Plastic-additive bisphenol A linked to diabetes and cardiovascular events in NHANES analysis

September 16, 2008

Chicago, IL - Elevated urinary levels of bisphenol A (BPA), an additive in plastic and other materials used in food packaging and consumer products and one of the world's most widely used industrial chemicals, significantly raise the chances of also having diabetes or a history of cardiovascular events, according to a study based on the 2003-2004 National Health and Nutrition Examination Survey (NHANES)[1].


A one-standard-deviation rise in BPA concentrations was associated with a 63% increased risk of having been diagnosed with coronary heart disease, a 40% greater likelihood of having had a "heart attack," and a 39% increased risk of diabetes, in the cross-sectional analysis adjusted for age, sex, and other risk markers. In the NHANES cohort of more than 1400 patients, the same degree of BPA elevation was also associated with abnormally high liver enzymes.

The analysis, published online today in the Journal of the American Medical Association and appearing in the September 17, 2008 issue, "is the first-ever large-scale study on BPA in a human population," according to the authors, led by Dr Ian A Lang (Peninsula Medical School, Exeter, UK), in a statement they prepared for the media. "This is also the first time that evidence has emerged of higher BPA levels being associated with disease in adults," they write.

"We regard it very much as a first study—very important for raising questions. And with bisphenol, there are a lot of questions still to answer," Dr David Melzer (Peninsula Medical School), the report's corresponding author, told heart wire . "As epidemiologists, we were more than a little surprised that there hadn't been a prior population study of this compound."

"Widespread exposure to BPA"



BPA is added to the polycarbonate plastic used to make baby bottles and sports bottles, compact discs, and many other products and is in the epoxy resins used to line the inside of food cans, among many other uses. The overwhelming majority of people living in industrialized countries are believed to have it in their bodies.

BPA is thought to bind to estrogen receptors and mimic some of the hormone's physiologic activities. Studies of its effects in humans are scarce, and interpretations of animal and in vitro studies of the chemical vary. Some, but not all, suggest that BPA can interfere with normal development of the neurologic or reproductive systems and damage hepatocytes and pancreatic beta cells. Much of the public debate on the effects of BPA ingestion in humans has focused on reproductive health.

Last year, the Centers for Disease Control and Prevention announced that BPA was detected in the urine of 93% of tested participants, in the same overall NHANES data base, who were six years old or older, "a finding that indicates widespread exposure to BPA in the US population.[2]" Concentrations varied inversely with age and with income, and women had higher levels than men.

This is . . . the first time that evidence has emerged of higher BPA levels being associated with disease in adults.

NHANES participants are considered typical of a community-living US population. Most of the limited prior human data on BPA have been from select populations with high exposure in industrial settings. Evaluations of potential BPA health risks and estimated safe exposure levels, including one the FDA released in August in draft form[3], are almost entirely based on animal studies.

"Animal studies are often very valuable, but in this particular case, rats and mice actually metabolize this compound completely differently from humans. It's just a completely different pathway," Melzer said.

FDA hearing to coincide with the study's publication

Meltzer said he will be briefly presenting the BPA analysis during a public hearing the FDA is conducting today on the draft report released in August, which reviews uses of the chemical in "food-contact applications" and weighs in on how much it poses a health risk. "The FDA has concluded that an adequate margin of safety exists for BPA at current levels of exposure from food contact uses, for infants and adults," it reads. The agency also proposed strategies for minimizing exposure.



"You can really count on one hand the number of human studies that have been done looking at bisphenol A and whether it affects health end points," Dr Russ Hauser (Harvard School of Public Health, Boston, MA), an epidemiologist who studies BPA and other environmental toxins primarily for their effects on reproductive health, told heartwire . "Based on the experimental data, I'd say the study [from Lang et al] has good biological plausibility, at least for the alterations in liver function and diabetes," said Hauser, who is unconnected to the research and said he doesn't know the authors.

On the other hand, there seems to be far less, if any, direct supporting evidence for the observed BPA link with cardiovascular disease, which Melzer acknowledged was a bit out of the blue. As an independent finding in the NHANES analysis, he confirmed for heartwire , it does not appear to be totally mediated by diabetes.

Based on the experimental data, I'd say the study has good biological plausibility.

He said his group had not explored whether BPA, as a probable mimicker of estrogen, might mediate CV risk by being prothrombotic.

"I would consider the findings really provocative in that they suggest that BPA may be potentially associated with these adverse health outcomes, which we know have a large public-health impact," Hauser said. Although the study is far from conclusive, he said, it has a number of strengths, including a well-characterized database and a "sophisticated and state-of-the-art statistical analysis" that includes multiple sensitivity analyses, which address limitations of it being a cross-sectional study and make the data more robust.

Evidence, but no proof

The plastics industry has staunchly defended the use of BPA. "Studies on human volunteers have confirmed that bisphenol A is efficiently converted to a metabolite after oral exposure. The metabolite is then rapidly excreted from the body," according to[4], an industry-backed website. "While in the body, bisphenol A is in the form of a metabolite that has no known biological activity and, in particular, has been shown to be nonestrogenic. These properties indicate that bisphenol A is likely to have low toxicity."


On the other hand, CV disease and diabetes are primarily chronic disorders, and human BPA exposure in the community is nearly continuous. Still, "there's no exact method of estimating daily exposure and there are no established limits for urine specimens," Melzer said. "We had to estimate daily exposure from the single urine specimen from the NHANES study, using a published method."

He and his colleagues observed that their numbers are only approximations and in their report acknowledge a number of other limitations of their study, particularly relating to its cross-sectional nature. But that said, their numbers suggest that the increased diabetes and CV risks occurred "at levels of daily exposure that are 50 to 100 times lower than what has been regarded as a safe level," according to Melzer.

"Has a doctor ever told you that you have . . . "

Total concentrations of BPA, one of many environmental toxins examined in NHANES, were measured from urine samples collected once from a randomly selected sample of 1455 adult survey participants. As the authors relate, the group was also asked whether "a doctor or other health professional has ever told you that you have" arthritis, cancer, cardiovascular disease, angina, coronary heart disease, heart attack, diabetes, liver disease, respiratory disease (including asthma and either bronchitis or emphysema), stroke, or thyroid disease. A range of serum-based risk markers was also assessed.

Odds ratio* (95% CI) for a diagnosis of diabetes and cardiovascular disease associated with a 1-standard-deviation increase in urinary levels of BPA, NHANES 2003-2004 data
Diagnosis OR (95% CI) p
Diabetes 1.39 (1.21-1.60) <0.001
Cardiovascular disease 1.39 (1.18-1.63) 0.001
Angina 1.28 (1.09-1.50) 0.006
Coronary heart disease 1.63 (1.18-2.26) 0.006
Heart attack 1.40 (1.11-1.78) 0.008
*Adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration

No significant associations were observed with the other clinical diagnoses explored in the survey. However, two of the eight assessed laboratory markers were independently associated with urinary BPA.

A one-standard-deviation BPA elevation corresponded to 48% and 29% increased adjusted risks of having "clinically above-normal" elevations in alkaline phosphatase (p=0.002) and -glutamyltransferase (p<0.001), respectively. There were no such independent associations between increased BPA and LDL cholesterol, triglycerides, fasting glucose, insulin, or two markers used to assess glucose metabolism, including one measuring beta-cell function.

Is there a call to action?
Worldwide BPA production has now reached approximately seven billion pounds per year.

The new NHANES analysis, "while preliminary with regard to these diseases in humans, should spur US regulatory agencies to follow the recent action taken by Canadian regulatory agencies, which have declared BPA a 'toxic chemical' requiring aggressive action to limit human and environmental exposures," according an accompanying editorial from Dr Frederick S vom Saal (University of Missouri, Columbia) and Dr John Peterson Myers (Environmental Health Sciences, Charlottesville, VA)[5].

"Since worldwide BPA production has now reached approximately seven billion pounds per year, eliminating direct exposures from its use in food and beverage containers will prove far easier than finding solutions for the massive worldwide contamination by this chemical due its to disposal in landfills and the dumping into aquatic ecosystems of myriad other products containing BPA," they write. "The good news is that government action to reduce exposures may offer an effective intervention for improving health and reducing the burden of some of the most consequential human health problems."

The editorial writers, "who have a better view of the [BPA] literature," Melzer said, are more "hawkish" than he and his colleagues about whether their findings are actionable other than as a call for exploring the observed potential BPA risks in more conclusive studies. "We as a research group don't feel that our particular results are strong enough to make recommendations to the public. We have enormous respect for the [FDA] committee that has to do that job. We feel that more science needs to be done."

Coauthor Dr Tamara S Galloway (University of Exeter , UK ) reports " having served as a paid independent expert for the United Kingdom Bisphe nol A Ecotoxicology Review Panel," and coauthor Dr Michael Depledge (Peninsula Medical School) reports " that he is a member of the United Kingdom Royal Commission on Environmental Pollution and serves as a board member of Natural England. " v om Saal reports that he served as " an expert witness for the defendant in a trial in 2004 regarding the health effects of bisphenol," as a consultant for " in-preparation litigation regarding BPA ," and is serving as " chief executive officer of XenoAnalytical LLC ." Myers reports serving as "chief executive officer/chief scientist of a nonprofit organization, Environmental Health Sciences," and coauthoring Our Stolen Future, "a book that briefly mentions BPA" for whic h he has received less than $10 000 in royalties. Hauser said he has no industry relationships and that his research is funded by the Environmental Protection Agency , the National Institutes of Health , and the National Institute for Occupational Safety and Health .


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