Joseph A Fisher
TOX 512 – Assigned Paper
Oregon State University
11 March 2008
Per Position Statement:
Polycarbonate clear plastic is safe for human use in spite of detection of bisphenol A and any risk does not
outweigh the benefits of use.
INTRODUCTION
Bisphenol A (BPA) is an industrial chemical used to make polycarbonate plastics, epoxy resins, and other
products. Its use is widespread and the number of products that contain BPA are ubiquitous throughout
society. Recent press has suggested that low dose exposure to BPA leached from polycarbonate plastic and
other products is harmful to humans. BPA was first synthesized in 1905 and has experience widespread use
over the last 50 years since the invention of polycarbonate in 1953 [1]. Toxicological testing on BPA has been
conducted over the last 40 years and produced an extensive amount of data. This data indicates that
consumer products including food contact materials made with BPA, are safe for their intended use and pose
no known risks to human health. The US FDA, EPA, EU Food Safety Authority, and other national and
international agencies charged to protect public health fully support the use of this chemical.
Humans are exposed to an enormous number of different chemicals every single day including BPA. Many
chemicals that find their way to humans are investigated and safe dose levels are determined. A large number
of pharmacological test results from major studies indicate that the low dose concentrations of BPA normally
experienced by consumers in their daily living, do not pose a risk to their health. Still, there is some concern
regarding low dose effects in susceptible populations, and agencies are conducting further research [2].
In 2002 approximately 2.8 million tons of BPA was produced globally and used in the manufacture of
thousands of different products [3]. End user products include DVDs/CDs, electrical and electronic equipment,
automobiles, sports equipment, food and drink containers, plastic food wraps and cookware, pvc piping, and a
large number of other products. Humans are exposed to BPA though multiple pathways but 99% of the
absorbed dose is considered to be via an oral route. Once inside the body, BPA is quickly metabolized.
Statistics in the US population regarding BPA indicate that dietary related sources account for 99% of the
exposure and that 95% of the populations urine contains low quantities of BPA and its metabolites [4]. In 1986
the European Commission SCF, and in 1988 the US EPA, set the human oral reference dose (RfD) value to be
50 ug/kg/day [5,6]. What this means is that SCF and EPA considers anything less than 50 ug/kg/day over a
persons lifetime to be safe for consumption. This value would represent a maximum daily dose of 150 ug/day
for a 3 kg (6.6 lb) newborn, to a value of 3,750 ug/day for a 75 kg (165 lb) adult.
This article is a brief review of the topic of concern from a toxicological perspective. On the basis of the
literature review, a conclusion is reached that polycarbonate clear plastic is safe for human use in spite of
detection of BPA and any risk does not outweigh the benefits of use. EPA set the human RfD value to be 1,000
times lower than the lowest observable adverse effect level (LOAEL) from rat animal studies. This value is
conservative and safe. Every substance or chemical is toxic in sufficient quantity including salt and sugar. BPA
is just another substance or chemical. The use of BPA in various products including polycarbonate clear plastic
provides significant benefit to consumers, and its use should continue.
THE BASIC CHEMISTRY
Bisphenol A (BPA) (C15H16O2 , CAS No: 80-05-7, ICSC 0634) is an organic compound synthesized from phenol
and acetone. Two phenol groups are combined with one acetone unit to produce BPA and water. Since the
only byproduct is water (H20), BPA production is called a "green chemical" reaction. When in its dry or solid
form, BPA appears as a white flake solid with a mild phenolic odor [7]. BPA has a molecular mass of 228.29
g/mol, a slightly soluble relative density of 1.2 (water = 1), melting or liquification point of 158 C (316 F), boiling
or vaporization point of 220 C (428 F), and flash or ignitable point of 227 C (441 F). BPA vaporizes only slightly
at room temperature due to its low vapor pressure of 5E-6 pascals at 20 C (68 F).
Synthesis of Bisphenol A
BPA was first reported in 1891 and first synthesized in 1905. It is used mainly as an intermediate in the
production of polycarbonate, epoxy, and polyester resins. As an industrial chemical, it has many attributes
including the ability to harden plastic and provide heat resistance. Its use has become widespread since 1953
when polycarbonate was invented [1]. It can be found in plastic microwave cookware, plastic food wraps,
bottles, sealants, metal cans and bottle tops, water supply lines, and many other consumer and non-consumer
products.
There are currently 6 BPA manufacturing facilities in the US and coincidently 6 BPA manufacturing plants in
the European Union [8]. Some of these plants are embedded in polycarbonate manufacturing facilities and
some are stand alone. BPA is primarily released to the environment as a result of manufacturing or processing
facilities, but due to its low volatility and short half life it does not stay in the atmosphere for long nor does it
travel far from its source. When in the atmosphere, BPA is normally degraded by photolysis or
photodegradation with an estimated half life of 0.2 days. Other studies determined biodegradation half lives in
water as 2.5 to 4 days and 5 to 30 days for soil and sediments [7,9]. EPA conducted biological oxygen demand
(BOD) tests on BPA. Results from the study found a 5-day BOD/ThOD of 26% and a 20-day BOD/ThOD of
71%. According to EPA these values meet the criteria of ready biodegradability [10]. The fact that BPA does
not travel far from its source and readily biodegrades, increases its safety as a chemical.
BPA does hydrolyze and leach from polycarbonate products under high heat, alkaline (extreme pH), and long
contact times. The amount of leaching increases as a function of use. Older and more degraded products
(cracked or yellowed) were found to leach more BPA than newer products [11,12]. Low levels of BPA leachant
are commonly found in sewage treatment plants, landfills, and recycling facilities.
THE POTENTIAL FOR HUMAN EXPOSURE
Toxicological interest in BPA has primarily been oriented to polycarbonate products that come into physical
contact with food or liquid items and lead to an oral human exposure. This is a fact because BPA is known to
leach in small quantities from polycarbonate products including food containing products [7]. Once the BPA
leachants are released, they enter humans orally into the gastrointestinal (GI) system. Fortunately, studies
indicate that BPA lechant quantities entering humans on a daily basis are at least 10 times less than the US
and EU tolerable daily intake values of 50 ug/kg/day.
In a recent US study on the amount of BPA found in food products, researchers found solid food values ranged
(n = 309) from 3.5 to 4.3 ug/kg of food. In liquid food (n = 287), values ranged from 0.5 to 0.8 ug/kg liquid [4]. In
addition since BPA does not bioconcentrate or bioaccumulate, eating or drinking different types of foods from
different locations would not be a factor in the results. Comparing these values to the EPA RfD value of 50
ug/kg/day, we can see that humans could not possible consume enough food or liquid in a single day to
exceed this value. For example, a newborn would have to consume approximately 35 kg (77 lb) of food and an
adult 872 kg (1,922 lb) of food per day. Consumption of this much food per day is highly unlikely and the
comparisons for liquid consumption are even more extreme.
TOXICITY – ANIMAL DATA
There has been a significant amount of data produced on the toxicological and biological effects of BPA on
animals. The US EPA and EU SCF both utilized rat studies to determine their original estimates of safe BPA
values for humans. Considerable numbers of in-vivo and in-vitro studies have since been conducted on fish,
frog, rat, mice, hamster, rabbit, monkey, chimpanzee, guinea pig, chicken, birds, and other animals.
Rodent studies (rats and mice) occur most often. Results from these studies indicate that BPA does not cause
malformations or birth defects in rats or mice at levels up to the highest doses evaluated: 640,000 ug/kg/day
(rats) and 1,250,000 ug/kg/day (mice). It does not alter male or female fertility after gestation exposure at
levels up to: 450,000 ug/kg/day (rat) and 600,000 ug/kg/day (mice). It does not permanently affect prostate
weight at doses up to 475,000 ug/kg/day (rat) and 600,000 ug/kg/day (mice). It does not cause prostate cancer
at doses up to 148,000 ug/kg/day (rat) and 600,000 ug/kg/day (mice) [8].
On the other hand, there is some data that shows that BPA can accelerate the onset of puberty in rats and
mice: 475,000 ug/kg/day (male rat), 600,000 ug/kg/day (male mice), and 240 ug/kg/day (female mice).
Additionally, reproductivity toxicity has been found in rodents: 47,500 ug/kg/day (male/female rats and mice)
[8]. At first glance these effects may appear concerning, but not when we consider that they are 5 to 12,000
times higher than the human reference dose or allowable daily intake (RfD = ADI = 50 ug/kg/day).
TOXICITY – HUMAN DATA
BPA enters humans orally into the GI system where it is mostly metabolized. When metabolized, BPA is
rapidly glucuronidated or sulfated during first pass metabolism in the gut wall and liver by the phase II UDP
Glucuronosyltransferases (UGT) and Sulfotransferese enzymes. The quantity of UGT and Sulfotransferese
enzymes in humans is large and a common clearance system, but some polymorphisms do exist. There is no
evidence of hepatic BPA recirculation in humans [13]. Most BPA is excreted by urine within 5 hours of
ingestion ≥84% [14] and 100% [15] within 42 hours of ingestion. Urinary profiles were reported at ~33–70%
bisphenol A glucuronide, ~10–33% parent compound -- "unmetabolized", and ~5–34% bisphenol A sulfate
conjugate [16,17]. Sometimes BPA is also passed unmetabolized to feces.
BPA is found in human fetal tissue and fluids [18,19]. Studies indicate that BPA concentrations are the same
order of magnitude in maternal blood concentrations [18] and ~1 order of magnitude lower in amniotic fluid
[19]. Expert panels have expressed "some" but no alarming concern that fetuses from pregnant women,
nursing infants, and small children could be at risk from neural and behavioral effects and they recommend
that further studies be conducted to fill gaps in conclusions [8]. These recommendations are largely driven by
the fact that fetuses in particular are known to have less glucuronidataion and sulfation capacity [20].
Epoxy resin dental sealants have become very popular in recent years as a substitute for mercury amalgam
fillings. While both methods provide substantial benefit to dental hygiene, they both release over time their
associated components to the human body. Dental amalgams are know to release elemental mercury vapor to
the lungs, thus exposing the recipient to a known hazardous metal. Epoxy resin dental sealants release BPA in
very small amounts that are quickly absorbed in the GI system. BPA exposures from dental sealants are
reported to be 50,000 times lower than levels shown to cause toxicity in animal studies. These exposures are
acute and so small that they represent an insignificant percent of the overall human absorption.
During the research review, no significant induction substrates were found for BPA but two CPY P450
inhibitors were mentioned. One study indicated that CYP2C8 and CYP3C19 were found to be somewhat
hepatically inhibited by unmetabolized BPA [21]. These findings or lack of findings indicate that BPA might not
be a great concern regarding its inhibition or induction capabilities on other enzymes or gene expression.
BPA is not found to be genotoxic or carcinogenic in humans [7,22]. One of the biggest and most largely
publicized issues in the press regarding BPA, is its effect on the human endocrine (hormonal) system. BPA
does appear to the human system as a weak estrogen. The scientific debate is largely inconclusive but
government sponsored research groups in the US, EU, and Japan, have recommend further studies on the
BPA effect in the endocrine system and its related hormone response.
AREAS OF UNCERTAINTY
In January 2008, US House Representatives Dingell and Stupak launched an investigation into BPA, writing
seven prominent manufacturers of baby food, as well as the FDA requesting information on how these
organizations determined the safety of human exposure to BPA. In February 2008, the investigation was
expanded to include the Weinberg Group, a well known scientific and regulatory consulting firm that was
highered by chemical companies to possible “shape the debate” regarding BPA. The Weinberg Group has had
considerable involvement in the scientific debates of Perfluorooctanoic acid (PFOA), Agent Orange, and BPA.
Results from this investigation are pending.
The National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NIH, US HHS)
delivered an expert report on the Reproductive and Developmental Toxicity of BPA in November 2007 [8]. The
report summarizes the toxicology and medical data available in the literature through February 2007. The study
group consisted of a 12 member independent panel of government and non-government scientists. Their
mission was to evaluate the available scientific studies on the potential reproductive and development hazards
of BPA. Some of their data was included in this paper. The study concludes with "minimal" concerns for
reproductive effects and "some" concern for developmental effects. The panel stated that inconsistent findings
reported in low dose studies made it difficult reach more specific conclusions. They recommend a list of critical
data needs to better ascertain the effects of BPA on humans.
Industry organizations support an opinion that BPA is safe for human exposure. One "Bisphenol-A" website
sponsored by the American Chemistry Council and referenced by many industry organizations, provides
information regarding the safety of BPA [23]. The authors review of this site found a substantial amount of
good information although perhaps somewhat bias and an obvious pro BPA stance. A review of other industry
websites found a continued common theme that BPA is safe at doses below the 50 ug/kg/day recommended
daily limit.
CONCLUSION
Based on the scientific literature and low quantities of exposure to BPA leachant, polycarbonate clear plastic is
safe for human use in spite of detection of BPA and any risk does not outweigh the benefits of its use. BPA
production and use is expected to grow 8% annually due to the popularity of polycarbonate based products
[24]. These products are light, shatter resistant, durable, heat resistant, and provide significant benefit to a
worldwide market. The quantities of BPA that leach from polycarbonate products and enter humans via oral
exposure is well below the EPA RfD value of 50 ug/kg/day over a persons lifetime. Additionally, the European
Commission which had previously set a temporary value of 10 ug/kg/day in 2002, has since raised this value to
50 ug/kg/day in 2007.
There have been a small number of studies that have demonstrated an association between low dose BPA
exposure and risk in susceptible human populations. Review of these studies from the expert scientific
community have suggested that for certain toxicological endpoints, the level of concern should be raised from
"minimal" to "some" concern. EPA has recommend that research and testing continue to evaluate the safety of
BPA. Whether these scientific studies will lead to a change in the daily acceptable dose levels of BPA in the
future is unknown. For now, the scientific risk assessment is that BPA is safe at the quantities normally
experienced by consumers in their daily living and it does not pose a risk to their health. After an extensive
unbiased review of Bisphenol-A (BPA) in the literature, this author concludes that polycarbonate clear plastic is
safe for human use in spite of detection of bisphenol A and any risk does not outweigh the benefits of its use.
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