Transcript The ubiquity of BPA - UNM Biology Department Home Page

Bisphenol A: A Public Health
Hazard
Teal Clocksin, Sandy Duong, and Ginny
Morriss
The Controversy
Video
Two government panels convened by the National Toxicology Program and the National Institute of
Environmental Health and Safety reached different conclusions on the potential effect of BPA as an
endocrine disruptor, leading to a widely publicized controversy.
What is Bisphenol A?
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BPA is one of the world’s most highly produced chemicals.
More than 2 million metric tons were produced in 2003.
Demand for BPA increases 6% to 10% annually.
It is used in polycarbonate plastics.
BPA monomers are released when exposure of the polymer
to high temperatures or acidic or basic substances causes
hydrolysis of the ester bonds which link the molecules
together.
Humans are widely exposed through food, drinks, dental
sealants, dermal exposure and inhalation of household dusts.
BPA is detectable in more than 90% of the US population.
Burridge E. Eur Chem News. 2003;78(2048):17.
Calafat AM., et al. Environ Health Perspect. 2005;113(4):391-395.
Calafat AM., et al. Environ Health Perspect. 2008;116(1):39-44.
Rubin and Soto. Molecular and Cellular Endocrinology 2009; 304: 55-62
Vandenberg LN, et al. Reprod Toxicol. 2007;24(2):139-177.
Environmental exposure and risk of
BPA
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Core principle of regulatory toxicology suggests that studies using
high doses of a chemical can reveal the potential effects of low
doses and no testing is performed below that dose in which there is
no observed adverse effect (NOAEL)
This principle assumes a monotonic dose-response curve (slope
never changing between positive and negative values)
Examples of monotonic doseresponse curves
Examples of non-monotonic
dose-response curves
Myers et al. Environmental Health Perspectives 2009; 117: 1652-1655
Figures from http://www.ourstolenfuture.org/newscience/lowdose/nmdrc.htm
Environmental exposure and risks of
BPA
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BPA exhibits a non-monotonic dose-response curve,
effects have been observed at levels well below those
tested at the No Observed Adverse Effects Level
Myers et al. Environmental Health Perspectives 2009; 117: 1652-1655
Tolerable Daily Intake Dose
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The current FDA accepted Tolerable Daily Intake dose is 50 mg kg-1
The National Toxicology Program (NTP) states that low doses are 0.05 mg
kg-1
Levels of BPA used in scientific literature are typically 1 mg kg-1 or less
The NTPs Center for the Evaluation of Risks to Human Reproduction
concluded that current levels of BPA exposure are of concern for
development of the prostate glands, mammary glands, and brain and for
behavioral defects, and reproductive and developmental toxicity in fetuses,
infants, and children, or pregnant women.
The NTP studies suggest that since BPA has a fast metabolism rate (halflife time <6 hrs) it is likely that there is a continuous exposure to BPA in the
US population
Bondesson et al. Reproductive Toxicology 2009; 28:563-567.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press.
Li et al. Human Reproduction 2009; 00: 1-9.
Metabolites
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Ten different BPA metabolites have been identified after
biotransformation, some of which are more potent than
the parental compound.
Effects of these metabolites with simultaneous exposure
to other compounds may be additive, synergistic, or
antagonistic to developmental processes.
Most notable effects are seen in fetal or early childhood
developmental stages (≤7 years of age).
Bondesson et al. Reproductive Toxicology 2009; 28:563-567.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press.
Rubin and Soto. Molecular and Cellular Endocrinology 2009; 304: 55-62
Structures of BPA and chlorinated
derivatives.
Jan-Åke Gustafsson, University of Houston.
BPA’s possible mechanisms of action…
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Endocrine disruption
Developmental disruption
Other mechanisms previously reported:
 Intracellular signal transduction pathway alteration
 Neuronal toxicity
 Alteration of immune response
Y.B. Wetherill, et al. Reproductive Toxicology 2007;24:178–198.
Walsh DE., et al. Mol Cell Endocrinol 2005;230(1/2):23–30.
Yoot Mo Lee, et al. J. Vet. Sci. 2007;8(1):27–38.
Bondesson, M., et al. Reproductive Toxicology 2009;28:563-567.
Yoshino S., et al. Immunology 2004;112(3):489–95.
BPA is an Endocrine Disrupting Chemical
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Endocrine disrupting chemical (EDC)- an exogenous
agent that interferes with the production, release,
transport, metabolism, binding, action, or elimination
of natural hormones in the body responsible for the
maintenance of homeostasis and developmental
processes.
Many of BPA’s harmful mechanisms of action are
the result of its EDC properties.
Kavlock RJ., et al. Environ. Health Per. 1996;104(Suppl 4):715–40.
Y.B. Wetherill, et al. Reproductive Toxicology 2007;24:178–198.
Endocrine disruption is the primary cause
of developmental defects due to BPA
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Mimicking the action of endogenous
estrogens, androgens and thyroid hormones.
Blocking the action of endogenous estrogens,
androgens and thyroid hormones.
Altering the synthesis, transport, metabolism,
or excretion of endogenous hormones.
Bondesson, M., et al. Reproductive Toxicology 2009;28:563-567.
Y.B. Wetherill, et al. Reproductive Toxicology 2007;24:178-198.
Nuclear endocrine receptors regulate
transcription.
Normal endocrine activity
Jan-Åke Gustafsson, University of Houston.
BPA disrupts normal endocrine
activity by blocking access to
receptors
Effect of BPA on fetal and neonatal
development
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Fetal development is vulnerable at specific
windows of time.
Fetuses are exposed to BPA at low doses.
In pregnant mice, BPA is quickly transported
to the fetus.
Fetuses and infants metabolize BPA less
effectively, due to a limited capacity for fetal
and neonatal livers to conjugate BPA, and
may be more sensitive to toxicity.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press
Example of fetal exposure to BPA
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Body weight of rats born to mothers exposed to low levels of BPA
(0.1 mg kg-1 d-1), high levels of BPA (1.2 mg kg-1 d-1), or no BPA
Both females and males exposed to BPA exhibited increases in
body weight, results more prominent in females.
Response in females dose-dependent, exhibiting a non-monotonic
response similar to the pattern suggested for other actions of BPA.
Low dose-exposed females showed significantly increased body
weight compared with high dose-exposed females and non-exposed
females
▲ - low dose (0.1 mg kg-1 d-1)
■ - high dose (1.2 mg kg-1 d-1)
◊ - no BPA
Rubin and Soto. Molecular and Cellular
Endocrinology 2009; 304: 55-62
Proposed actions of perinatal BPA exposure
possibly influencing body weight
From Rubin and Soto. Molecular
and Cellular Endocrinology 2009;
304: 55-62
BPA effects on fetal and neonatal
development
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BPA and Thyroid hormone together result in a
20-30% inhibition of Thyroid hormone signaling.
TH-dependent development in tadpoles
antagonizes TH dependent transcription
regulation.
BPA exposure in small doses has been shown
to increased prostate size; exposure in large
doses has the opposite effect.
Rubin and Soto. Molecular and Cellular Endocrinology 2009; 304: 55-62
The effect of BPA on juvenile
development
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In rodents, BPA has been shown to affect brain morphology,
neuroanatomy, neurochemical makeup and behavior.
BPA causes induction of estrogen and thyroid hormone
effects, estrogen and thyroid hormone independent effects,
and also alters expression of hormone receptors.
BPA, like estrogen, was shown to have an effect the brain
areas of emotion, perception, memory, and learning; however,
different brain regions respond differently.
 For example, in the hippocampus, BPA and estrogen had
opposite effects on transcribed gene but in the anterior
amydala, estrogen and BPA had common regulatory
effects on 40% of the transcribed genes.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press.
Rubin and Soto. Molecular and Cellular Endocrinology 2009; 304: 55-62
BPA affects juveniles
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Epigenetic mechanisms used in development such as
methylation could be both altered or normally regulated
by BPA.
Behavioral changes associated with BPA are
hyperactivity, learning deficits, increased susceptibility to
drug addiction and increased aggression.
BPA has also been associated with immune disorders,
increased growth rate, and early secondary sexual
maturation.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press.
Rubin and Soto. Molecular and Cellular Endocrinology 2009; 304: 55-62
Effects of BPA on adults
(reproductive development)
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BPA affects chromosome segregation and
can result in nondisjunction in cell culture and
in vivo resulting in abnormal sperm
production in males and oocytes in females.
Interaction with tubulin disrupts spindle
organization and can lead to meiotic arrest.
This error prone segregation increases with
nitric oxide synthesis defects.
Bondesson, M., et al. Reproductive Toxicology 2009;28:563-567.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press.
Effects in adults continued
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BPA also mimics estrogen activity in metabolic pathways, altering
blood glucose homeostasis, decreasing glycemia, increasing insulin
levels, and increasing differentiation of adipocytes.
Similar structure and action as diethylstilbestrol (DES) that has been
linked to increased risk of vaginal and breast cancer.
BPA increases prolactin release and stimulates uterine, vaginal, and
mammary growth.
BPA also has antiandrogenic activity.
Altered hormone production often leads to disruption of fertility in
both males and females.
Exposure has also been linked to increased incidence of diabetes,
cardiovascular disease, and liver enzyme abnormalities.
Li et al. Human Reproduction 2009; 00: 1-9
Iain A. Lang, et al. JAMA. 2008;300(11):1303-1310.
Study on the effect of BPA in adult males (Li et al.
Human Reproduction 2009; 00: 1-9)
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Occupational exposure to BPA and its effects on
sexual function were measured.
Used cohort of unexposed workers as control
Authors controlled for factors such as age,
education, marital status, employment history,
exposure to other chemicals and/or heavy
metals, diseases that may contribute to risk of
sexual dysfunction, and habits (smoking or
alcohol consumption) that may alter sexual
function.
Li et al 2009 study continued
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Measurement of sexual dysfunction covered four domains commonly used
in similar studies—sexual desire, erectile function, orgasmic function, and
overall satisfaction with sex life
Results (exposed workers compared with unexposed workers):
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4-fold increased risk of reduced sexual desire (OR 3.9, 95% CI 1.8 – 8.6)
Greater than 4-fold risk of erection difficulty (OR 4.5, 95% CI 2.1 – 9.8)
Greater than 7-fold risk of ejaculation difficulty (OR 7.1, 95% CI 2.9 – 17.6)
Almost 4-fold risk of reduced overall satisfaction with sex life (OR 3.9, 95% CI 2.3
– 6.6)
Results were similar for cohorts in the study working for different lengths
of time as well as in different areas.
The results exhibited a dose-dependent response.
Other studies have indicated changes in sexual behavior among nonhuman animals to environmental levels.
Actual results on next slide
Results of Li et al. study
Studies show strong association of BPA
with disorders common in U.S.
Iain A. Lang, et al. JAMA. 2008;300(11):1303-1310.
Summary
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Most studies performed on animal models
suggest disruption of major biological
processes due to BPA exposure at levels
below currently accepted values
Consistent results have been observed in
human studies based on blood and urine
analysis and genomic association studies
Studies suggest the affect of BPA on
development is context dependent.
Approval of BPA
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Since the 1940s, BPA has been used as a component of
plastics.
In 1976, the EPA (Environmental Protection Agency) has
deemed BPA safe.
In 1993, EPA determined the safe level to be 50 mg/kg.
Since the 1990s, the adverse effects of low doses of
BPA have become more recognized.
Although the FDA has previously accepted low doses of
BPA as “safe” it has recently softened its stance on BPA
stating it is of “some concern” for fetuses and children
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press
Consequences of the studies
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Various states are recognizing the dangers of
BPA and have proposed legislations banning
BPA products in a wide range of plastics
especially plastics exposed to babies and
young children.
Bailin et al. Investor Environmental Health Network 2008.
Examples of proposed legislation:
State
Year
Bill Number
Title,
description
of the
legislation
Status
California
2008
SB 1713
Toxin-Free
Toddlers and
Babies Act,
Senate Bill
Committee on
Health. Read
three times,
Refused
Passage. August
29, 2008.
Connecticut
2008
HB 5601
Banning
Children's
Products
Containing Lead,
Phthalates or
BPA
Legislative
Commissioners’
Office. Tabled for
calendar Year
2008.
Maryland
2008
HB 56
Phthalates and
Bisphenol-A—
Prohibitions—
Toys and Child
Care Articles
Withdrawn.
March 22, 2008.
Erler and Novak. Journal of Pediatric Nursing 2009; Article in Press
Plastic companies response
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The Dow Action Network acknowledged that the
Assembly men representing the district, including
Dow’s Plant, is on the record for abstaining SB
1713. After the FDA approved BPA as a safe
product, the SB 1713 was defeated a week after.
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Both Dow Chemical Company and Playtex Products
Incorporated downplayed any acknowledged risk
with BPA but cited the reason for the BPA-free
products was due to consumer response.
Bailin et al. Investor Environmental Health Network 2008.
Public Response
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Five leading manufacturers of polycarbonate baby bottles, namely,
Gerber, Evenflo, Avent, Playtex, and Dr. Brown's,are facing a classaction lawsuit filed in Los Angeles Superior Court due to the
presence of BPA.
May 1, 2008: A putative billion dollar class action lawsuit, Wilson et
al v. Avent America, Inc. et al., was filed in the United States District
Court for the District of Kansas against the top five baby bottle
manufacturers (Avent America, Evenflo, Gerber, Handi-Craft (Dr.
Brown's) and Playtex) for their use of Bisphenol A in polycarbonate
plastic baby bottles and toddler training cups, in violation of Kansas
consumer protection laws. As with the LA and MO suits, this one is
being brought by Rights For America attorney Robert H. Weiss.
(Case Number: 2:2008cv02201).
Bailin et al. Investor Environmental Health Network 2008.
Retailer’s response
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The retailing companies, such as Wal Mart and
Toys R Us, are no longer stocking baby bottles
with BPA. In April 2008, Nalgene started phasing
out their water bottle products containing BPA.
Playtex Products Incorporated announced they
will have BPA free products.
Bailin et al. Investor Environmental Health Network 2008.
Alternatives to BPA
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Glass-there has been a
shortage of glass baby bottles
due to the BPA scare of
February 2008.
Steel/Aluminum-since 2008,
SIGG, an aluminum sports
bottle producer has seen
increase in sales by fivefold.
These bottles sell for $20, twice
the amount as a polycarbonate
bottle.
Bailin et al. Investor Environmental Health Network 2008.
Japanese Substitute
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Japan can manufactures have
been using alternatives to BPA
for at least a decade. They
started using polyethylene
terephthalate (PET), a polyester
based alternative. It leaches only
5% as much BPA as their
American counterparts. PET is
only used in canned beverages
served hot.
Bailin et al. Investor Environmental Health Network 2008.
Polycarbonate alternative
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Tritan: tritan copolyester was introduced in October 2007
by the Eastman Chemical Company. Eastman
developed this chemical in response to a plastic that can
withstand heat. Relative to polycarbonate, Tritan is
lighter weight due to its lower density, and has the
stress-, water-, scratch- and chemical-resistance.
A copolyester is a modified polyester using diols and
diacids. They retain their strength, clarity, and other
mechanical properties despite being exposed to a variety
of chemicals as seen in polycarbonates.
Bailin et al. Investor Environmental Health Network 2008.
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Tritan is cleared for food contact
applications in the U.S. under the
FDA food contact notification
scheme. Food contact substances
must satisfy FDA requirements
regarding environmental, chemical
and toxicological risks.
There is no substantial data stating
whether or not Tritan is safe
because no toxicology studies have
been completed and no acceptable
daily intake levels have been
established.
Bailin et al. Investor Environmental Health Network 2008.
Are the alternatives safer?
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Some alternative to plastics seem safer, but
on the other hand, some can pose health
risks equal to or more so than BPA.
It is unlikely that the FDA’s past reviews have
fully assessed the safety of these alternatives
especially in respect to their endocrine
disrupting abilities.
For the most part they are deemed safer than
polycarbonates.
Bailin et al. Investor Environmental Health Network 2008.
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