Bisphenol en
de kans op hartziektes en diabetes*
Hier drie artikelen over de chemische stof bisphenol A, die wordt gebruikt voor de productie van polycarbonaat, een transparante plastic die onder andere gebruikt wordt als drager van CD's en DVD's en voor onbreekbare flessen voor (baby)voeding, voor tafelbestek, en voorwerpen voor gebruik in microgolfovens. Het wordt ook gebruikt in epoxyharsen die als beschermende coating aan de binnenkant van voedingsverpakkingen in blik of karton worden aangebracht, of in leidingen en reservoirs voor drinkwater. Bisfenol A wordt ook gebruikt in vlamvertragende middelen, ook in tandvullingen en als
oplosmiddel voor drukinkten. Bisphenol komt voornamelijk het lichaam binnen door eten en drinken, maar ook door het inademen van huisstof. Bij negen op de tien mensen wordt Bisphenol in het bloed aangetroffen.
Hieronder de laatste studie en het laatste overzicht van alle studies over Bisphenol en verder wellicht de reden waarom de waakhond van de Amerikaanse overheid (FDA) zonder problemen bisphenol als veilig beschouwd; de verantwoordelijke directeur blijkt indirect 5 miljoen dollar ontvangen te hebben van een fabrikant die
vindt dat bisphenol 100% veilig is.
De laatste studie:
De chemische stof Bisphenol A (BPA) verhoogt het risico op hartziektes en diabetes bij volwassenen. Dit blijkt uit een studie onder 1.455 volwassenen tussen de 18 en 74 jaar.
In de studie bleek dat degenen met de hoogste concentraties BPA in de urine bijna drie keer zoveel kans had op een hartziekte dan de mensen met de laagste concentratie BPA. De eerste groep had 2,4 keer meer kans op diabetes dan de andere groep. De groep met de meeste BPA kreeg gemiddeld 0,035 milligram per dag binnen, terwijl de huidige veiligheidsnormen 3,25 milligram per dag als veilig beschouwen voor volwassenen. De onderzoekers konden geen oorzakelijk verband vaststellen tussen het bisphenol en het verhoogd risico. Het Europees agentschap voor veilige voeding EFSA verhoogde begin 2007,
wellicht onder druk van de industrie de aanvaardbare dagelijkse norm van 0,01 naar 0,05 milligram BPA per kilo lichaamsgewicht omdat BPA niet zo schadelijk zou zijn voor de gezondheid.
Association of Urinary Bisphenol A Concentration With Medical Disorders and Laboratory Abnormalities in Adults
Iain A. Lang, PhD; Tamara S. Galloway, PhD; Alan Scarlett, PhD; William E. Henley, PhD; Michael Depledge, PhD, DSc; Robert B. Wallace, MD; David Melzer, MB, PhD
JAMA. 2008;300(11):1303-1310. (doi:10.1001/jama.300.11.1303).
Context Bisphenol A (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans.
Objective To examine associations between urinary BPA concentrations and adult health status.
Design, Setting, and Participants Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of P < .05.
Main Outcome Measures Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes.
Results Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P = .001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P < .001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes -glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P < .001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P = .002).
Conclusion Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.
Author Affiliations: Epidemiology and Public Health Group (Drs Lang and Melzer) and Environment and Human Health Group (Dr Depledge), Peninsula Medical School, Exeter, United Kingdom; School of Biosciences, University of Exeter, Exeter (Drs Galloway and Scarlett); School of Mathematics and Statistics, University of Plymouth, Plymouth, United Kingdom (Dr Henley); and University of Iowa College of Public Health, Iowa City (Dr Wallace).
Overzicht:
Bisphenol A and Risk of Metabolic Disorders
Frederick S. vom Saal, PhD; John Peterson Myers, PhD
JAMA. 2008;300(11):1353-1355. (doi:10.1001/jama.300.11.1353).
In this issue of JAMA, Lang and colleagues1 report the results of the first major epidemiologic study to examine the health effects associated with the ubiquitous estrogenic chemical bisphenol A (BPA). This compound is the base chemical (monomer) used to make polycarbonate plastic food and beverage containers, the resin lining of cans, and dental sealants; it also is found in "carbonless" paper used for receipts as well as a wide range of other common household products. Based on their analysis of data from the National Health and Nutrition Examination Survey 2003-2004, Lang et al report a significant relationship between urine concentrations of BPA and cardiovascular disease, type 2 diabetes, and liver-enzyme abnormalities in a representative sample of the adult US population. This report, suggesting links between BPA and some of the most significant and economically burdensome human diseases, is based on a cross-sectional study and therefore cannot establish causality; follow-up longitudinal studies should thus be a high priority. Yet many peer-reviewed published studies report on related adverse effects of BPA in experimental animals,2 and cell culture studies identify the molecular mechanisms mediating these responses.3 These experimental findings add biological plausibility to the results reported by Lang et al.1
Based on this background information, the study by Lang et al,1 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.4 Alternatively, Congressional action could follow the precedent set with the recent passage of federal legislation designed to limit exposures to another family of compounds, phthalates, also used in plastic. Like BPA,5 phthalates are detectable in virtually everyone in the United States.6 This bill moves US policy closer to the European model, in which industry must provide data on the safety of a chemical before it can be used in products.
Subsequent to an unexpected observation in 1997, numerous laboratory animal studies2 have identified low-dose drug-like effects of BPA at levels less than the dose used by the US Food and Drug Administration (FDA) and the Environmental Protection Agency to estimate the current human acceptable daily intake dose (ADI) deemed safe for humans. These studies have shown adverse effects of BPA on the brain, reproductive system, and—most relevant to the findings of Lang et al1—metabolic processes, including alterations in insulin homeostasis and liver enzymes.2 However, no prior studies examining BPA for effects on cardiovascular function have been conducted in laboratory animals or humans.
Epidemiologists are informed by animal studies that identify potential human health hazards when the animal models and exposure levels are relevant and effects are mediated via response mechanisms present in humans. For example, when adult rats were fed a 0.2-µg/kg per day dose of BPA for 1 month (a dose 250 times lower than the current ADI), BPA significantly decreased the activities of antioxidant enzymes and increased lipid peroxidation, thereby increasing oxidative stress.7 When adult mice were administered a 10-µg/kg dose of BPA once a day for 2 days (a dose 5 times lower than the ADI), BPA stimulated pancreatic β cells to release insulin. After administration of 100 µg/kg per day of BPA via injection or feeding for 4 days, mice developed insulin resistance and postprandial hyperinsulinemia. Follow-up studies showed that stimulation of mouse β-cell insulin production and secretion by between 0.1 to 1 nM of estradiol or BPA (23-230 pg/mL of BPA) is mediated by activation of the extracellular signal-related protein kinase 1/2 pathway by binding of BPA to estrogen receptor and that via this nonclassical estrogen-response mechanism, BPA and estradiol have equal potency and efficacy.8 BPA and estradiol are also equipotent at inhibiting adiponectin release from human adipocytes at 1 nM, further implicating BPA at current human exposure levels in insulin resistance and the metabolic syndrome.9
The effects of BPA on β cells confirm that BPA acts as a potent estrogen via this recently discovered estrogen-response pathway, one also present in human tissues.3 Importantly, while low doses of BPA and estradiol stimulated this response in β cells, 100-fold higher doses of BPA and estradiol did not stimulate β-cell insulin production in the mouse model8 or adiponectin release from human adipocytes.9 The biphasic or nonmonotonic dose-response curves observed in this and many other studies of BPA follow an inverted U shape, which is a common finding for endocrine-active chemicals and drugs, for which high doses inhibit (down-regulate) the low-dose response system while initiating a wide array of other adverse effects via different response mechanisms.10 Despite decades of published observations by endocrinologists reporting nonmonotonic dose-response curves for hormonally active compounds, the core assumption used by the FDA, the Environmental Protection Agency, and the European Food Safety Authority in estimating ADIs for environmental chemicals is still based on a concept first articulated in the 16th century: "The dose makes the poison"11; ie, dose-response curves are assumed to be monotonic for environmental chemicals.
The FDA and the European Food Safety Authority have chosen to ignore warnings from expert panels12 and other government agencies,4, 13 and have continued to declare BPA "safe."14-15 The findings by Lang et al1 that BPA is significantly related to serum markers of liver damage, such as increased -glutamyltransferase levels, that were predictive of metabolic disease, cardiovascular disease, and increased mortality in the Framingham longitudinal study,16 challenge the safety of BPA. One factor that may be contributing to the refusal of regulatory agencies to take action on BPA in the face of overwhelming evidence of harm from animal studies reported in peer-reviewed publications by academic and government scientists is an aggressive disinformation campaign using techniques ("manufactured doubt") first developed by the lead, vinyl, and tobacco industries to challenge the reliability of findings published by independent scientists.17-18
Therefore, a marked discordance exists between the currently accepted ADI for BPA of 50 µg/kg per day and numerous adverse effects in animals occurring at levels far below this dosage in recent experiments using the tools of 21st-century biology.2 A fundamental problem is that the current ADI for BPA is based on experiments conducted in the early 1980s using outdated methods (only very high doses were tested) and insensitive assays. More recent findings from independent scientists were rejected by the FDA, apparently because those investigators did not follow the outdated testing guidelines for environmental chemicals, whereas studies using the outdated, insensitive assays (predominantly involving studies funded by the chemical industry) are given more weight in arriving at the conclusion that BPA is not harmful at current exposure levels.15
If adults with increased levels of BPA are at greater risk for metabolic diseases, as is suggested by the findings reported by Lang et al,1 follow-up longitudinal studies on infants, children, and adolescents, as well as pregnant women and fetuses, would be a high priority for 2 reasons. First, there is consensus from a National Institutes of Health–sponsored expert panel12 and other government agency reports, including the US National Toxicology Program13 and Canadian Ministry of Health,4 that exposure to BPA during development poses the greatest risk for adverse effects; the fetus and infant are believed to be more susceptible to the estrogenic effects of BPA because of small body size and limited capacity to metabolize BPA.19 Second, along with the exponential increase in the use of BPA in products during the last 30 years, there has been a dramatic increase in the incidence of obesity and type 2 diabetes in children.20 Very low doses of BPA during fetal/neonatal life in rodents increase the rate of postnatal growth as well as advance puberty, with subsequent disruption of neuroendocrine function.2 A causal role for BPA in these trends is plausible because BPA can alter the programming of genes during critical periods in cell differentiation during fetal and neonatal development. This process, referred to as "epigenetic programming," can result in the expression of metabolic disease and cancers during later life.21-22 Examining developmental effects will require biomonitoring of BPA (and other endocrine-disrupting chemicals) in longitudinal studies that relate exposures during critical periods in development to subsequent disease. However, further evidence of harm should not be required for regulatory action to begin the process of reducing exposure to BPA.4
The report by Lang et al1 should stimulate further studies and reevaluation of the basic assumptions in chemical risk assessments that led to FDA assurances that BPA is safe.15 Their findings also heighten incentives for green chemistry (a new field based on collaboration between biologists and chemists to develop biologically inert chemicals for use in products) to find cost-effective replacements for BPA applications contributing to widespread human exposures.23 Since worldwide BPA production has now reached approximately 7 billion pounds per year,17 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, which Canada has already declared to be a major environmental contaminant.4
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. Thus, even while awaiting confirmation of the findings of Lang et al,1 decreasing exposure to BPA and developing alternatives to its use are the logical next steps to minimize risk to public health.
AUTHOR INFORMATION
Corresponding Author: Frederick S. vom Saal, PhD, Division of Biological Sciences, 105 Lefevre Hall, University of Missouri, Columbia, MO 65211 (vomsaalf@missouri.edu ).
Financial Disclosures: Dr vom Saal reported serving on the organizing committee of a National Institutes of Health (NIH)–sponsored conference on bisphenol A (BPA) held in Chapel Hill, North Carolina, in 2006; serving as an expert witness for the defendant in a trial in 2004 regarding the health effects of bisphenol; serving as a consultant for in-preparation litigation regarding BPA; serving as chief executive officer of XenoAnalytical LLC, which uses a variety of analytical techniques to measure estrogenic activity and BPA in tissues and leachates from products; and maintaining a Web site (http://endocrinedisruptors.missouri.edu/vomsaal/vomsaal.html) that contains a document with references and abstracts for published articles on BPA. Dr Myers reported serving on the organizing committee of the NIH-sponsored conference on BPA held in Chapel Hill, North Carolina, in 2006; serving as chief executive officer/chief scientist of a nonprofit organization, Environmental Health Sciences, which aggregates and redistributes news about the environment and health from media sources around the world (EnvironmentalHealthNews.org; BPA coverage is included when it occurs, and no fees are charged for this service because it is supported by private foundations); publishing (with 2 coauthors) Our Stolen Future, a book that briefly mentions BPA (Dr Myers has received less than $10 000 in royalties for this book since publication); and publishing a companion non–revenue-generating Web site (OurStolenFuture.org) that summarizes emerging science about endocrine disruption, including findings on BPA.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Author Affiliations: Division of Biological Sciences, University of Missouri, Columbia (Dr vom Saal); Environmental Health Sciences, Charlottesville, Virginia (Dr Myers).
REFERENCES
1. Lang IA, Galloway TS, Scarlett A; et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 2008;300(11):1303-1310.
2. Richter CA, Birnbaum LS, Farabollini F; et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007;24(2):199-224.
3. Wetherill YB, Akingbemi BT, Kanno J; et al. In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007;24(2):178-198.
4. Environment Canada. Draft Screening Assessment for The Challenge: Phenol, 4,4'-(1-methylethylidene)bis-(Bisphenol A). Chemical Abstracts Service Registry No. 80-05-7. Environment Canada Web site. http://www.ec.gc.ca/substances/ese/eng/challenge/batch2/batch2_80-05-7.cfm. 2008. Accessibility verified August 20, 2008.
5. Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007;24(2):139-177.
6. Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect. 2007;115(6):876-882.
7. Bindhumol V, Chitra KC, Mathur PP. Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology. 2003;188(2-3):117-124.
8. Alonso-Magdalena P, Ropero AB, Carrera MP; et al. Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLoS ONE. 2008;3(4):e2069.
9. Hugo ER, Brandebourg TD, Woo JG, Loftus J, Alexander JW, Ben-Jonathan N. Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes [published online August 14, 2008]. Environ Health
Perspect. doi:10.1289/ehp.11537.
10. Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures, III: endocrine mechanisms mediating effects of bisphenol A at levels of human
exposure. Endocrinology. 2006;147(6)(suppl):S56-S69.
11. Trautmann N. The dose makes the poison—or does it? ActionBioscience.org Web site. http://www.actionbioscience.org/environment/trautmann.html. 2005. Accessed August 7, 2008.
12. vom Saal FS, Akingbemi BT, Belcher SM; et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol. 2007;24(2):131-138.
13. National Toxicology Program (NTP). Draft NTP brief on bisphenol A. NTP Web site. http://cerhr.niehs.nih.gov/chemicals/bisphenol/BPADraftBriefVF_04_14_08.pdf. April 14, 2008. Accessed July 5, 2008.
14. European Food Safety Authority. Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission related to 2,2-BIS(4-HYDROXYPHENYL)PROPANE (Bisphenol A). EFSA J. 2006;428:1-76.
15. Statement of Norris Alderson. PhD, Associate Commissioner for Science, Food and Drug Administration, Department of Health and Human Services, before the Subcommittee on Commerce, Trade and Consumer Protection, Committee on Energy and Commerce, US House of Representatives. US Food and Drug Administration Web site. http://www.fda.gov/ola/2008/BPA061008.html. June 10, 2008. Accessed August 12, 2008.
16. Lee DS, Evans JC, Robins SJ; et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2007;27(1):127-133.
17. vom Saal FS, Hughes C. An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment. Environ Health Perspect. 2005;113(8):926-933.
18. Michaels D. Doubt Is Their Product: How Industry's Assault on Science Threatens Your Health. New York, NY: Oxford University Press; 2008.
19. Taylor JA, Welshons WV, vom Saal FS. No effect of route of exposure (oral; subcutaneous injection) on plasma bisphenol A throughout 24 hr after administration in neonatal female mice. Reprod Toxicol. 2008;25(2):169-176.
20. De Ferranti SD, Osganian SK. Epidemiology of paediatric metabolic syndrome and type 2 diabetes mellitus. Diab Vasc Dis Res. 2007;4(4):285-296.
21. Newbold RR, Padilla-Banks E, Jefferson WN, Heindel JJ. Effects of endocrine disruptors on obesity. Int J Androl. 2008;31(2):201-208.
22. Prins GS, Birch L, Tang WY, Ho SM. Developmental estrogen exposures predispose to prostate carcinogenesis with aging. Reprod Toxicol. 2007;23(3):374-382.
23. Anastas PT, Beach ES. Green chemistry: the emergence of a transformative framework. Green Chem Let Rev. 2007;1(1):9-24.
Gift to Center Headed by FDA Panel Chairman Raises Questions
By Susanne Rust and Meg Kissinger
Milwaukee Journal Sentinel
Monday, October 13, 2008; A11
A retired medical supply manufacturer who considers bisphenol A to be "perfectly safe" gave $5 million to the research center headed by the chairman of a Food and Drug Administration panel about to rule on the chemical's safety.
The July donation from Charles Gelman is nearly 50 times the annual budget of the University of Michigan Risk Science Center, where Martin Philbert is founder and co-director. Philbert did not disclose the donation to the FDA, and agency officials learned of it when reporters asked about it.
Norris Alderson, the FDA's associate commissioner for science, looked into the matter and said he was satisfied that there was no conflict of interest because Philbert's salary is not paid by the donation.
Gelman said he considers the chemical, which is used to make baby bottles and aluminum can liners, to be safe. Worries about health risks posed by the chemical are exaggerated by "mothers' groups and others who don't know the science," Gelman said.
He said he had made his views clear to Philbert in several conversations.
Philbert denied that.
"At no time have the Gelman family or any other interested/disinterested person, persons, corporations or other entity contacted me or attempted to influence my scientific judgment on the matter," Philbert wrote in an e-mail.
Philbert's committee is expected to release its opinion this month. It will advise the FDA on a draft assessment released by the agency in September. That draft found that products made with bisphenol A are safe for food storage.
The decision of Philbert's committee is expected to have huge implications on the regulation and sale of the chemical in items such as baby bottles, reusable food containers and plastic wraps.
Since the late 1990s, studies have linked bisphenol A to cancer, heart disease, obesity, reproductive failures and hyperactivity in laboratory animals.
Gelman, a retired manufacturer of syringes and medical filtration devices, has fought against government regulation of pollutants for years.
He is an anti-regulation activist and an outspoken supporter of organizations such as JunkScience.com, the Cato Institute and the Competitive Enterprise Institute that attack the credibility of government and academic scientists on such topics as global warming and hazardous chemicals.
Gelman said he and Philbert talk often. He said Philbert eventually told him that he did not want to have any more discussions on the subject of bisphenol A because he was concerned about the appearance of impropriety. But, Gelman said, "He knows where I stand."
Philbert steadfastly denied any conflict of interest.
"Until today, no question has been raised with respect to my impartiality in this matter," he wrote in an e-mail. "I am not open to any undue influence and have taken on this (unwelcome) task with all due diligence and
seriousness." (Oktober
2008)
