This came from a great concerned and involved patient who forwarded a post by Dr. Jay Gordon (my family's pediatrician) in Los Angeles, California. The lovliest man, and a great doctor on the subject of plastic toxicity. Then I posted an article from another awesome patient on some easy solutions to reducing plastic toxicity. This is important stuff for our children and ourselves in the battle toward wellness from IC and the general ills of poor health!
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):(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).
RELATED ARTICLE
Bisphenol A and Risk of Metabolic Disorders
Frederick S. vom Saal, PhD; John Peterson Myers, PhD
JAMA. 2008;300(11):(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¡Xmost relevant
to the findings of Lang et al1¡Xmetabolic 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-£gg/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-£gg/kg
dose of BPA once a day for 2 days (a dose 5 times lower than the ADI), BPA
stimulated pancreatic £] cells to release insulin. After administration of
100 £gg/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 £]-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 £] 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 £] cells, 100-fold higher doses of BPA and estradiol did not
stimulate £]-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 £gg/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¡Vsponsored 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@...).
Published Online: September 16, 2008 (doi:10.1001/jama.300.11.1353).
Financial Disclosures: Dr vom Saal reported serving on the organizing
committee of a National Institutes of Health (NIH)¡Vsponsored 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¡Vrevenue-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. PUBMED
3. Wetherill YB, Akingbemi BT, Kanno J; et al. In vitro molecular mechanisms
of bisphenol A action. Reprod Toxicol. 2007;24(2):178-198. PUBMED
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. PUBMED
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. PUBMED
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. PUBMED
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. PUBMED
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. FREE FULL TEXT
11. Trautmann N. The dose makes the poison¡Xor 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. PUBMED
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.
FREE FULL TEXT
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. PUBMED
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.
PUBMED
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.
PUBMED
21. Newbold RR, Padilla-Banks E, Jefferson WN, Heindel JJ. Effects of
endocrine disruptors on obesity. Int J Androl. 2008;31(2):201-208. PUBMED
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. PUBMED
23. Anastas PT, Beach ES. Green chemistry: the emergence of a transformative
framework. Green Chem Let Rev. 2007;1(1):9-24.
--- End forwarded message ---
