded studies, but are seldom followed by independent academic and government researchers. The guidelines establish standards for the conduct of research–covering issues like recordkeeping, sample sizes and the training of technicians–but not its underlying quality.
The risks of using Good Lab Practice standards as the defining mark of good science were underscored in the government evaluation of BPA, a review by 100Reporters has found.
One of the two industry-backed studies that government regulators relied on to clear BPA tested the chemical on rats that were resistant to its harmful effects. Nevertheless, the study followed the standards of Good Laboratory Practice, and so passed regulatory muster.
BPA is a plastic hardener widely used in the epoxy resin lining of food and drink cans, dental sealants, cash register receipts, electronics, compact discs and medical devices. The Centers for Disease Control and Prevention found BPA, a known endocrine disruptor, in more than 90 percent of urine samples representative of the U.S. population as a whole.
“It’s not the flaws of GLP per se but blind adherence to GLP,” said Dr. Jennifer Sass, senior scientist with Natural Resources Defense Council. “It’s scientific stupidity.”
The organization filed a petition in 2008 to prohibit use of BPA in human food and packaging. Sass said the FDA’s 15-page letter rejecting the petition found fault with individual studies but failed to look at the overwhelming body of evidence.
“There is no way you can say bisphenol A is safe,” said Sass. “Not one independent study says it’s safe.
“Really, this just kicks the can down the road.”
Every person in Europe and the United States is affected by the regulatory embrace of Good Laboratory Practice. It is the standard for evaluating the safety of food, color additives, animal food additives, human and animal drugs, medical devices for human use, biological and even electronic products.
The federal regulation establishing GLP includes dozens of requirements from the size and design of the laboratory to clothing worn by lab workers, methods for archiving data, record keeping, equipment calibration and maintenance. What it fails to assess is rigor of the research design, integrity of the science and influence industry may exert over the outcome.
Even critics of GLP are not calling for its abandonment. Rather, they want all valid research to be considered equally in the regulatory process rather than giving greater consideration to GLP studies.
Dr. Frederick vom Saal, professor of biological sciences at University of Missouri, Columbia, said GLP creates an evaluation process so fundamentally flawed it puts the public at risk.
“The system is profoundly broken and corrupted by industry influence,” vom Saal said. “This is smoke and mirrors at the regulatory level to make it seem that industry science is good and academic science is unreliable.”
GLP studies are almost always private, industry-funded research. Academic and government research facilities rarely adhere to GLP because it is expensive and burdensome.
GLP is “FDA’s misguided gold standard,” vom Saal said, noting even the terminology “good laboratory practice” is used to imply good science comes from GLP labs and pseudo-science comes from non-GLP labs.
Born by Scandal
GLP was devised and implemented in the late 1970s following a scandal over poor quality research and altered data at a number of private research companies. A criminal investigation resulted in convictions for three executives of Industrial Bio-Test Laboratories charged with deliberately doctoring data. No academic labs were involved in the scandal, but the GLP standard that emerged is now used by regulators in the United States and Europe.
“I’d like to see the name changed. GLP does not guarantee good science. It’s just about good recordkeeping. Let’s call it GRKP . . . Good Recordkeeping Procedures,” vom Saal said. “People doing GLP research often have no knowledge of the science underlying their work. They are doing prescribed work using 20th century technology.”
That happens, he said, because the objective of corporately-funded research is to protect the profitability of the product.
In the case of BPA, that’s a $10-billion-a-year industry, said a colleague of vom Saal, Dr. Wade Welshons, associate professor of veterinary biomedical sciences at University of Missouri.
“Ten billion dollars a year is about $25 million a day or a million dollars an hour,” Welshons said. “For every hour the regulation of BPA is delayed, the industry is making a million dollars.”
Citing a jump in production from six billion pounds in 2004 to over eight billion pounds today, Welshons called the growth “extraordinary. The money involved runs over every human health concern,” he said.
In an emailed response to questions from 100Reporters, the FDA stated that it did not rely solely on GLP research in ruling on bisphenol A, though it acknowledged using industry-funded research in a crucial way: to set the level at which regulators would measure detectable damage from BPA exposure. Based on that calibration, the FDA concluded that said the levels at which BPA leached into food did not pose a serious risk to human health.
According to figures from the Center for Responsive Politics, the American Chemistry Council, the main industry representative for BPA, dramatically intensified its lobbying efforts in the final three months of 2011, just as government regulators turned to making health assessments of BPA and formaldehyde, a known carcinogen. The council spent $5.37 million lobbying Congress and government agencies in the last quarter of 2011, more than double their spending the year before.
The American Chemistry Council responded by email to written questions, indicating it supports giving “appropriate weight” to both GLP and non-GLP research. It said GLP studies should carry greater clout because they permit for more meaningful statistical analysis.
These studies typically submit all raw data, allowing government regulators to review and audit research studies. In contrast, the council said, non-GLP studies published in peer-reviewed academic journals are typically limited in the thoroughness of reporting, and the FDA is often unable to validate the studies.
Countering that notion, vom Saal said it’s routine for scientists to duplicate findings of research published in peer-reviewed journals. He said GLP studies often rely on outdated, insensitive measurements designed to find nothing . . . “like looking for a landing spot on the moon using binoculars.”
He noted that one of the two initial studies the FDA relied upon in approving BPA used over 8,000 rats and found no harmful results from exposure to BPA. But the study, published in the journal Toxicological Sciences 10 years ago, used a strain of resistant animals. The researcher, Dr. Rochelle Tyl of Research Triangle Institute, N.C., responded to criticism from other scientists by duplicating the research with non-resistant mice and said that once again there was negligible damage from BPA exposure, proving the chemical is safe.
Vom Saal said large sample sizes do not insure accuracy but demonstrate “no understanding or training in statistics.” Using resistant animals, he said, is another way to insure no harm is found from BPA exposure.
A group of 37 scientists criticized the two BPA studies in letters published in the scientific journal Environmental Health Perspectives. In response, Tyl defended GLP as the only international legal framework that establishes quality standards and independent government-mandated inspections of research facilities.
Another scientist who requested anonymity for fear of losing research funding if he spoke openly said, “Unfortunately, at the EPA, FDA and other regulatory agencies, the way it’s set up is that industry pays the bills, and thus they kind of set the standards and review practices.”
Although the European Food Safety Authority, like the FDA, favors GLP, cracks are eroding support of GLP in the European Union. The EU, Canada and 11 U.S. states have banned BPA in baby bottles. Now a new French initiative calls for elimination of BPA for all food packaging by 2014. Britain and a number of EU members are objecting to the French move. They claim it is based on bad science, and would breach trade rules.
Too Expensive for Academic Labs
Dr. Jason Rohr, an integrative biologist at the University of South Florida, is a leading researcher on atrazine, but his lab, like most academic labs, does not adhere to GLP protocol.
“I’ve never made an attempt to get it. It’s a lot of work, and I’ve never felt it improves the science at all,” he said. “It is record keeping, not science. You can design an experiment to intentionally not find results and still meet GLP.”
Rohr and other researchers contend that GLP gives a false sense of authority to often dubious research and tends to mask conflicts of interest and serious flaws.
Rather than GLP, academic scientists rely on control groups and peer review prior to publication of their research to assess the quality and integrity of the science.
“Peer-review offers the opportunity to evaluate the science. GLP does not,” Rohr said.
In a paper published in Conservation Letters in 2010, Rohr reviewed conflicts of interest with industry-funded GLP research conducted on BPA and atrazine, and found numerous instances of such conflicts. In one, for example, an industry-funded researcher did a comprehensive analysis of research on atrazine, citing 144 misleading statements or errors. Of these, 96.5 percent of the cited “mistakes” would have benefitted Syngenta Corp., the manufacturer of atrazine–which also happened to be the company financing the review.
“Fortunately, misconceptions and biases of the magnitude presented here are relatively rare in peer-reviewed literature,” Rohr wrote, adding that “although the peer review system is not infallible, there is no indication that it is widely corrupted either.”
When evaluating the safety of atrazine, EPA regulators did not consider Rohr’s research showing harmful effects on fish and amphibians.
“The science advisory panel at the EPA for the most part ignored most work from non-GLP labs,” he said, noting that adhering to the Good Lab Practice standard is burdensome, and comes at a cost.
“GLP is time consuming, and I’d rather answer additional (scientific) questions,” Rohr said. “I don’t have any problem with GLP, but it becomes problematic and increases the risk to society when agencies place greater weight on GLP studies over other studies.”
Sass, of the National Resources Defense Council, said the dispute over GLP is political, not scientific. She contrasts industry research versus academic research, explaining industry designs research to look for a specific risk assessment.
“Academic research is designed to look for the unknown, to move science forward, often using new methods to get to places scientifically we’ve never been to before,” she said.
Dr. Olga Naidenko, a senior scientist with the not-for-profit Environmental Working Group, views GLP as an evolution from the 1970s, when there was fraud in reporting research results, to today, when GLP provides transparency and oversight but sometimes flawed science. It is now widely recognized GLP is not enough. Government approval of the arthritis drug Vioxx, she noted, was based on GLP research, only to force the drug from the market after it was linked to heart attacks, strokes and deaths.
Naidenko said regulatory agencies overwhelmingly rely on GLP and don’t know how to incorporate academic research into their evaluations. As a result, she said, many chemicals previously considered safe under the GLP model of evaluation may not, in fact, be safe at all.
By relying on GLP, vom Saal said, government regulatory agencies are acting like trade organizations, protecting the marketplace. He likens regulatory approval of BPA to the government’s earlier handling of nicotine. In the early 1990s. virtually everyone in science and medicine knew nicotine was bad, but the government allowed industry-funded studies to cast doubt on the health risks of smoking cigarettes.