Effect Measure

BPA cardiovascular findings replicated

It’s been over a year since we discussed the Journal of the American Medical Association (JAMA) article on bisphenol-A (BPA), a high volume chemical used in plastic components of food and drinks packaging and found in 90% of all Americans screened for the chemical. It is also a chemical that disrupts the endocrine system, a complex chemical signaling system that coordinates the actions and responses of various tissues and organs. The JAMA article examined self report in adults of cardiovascular disease and diabetes (“has a doctor ever told you that you had . . . “) and measured liver enzyme levels in relation to urinary BPA metabolite excretion in a one third random sample of the National Health and Nutrition Examination Survey (NHANES). NHANES is a cluster sample of the US population performed on a 2 year cycle.

The JAMA article reported on the first time such a study had been done and it linked increased BPA excretion with heart disease, diabetes and liver enzyme elevations in subjects from the 2003-2004 NHANES cycle. Although based on a hypothesis from animal studies, associations like this can come up accidentally, so replication of the result is an important. Consequently the same research team looked at the same variables in the 2006-2008 NHANES cycle whose subjects were completely different than the previous one. They report their results in PLoS-ONE:

Methodology and Findings

A cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18-74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant.

Conclusions

Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed. (Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS (2010) Association of Urinary Bisphenol A Concentration with Heart Disease: Evidence from NHANES 2003/06. PLoS ONE 5(1): e8673http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008673. doi:10.1371/journal.pone.0008673)

Translation: Average urinary BPA levels were lower in the later NHANES cycle but the relationship with heart disease was essentially the same as in the earlier one, meaning the result was confirmed in the independent data. The the evidence of increased report of diabetes was still visible although it just missed the 5% level of statistical significance in the later cycle but remained significant when both cycles were pooled. The liver enzyme data did not show in increase in the later cycle, although the pooled estimate remained significant. In magnitude, a 60 year old male in the highest urinary BPA level had a 45% increased risk of reporting he had been told by his doctor he had coronary disease.

We read these data as confirming the heart disease and diabetes findings while leaving the liver enzyme results discordant. This study adds weight to the earlier finding and raises red flags higher for this ubiquitous chemical. While we don’t know a great deal about the half life of BPA in humans, animal data suggests it may be relatively short, so the levels seen in NHANES are indicative of recent and ongoing exposure.

BPA is now out of baby bottles and Health Canada has declared BPA a toxic compound. So far the US FDA has not acted. But don’t worry:

The American Chemistry Council, an industry trade group representing BPA manufacturers, criticized the study and defended the safety of the chemical, which has been approved for use by regulatory bodies. ?The study itself does not establish a cause-and-effect relationship between BPA exposure and heart disease,? commented Steven Hentges, a spokesman for the group. (Martin Mittelstaedt, Globe and Mail)

You can find out more about the BPA talking points here, here and here.

Comments

  1. #1 Ash
    January 14, 2010

    These studies are useful, but don’t in themselves show that BPA is causing heart disease and diabetes to me. The first question that comes to my mind is “why do these people have higher levels of BPA?”. If the elevated BPA in urine is a result of a poor diet with lots of canned foods, soft drinks, etc., then the diet could be the cause of both the heart disease/diabetes and the elevated BPA in urine.

    Note that I’m not saying BPA isn’t toxic or that we shouldn’t be trying to phase it out (I support phasing it out, particularly from infant-related products) – I’m just hesitant to read a cause-effect relationship from this sort of correlation, which the media will certainly blow out of proportion.

  2. #2 Hank Roberts
    January 14, 2010

    Brief thoughts:

    Popular press has an allergy to serious consequences and prefers ‘balance’ with the denial sources; this
    http://initforthegold.blogspot.com/2010/01/ok-getting-serious-again.html
    is re climate change, but more generally true.
    Pointed illustration:
    http://4.bp.blogspot.com/_QNv9CPAjNvE/S06gZ_U0ZDI/AAAAAAAAA0U/Lye6M_XEUPs/s1600/ClimateChangeReporting.jpg

    Cash register receipts as by far the major source (exposure may have decreased with the decrease in shopping during the current depression (or perhaps a change in the manufacturing, who knows?)
    http://www.sciencenews.org/view/generic/id/48084/title/Science_%2B_the_Public__Concerned_about_BPA_Check_your_receipts

    Industry PR a large-scale effort:
    http://www.google.com/search?q=industry+BPA+public+relations+science

    Industry PR masquerading as good advice from academic statisticians for journalists writing about science, especially about BPA:
    http://www.google.com/search?q=stats.org+bpa

    Long-available research:
    http://dx.doi.org/10.1016/j.envres.2005.09.001

  3. #3 daedalus2u
    January 14, 2010

    Ash, the problem isn’t that it is “toxic”, the problem is that it mimics a natural signaling molecule, and so it screws up what ever signaling that signaling pathway is trying to do. Physiology can’t “compensate” for that screw up because it is the compensatory pathways themselves that are affected.

    BPA does bind to the estrogen related receptor ERR-gamma with an constant of 5.5 nM. This corresponds to 1.25 ng/mL, right in the range measured in urine. ERR-gamma is involved in the regulation of transcription of many (hundreds) energy related proteins, a lot of mitochondrial proteins. Disruption of mitochondria energy status would be expected to cause obesity, heart disease, ischemia related problems. My thinking has been that low NO has been what is disrupting them, but it could be BPA.

    Exactly what ERR-gamma does is not fully understood. Its normal ligand is unknown. It is expressed a lot in placenta, in the brain during development and in many other tissues during development. It might be a key player in sexual development, neurodevelopment, in many things which we do not understand.

    Exposure in utero might have effects much later in life, menopause at an early age for example (speculation).

    They should eliminated it.

  4. #4 caia
    January 14, 2010

    Revere —

    Interesting. And disturbing. I have a BPA question related to how it gets into foods.

    I understand that it can leach into foods from cans, and am planning to buy canned tomatoes and beans and such from a company (Eden) that advertises BPA-free cans in the future. This meaning regular 15 or 28 oz cans. But I understand BPA is also used to line the larger #10 cans.

    I don’t buy anything wet in #10 cans. I get stuff like oats and flour and beans, because they last years unopened packed in cans with oxygen absorbers, and they’re good backup to have in case I run out. Given all the bad news about BPA, my hope is that it doesn’t get into solids the way it gets into liquids, particularly acidic or heated liquids, but that’s not based on anything. Do you know? Should I stop buying food this way?

  5. #5 revere
    January 14, 2010

    Ash: You are correct that this is another cross sectional study. It is important that an independent sample shows the same pattern. Now the objective should be to rule out the various possibilities (of which confounding is one).

    daedaulus2u: I agree with what you say. It is the reason BPA worries me, although Ash’s point is also correct.

    caia: I’d direct BPA questions like that to the Environmental Working Group (ewg.org).

  6. #6 caia
    January 14, 2010

    Thanks.

  7. #7 gmm
    January 15, 2010

    Interesting. I am wondering how this will fit in with our societal fixation on convincing people that their poor health is solely due to poor lifestyle choices. (sigh…)

  8. #8 M. Randolph Kruger
    January 16, 2010

    Remember folks, if you arent sure then look on the bottom of the bottle or container. If it has an A on it, then its not a good bottle. Dont ever reuse a bottle either, dishwasher soaps release a helluva lot of the stuff in it from chemical reaction with lye and bleach. Might just be contaminating the dishwasher too.

  9. #9 Hank Roberts
    January 16, 2010

    “… In the U.S., BPA ranks in the top 2 percent of high-production-volume chemicals. BPA is a monomer that makes polycarbonate plastics harder and more resilient. Polycarbonate plastics are typically clear and often designated by a “7” within their triangular recycle symbols…. BPA is also in thousands of other products….”

    http://www.americanscientist.org/issues/feature/2010/1/assessing-risks-from-bisphenol-a/1

  10. #10 Hank Roberts
    January 16, 2010

    I went looking for current information and found this.
    Hmmmmmmmmmm…..

    http://www.bisphenol-a.org/

    —- excerpts follow——–

    Welcome to the Bisphenol-A Website

    This website is a comprehensive resource for environmental, health and safety information about bisphenol A (BPA). Bisphenol A is an industrial chemical used primarily to make polycarbonate plastic and epoxy resins – both of which are used in countless applications that make our lives easier, healthier and safer, each and every day.

    On this site you’ll find the latest information about bisphenol A and a wealth of scientific data and resources to answer most any question you might have.

    For further questions, contact us.
    What’s New
    Here is the latest news on bisphenol A.

    Limited BPA Study Makes Unscientific Leap – January 12, 2010
    http://www.bisphenol-a.org/whatsNew/20100112.html

    —- end excerpt—–

    http://www.bisphenol-a.org/pdf/BPAsafe.pdf

    —- excerpts follow—–

    The Society of the Plastics Industry, Inc. Association of Plastics Manufacturers in Europe

    Washington, DC, U.S. Brussels, Belgium

    Bisphenol A Task Group
    Bisphenol A Working Group
    Aristech Chemical Corporation Bayer AG, Germany
    Bayer Corporation Dow Europe SA, Switzerland
    The Dow Chemical Company G. E. Plastics bv, The Netherlands
    G. E. Plastics Shell Chemicals Europe Ltd., UK
    Shell Chemical Company

    This guide, produced by a committee of the Society of the Plastics Industry, Inc. (SPI) in the United States (U.S.) and the Association of Plastics Manufacturers in Europe (APME), is intended to provide guidance for safety and handling of bisphenol A. The Committee suggests that these guidelines be followed by those involved in the distribution, handling, use, and disposal of bisphenol A. This guide is intended to provide safety and handling information in a “user-friendly” outline format ….

    … The Society of the Plastics Industry, Inc., the Association of Plastics Manufacturers in Europe and their respective member companies listed above, assume no legal responsibility, therefore.”

    … no significant bioaccumulation potential.
    … bisphenol A has been given a favorable
    pregnancy rating at this level (no adverse effects to unborn life)….
    … 50 lb or 25 kg sacks are commonly used for bisphenol A packaging….
    … 1000 – 2500 lb or 500 -1000 kg bulk sacks are commonly used for bisphenol A packaging….
    … hopper trucks and hopper cars …
    … Bucket Elevators can be used to load bisphenol A into the tops of storage bins …
    … Storage bins and silos…
    … Bisphenol A is used in such a way that only a certain group of workers, with a knowledge of the processes, come into contact with the chemical….

    … • A polyhydric phenol like bisphenol A and a chlorohydrin like epichlorohydrin are commonly reacted together to produce an epoxy resin ….
    … Some examples of epoxy resin uses include industrial protective coatings, can and coil coatings, powder coatings, electrical laminants, composites, and adhesives….
    … Polycarbonate is a synthetic thermoplastic resin usually made from bisphenol A and phosgene. It has a unique combination of properties including being transparent and heat resistant, and having high impact strength. It is also dimensionally stable, as well as resistant to mineral acids.

    Uses
    • Polycarbonate … Some examples of its use include structural parts, impact resistant glazing, street-light globes, household appliance parts, automotive applications, and bottles.
    Other Products
    • Bisphenol A/Formaldehyde Resins, prepared from bisphenol A and formaldehyde, can be incorporated into automotive primers and surface finishes, binders for abrasives, table and office furniture finishes, undercoats, and wrinkle finishes. Printing inks may also be prepared from this resin that dry rapidly, display high resistance to alkalis and have minimum penetration into paper.
    • Tetrabromobisphenol A (TBBPA), prepared from bromine and bisphenol A, is used as a fire retardant in resins.
    • Bisphenol A is used as an antioxidant in the formulation of hydraulic brake fluids.
    • Bisphenol A and substituted bisphenol A products also are effective as rubber antioxidants.
    • Bisphenol A is used as both an antioxidant and color stabilizer for soaps.
    • Bisphenol As fungicidal properties are important in textiles and asphalt-treated cable covering.
    • Bisphenol A is a good stabilizer for polyvinyl chloride (PVC) because it inhibits peroxide formation and color development in both the plasticizer and the PVC.
    • Bisphenol A increases the dyeability of certain materials such as polyesters and polyolefins….

    The Society of the Plastics Industry, Inc.
    1801 K Street, NW, Suite 600K
    Washington, DC 20006
    1-202-974-5200 • Fax 1-202-296-7005
    Association of Plastics Manufacturers in Europe
    Avenue E. Van Nieuwenhuyse 4, Box 3, B-1160
    Brussels
    32 2 675 32 97 • Fax 32 2 675 39 35

    BISPHENOL A: A Safety and Handling Guide
    Publication Number: AE-154
    July 1997

  11. #11 Hank Roberts
    January 16, 2010

    PS, best source I’ve found for rather long-term observations on the bisphenol industry’s PR is here:

    http://acronymrequired.com/mg/mt-search.cgi?search=bisphenol&IncludeBlogs=2&limit=20

    There’s a very professional PR effort claiming no important effect from low doses of the material, here:

    http://www.bisphenol-a.org/human/herLowDose.html

    Is there any one research scientists’ site (like Realclimate.org for climate change) focusing on this, to which people can look for assessment of the research?

  12. #12 Paula
    January 16, 2010

    I’d like to ask Hank Roberts’ question, but in regard to windturbine noise effects on health and quality of life: “Is there any one research scientists’ site (like Realclimate.org for climate change) focusing on this, to which people can look for assessment of the research?” It is obvious that, like the Society of the Plastic Industry’s assessment of BPA danger, the “research” on windturbine (WT) effects that is sponsored by AWEA,CWEA, etc. can hardly be considered gold standard, and much of the independent research ranges from observational to reportorial/anecdotal. Of course, Hersh’s article, back in 1969 or so, on My Lai was anecdotal too, but it would be good, for those perhaps endangered by industry-whitewashed WT-noise, to have access to independent evaluation of all this research.

  13. #13 Hibob
    January 17, 2010

    Shouldn’t there have been an observational study on the effects of BPA on people who work with epoxy fiberglass? Boat and surfboard building has often meant someone mixing (by hand, think of paint in a bucket) almost pure bisphenol with an epoxide, then spreading the mix by hand over fiberglass cloth (think painting a room with a roller), then sanding the resulting fiberglass (with residual uncured BPA monomer now flying about). It’s a messy job, and without the safety equipment that has come into play over the past few decades there was a huge potential for skin and inhalation exposure. So compare people who worked with epoxy against people who did similar jobs but used polyester resin instead. I could see endocrine disruption being strongly nonlinear, i.e., a little dab will do ya, but if there are effects from large chronic doses to be found than this is the population to find them in.

  14. #14 Hank Roberts
    January 18, 2010

    > compare people
    They’re hard to track down, and usually confounded.
    That worked for tobacco, eventually, but took decades:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2038856/

    The case for _longer_ animal studies is made here, with specific reference to BPA:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592260/

    The Limits of Two-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens

    Environ Health Perspect. 2008 November; 116(11): 1439–1442.
    Published online 2008 June 30. doi: 10.1289/ehp.10716.

    —-excerpt follows——

    “… all known human carcinogens that have been tested adequately are also carcinogenic in animals and, almost without exception, share identical target sites; and d) nearly one-third of human carcinogens were first discovered to induce cancer in animals (e.g., 1,3-butadiene, diethylstilbestrol, dioxins, ethylene oxide, 2-naphthylamine, formaldehyde, vinyl chloride), although most of these were not regulated until human evidence mounted. Thus, in light of the fact that animal bioassays predict human cancer risks, conducting more sensitive tests would better protect the public, and especially workers, from involuntary exposure to animal carcinogens.

    … recent studies of the widely used plasticizer additive BPA indicate that pre-natal exposures can induce obesity in offspring (Dolinoy et al. 2007), a phenomenon that has not been observed with postnatal exposures alone. Prenatal exposure of pregnant Agouti Avy mice to BPA, which is a major component of polycarbonate plastics and epoxy resins, significantly reduced DNA methylation (Dolinoy et al. 2007). Others have reported that prenatal BPA also increases mammary tumor development and other developmental abnormalities (Soto et al. 2008), and may increase recurrent miscarriages (Sugiura-Ogasawara et al. 2005). Thus, experiments of prenatal exposure to BPA find that such exposures imprint mammary cells, leaving them especially sensitized to later cell growth and hormonal stimulation—characteristics also found in tumors. It may also be relevant that low levels of BPA have been found to activate genes in noncancerous breast cells in a way that mimics that seen in highly aggressive breast cancer (Dairkee et al. 2008), indicating that BPA plays a critical role both prenatally and postnatally.

  15. #15 Coturnix
    January 21, 2010

    Is this on ResearchBlogging.org?

  16. #16 revere
    January 21, 2010

    Coturnix: No, never signed up.

  17. #17 Coturnix
    January 22, 2010

    Hmmmm, could have been a contender for the PLoS ONE Blog Pick Of The Month….

  18. #18 hankroberts
    January 23, 2010

    http://www.sciencenews.org/view/generic/id/55336/title/BPA_is_regulated_._._._sort_of

    Read the whole thing. Janet Raloff is really good.
    Links in the original page go to sources. Follow them.

    This piece begins:

    By Janet Raloff
    Web edition : Tuesday, January 19th, 2010

    Food and Drug Administration officials “say they are powerless to regulate BPA” because of a quirk in their rules, according to a story that ran Sunday in the Milwaukee Journal Sentinel. It comes from a reporter who has made an award-winning habit of documenting the politics that have helped make the hormone-mimicking bisphenol-A a chemical of choice for many manufacturers.

    Meg Kissinger’s latest followup on BPA politics comes on the heels of a turnabout in FDA policy, last Friday, on the safety of this chemical, which is used widely as the basis of polycarbonate plastics, of food-can liners and of dental sealants. Oh yes, and let’s not forget: Handling cash-register receipts may prove the biggest source of BPA exposure.

    Back in 1963, FDA’s regulators classified BPA as an indirect food additive that is GRAS — “generally regarded as safe.” Manufacturers get a bye when using a GRAS substance. They don’t even have to report its use in food-contact applications.

    That’s why, Kissinger reports, despite there being hundreds of different BPA recipes for epoxy linings used to protect the interior of food cans and the lids on jars, “manufacturers are not required to disclose to FDA the existence or nature of these formulations.” Reassuring, huh?

    She reports that e-mails her team at the Journal Sentinel pried out of FDA under the Freedom of Information Act show “industry scientists wrote sections of the FDA’s earlier draft declaring the chemical [BPA] to be safe for all uses. It later obtained e-mails that showed industry lobbyists were given priority treatment in scrutinizing studies and that FDA regulators looked to them for advice on how to deal with the media . . . [sometimes borrowing] the same tactics and some of the same people as the tobacco industry to downplay the health risks of their products.”

    Bottom line: Once a substance is declared GRAS, regulators pretty much have their hands tied on ferreting out use data, and thereby analyses of likely public exposure. Unless Congress gets involved.

    It shouldn’t take that…..

  19. #19 hankroberts
    January 23, 2010

    Revere(s), I hope you’ll sign up with ResearchBlogging, it’d be good exposure.

    Meanwhile, here’s a list of alternative products that don’t use BPA (some approved in Europe and Japan)
    http://www.oeconline.org/our-work/kidshealth/tinyfootprints/toxic-prevention/safer-alternatives-to-bisphenol-a-bpa

    Hat tip for that link goes to this article
    http://www.alternet.org/healthwellness/145246/one_of_the_most_common_chemicals_used_in_modern_life_is_now_being_seen_as_a_health_threat?page=2

    which says (excerpt)

    “… At the Oregon hearing, North American Metal Packaging Alliance representative William Hoyle described BPA epoxy resins as vital to food safety, stressing that viable, reliable alternatives are unavailable. Some alternatives do exist, however, and are being used by U.S. and Japanese manufacturers.

    On Friday the FDA announced it would actively support research and development of BPA alternatives. …

    The FDA’s January 15 BPA recommendations are open to public comment for 60 days. Timing was not specified but the FDA plans to update its formal 2008 assessment. A “chemical action plan” on BPA is also expected from the EPA.

  20. #20 Hank Roberts
    January 25, 2010

    So — Scienceblogs bloggers, you who are real scientists — will you be commenting?

    http://www.fda.gov/RegulatoryInformation/Dockets/Comments/default.htm

    “The Federal Dockets Management System Instruction Sheet tells how to submit comments electronically at regulations.gov.”

    http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm197739.htm

    http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm197739.htm#comment

    Public Comment and Next Steps for FDA’s Assessment of BPA

    FDA will open a public docket for comment on BPA. The docket will contain the Center for Food Safety and Applied Nutrition’s review of the low dose toxicity studies and recently published studies, the five expert reviews, and other relevant material. The agency welcomes comments on these documents, other available evidence, and the agency’s regulatory options. This docket will be open for public comment for 60 days.

    FDA will also continue to consult with other expert agencies in the federal government, including the National Institutes of Health (and National Toxicology Program), Environmental Protection Agency, Consumer Product Safety Commission, and the Centers for Disease Control and Prevention.

    Based on this outside input and the results of new studies, FDA will update its assessment of BPA and will be prepared to take additional action if warranted. As the scientific field is evolving rapidly, FDA anticipates providing further updates on BPA to the public as significant new information becomes available.