vom Saal, F and W Welshons. 2006.

Large effects from small

exposures. II. The importance of positive controls in low-dose
research on bisphenol A. Environmental Research 100: 50-76.

Part 1 of this series

More on bisphenol A

Contents
A review of BPA's history, basic chemistry and current uses
A review of the prediction that BPA would have biological impacts
at low exposures
Low-dose BPA results challenge the assumptions used in chemical
risk assessment
Evidence of bias in industry-funded research on BPA
Conclusions

Latest news about While chemical manufacturers claim

bisphenol A
Search
6 September Plastic debris clogs
our oceans and hurts wildlife.
Recycling and the proper disposal of
waste are necessary to help reduce
the amount of plastic trash.
Salisbury Daily Times, Maryland.
2 September Commentary:
Twenty-five years of endocrine
disruption science:
Remembering Theo Colborn.
Theo Colborn was a visionary leader
who excelled at synthesizing
scientific findings across disciplines.
Using her unique insights and strong
moral convictions, she changed the
face of toxicological research,
influenced chemical regulatory
policy, and educated the public.
Environmental Health Perspectives.
in public statements that "high-
quality repeat studies in independent
laboratories have not been able to
replicate" claims that bisphenol A
causes adverse effects at low levels
(for example on industry's
NoAB319 website), a careful
analysis of the 'high quality'
studies they reference reveals deep
flaws, and that industry-financed
research on the health effects of
bisphenol A is strongly biased
against finding adverse effects.
These flaws result from the way the
studies have been designed and
executed.
Read about industry's AB319 claims
According to vom Saal and
Welshon's analysis in this paper, of
30 August 10 things you need to
know about the new U.S.
chemicals law. The updated Toxic
Substances Control Act brings new
hope for protecting Americans’
health and environment. Here's
what it does — and doesn’t — do.
Ensia.
27 August FLASHBACK: That time
when Maine's controversial
Governor talked about BPA. The
political debate over bisphenol A is
heating up in Maine after Gov. Paul
LePage’s recent comments
questioning whether the
controversial chemical is as
dangerous as many scientists claim.
Bangor Daily News, Maine.
27 August FLASHBACK: That time
back in 2011 when Maine's
controversial Governor talked
about BPA. Today, the Bangor
Daily News reports on Maine
governor Paul LePage's weird
comments on the chemical
bisphenol A. Bangor Daily News,
Maine.
More news about
bisphenol A
the 130 studies of low dose effects
of BPA published as of summer
2005, 119 have been funded by
governments and 11 by industry.
92% of the government funded
studies report adverse effects. None
of the industry studies do. In this
paper, vom Saal and Welshons
examine in detail the government
and industry funded studies that
found no effects, and show several
reasons why poor study design
destined them to failure.
Not only is industry's own research
flawed, but they have repeatedly
chosen to ignore all but a handful of
the studies on low level effects of
bisphenol A that have been
published in the peer-reviewed
scientific literature. This is a classic
ploy, perfected by representatives of
tobacco companies, to undermine
progress toward better health
standards. They focus on a small
piece of the overall picture, focus on
creating the impression that that
piece is flawed, and then argue that
because of that flaw the entire body
of literature is invalid.

For bisphenol, this tactic requires them to ignore over 100 studies
that have been published in the peer reviewed literature by
independent scientists and to rely instead upon a small number of
demonstrable flawed studies conducted by industry labs.

What did vom Saal and Welshons do?

Section 1: A review of BPA's history, basic chemistry and current

uses.
  The ester bond that links BPA molecules into
polycarbonate and resins is subject to hydrolysis,
which results in leaching of BPA into water even
from new polycarbonate at room temperature. The
leaching rate increases over 1000-fold as it begins
to show signs of wear. Older studies that reported
no leaching used very insensitive methods. Hence
the FDA's assertion that "with baby bottles, we
haven't been able to detect BPA" is outdated.
 Until recently, BPA has been considered to be a
weak estrogen because in some assays it can be
10,000 to 100,000-fold weaker than estradiol,
based on binding affinity to the nuclear estrogen
receptor. New research contradicts, this however.
BPA can be just as powerful as estradiol, with
detectable effects at the lowest doses tested,
approximately 0.23 parts per trillion.

Section 2: A review of the original prediction that BPA would have

biological impacts at very low levels of exposure, published in
1997.

 Previous studies had used only high doses, and in

light of the relative low binding affinity to the
nuclear hormone receptor, this seemed reasonable.
But then Nagel et al. discovered that while serum
binding proteins bind with most of the estradiol in
serum, rendering it biologically inactive, they bind
with little of the BPA. This led them to calculate a
correction factor for the relative potency of BPA
compared to estradiol, and to calculate, based on
known effects of estradiol, that 20 µg/kg/day of
BPA fed to a pregnant female should stimulate an
increase in the prostate size, decrease sperm count
and alter other reproductive organs in male
offspring. This is in fact what they found.
 These findings have been replicated by an
independent laboratory and by vom Saal's lab.
 In this section vom Saal and Welshons also
introduce the first criticism of one of the failed
attempts by industry labs to replicate their
findings. This study, by Tyl et al. used a strain of
rats known to be insensitive to any exogenous
estrogen, including potent estrogenic drugs. Tyl et
al. used this strain because it was their standard
experimental animal in their laboratory. In
reviewing the work, the National Toxicology
Program concluded: "animal selection should be
 based on responsiveness to endocrine active
agents of concern, not on convenience and
familiarity." Unfortunately, Tyl et al. did not
include a positive control in their work. Based on
the overall insensitivity of the strain they used, it
is likely that the positive control would have
shown no reaction, proving the lack of validity of
the study. Without data on a positive control, Tyl
et al. cannot conclude that bisphenol A does not
have low dose activity.

Section 3: Low-dose BPA results challenge the assumptions used in

chemical risk assessment.
Findings by vom Saal's lab, and by many others, that low
level doses of BPA lead to diverse and permanent
changes in reproductive function and behavior are at
odds with the current health standards established by
the US EPA and FDA.

How was the current BPA standard derived? That

current standard, called the reference dose, is set at 50
µg/kg/day. The reference dose is the level considered to
be safe for human exposure. It was determined from data
published in 1982 showing that 50 mg/kg/day caused
weight loss in rodents. That exposure (50 mg/kg/day) was
the lowest exposure used in the experiments and was
deemed the 'lowest-observed-effect level, or LOEL. No
effort was made in those experiments to test lower doses.
Hence these experiments never determined a level at
which no effect was seen. Instead, according to the
Society of the Plastics Industry, it was assumed
that the "no effects level" was "probably not far below the
LOEL of 50 mg/kg/day. The EPA then applied a 1000-
fold safety factor to the LOEL to predict that 50
µg/kg/day would be safe. No attempt was made to verify
that experimentally.

The study by Nagel et al. published in 1997 was the first

experimental effort to determine whether effects were
caused at lower levels. They found effects at levels
25,000 times beneath the 'LOEL' identified in 1982. Other
researchers have subsequently reported effects up to
2,000,000 times beneath that level in rodent studies, and
even lower in snails and cells.

Clearly, the assumption that 50 mg/kg/day was near

the LOEL was erroneous. Yet those data are still the
basis for current EPA standards for BPA.

This conclusion is important not just for BPA. Most

toxicological studies examine the impact of high-level
doses and then assume that beneath the identified 'no
effects level' there are no adverse effects. They never
examine the effects at low doses, environmentally-
relevant doses, because the assumption is that if an effect
can't be seen at high doses, then it doesn't happen at low
doses. For compounds that interact with hormone
receptors, like BPA, this assumption can't be taken for
granted. Scientists working with these systems are
discovering that low dose effects can be very different
from what happens at high doses, and most important, not
predictable from those experiments. More...

We have no assurance that many other contaminants

don't behave similarly. Many examples have now been
published in the scientific literature showing patterns of
dose-response curves that fit this model, called 'non-
monotonic dose response curves.' Current methods used
to establish public health standards assume that dose-
response curves are monotonic. This is the assumption
that allows, for example, a 10-fold safety factor to be
added to calculate a reference dose from the 'lowest-
observed-adverse-effect level. The implication is that
many compounds will need to be retested, examining the
effects of dosages far beneath the current high-dose
standards.

According to vom Saal and Welshons: "It is well

established in endocrinology that high doses of hormones
and hormonally active drugs and chemicals can exert
inhibitory effects on processes that are stimulated at much
lower doses" resulting in non-monotonic curves. In other
words, when given at high levels, chemicals can suppress
(or kill) but at low levels they can stimulate.
Section 4: Evidence of bias in industry-funded research on BPA

As of July 2005, there are 40 published studies in animals

showing a wide range of adverse effects of BPA at and
below doses of 50 µg/kg/day, and 130 examining effects
beneath 50 mg/kg/day.

Of those 130,
84% found
adverse
effects. None
of the
industry
funded
studies
reported
effects.
(Table to
right, from
Vom Saal
and
Welshons
2006).
As of July 2005, there are 40 published studies in animals
showing a wide range of adverse effects of BPA at and
below doses of 50 µg/kg/day, and 130 examining effects
beneath 50 mg/kg/day.

Why do a small number of studies find no effect?

Industry has focused their argument and their research on

one specific endpoint, reported by Nagel et al. in 1967,
replicated by Gupta in 2000 and extended by Timms et al.
in 2005. That endpoint is enlargement of the prostate
following exposure to low levels of BPA in the womb.

Vom Saal and Welshons present a detailed analysis of

the experiments that failed and find 3 patterns:

1. The experiment didn't fail. One of the studies

widely cited by industry was conducted at the Chemical
Industry Institute of Toxicology. This study was
reviewed for the US EPA by a panel of 36 independent
scientists convened by the National Toxicology
Program, expressly to review the low-dose issue. Their
review was conducted prior to publication of the study.
The authors of the study concluded there was no effect.
The NTP panel of independent experts, in contrast,
reanalyzed the study's data and found that this conclusion
was "flawed," "illogical," and "misleading." The NTP
statistical review of the original data found adverse
effects. Even though these conclusions were made known
to the authors prior to publication of the article, the
authors ignored the review and kept their original
conclusion. The American Chemistry Council in public
comments to the EPA about the NTP panel reiterated the
finding of 'no effect,' citing this study. According to vom
Saal and Welshons "The authors ... thus misrepresented
their findings in the published article and the ACC
misrepresented the actual findings in their letter to the US
EPA."

This pattern of conclusions contradicted by data within

the same industry publication has been seen in other
chemical controversies, including atrazine.

2. The test system was

contaminated with an What are positive
estrogen. In several of the controls?
papers reporting negative
results, the control animals Positive controls are a
have prostates already almost crucial element of
as large as the exposed experimental design. A
animals in the studies that well-designed
found effects. This indicates experiment testing the
that the animals used in the impact of a contaminant
experiments had already been whose impact is
exposed to an estrogenic unknown will contain
contaminant. With even higher three basic treatment
exposures, prostate size begins groups
to decrease, so if animals
 Experimental.
(control and experimental) in
the experiment were The animals that
contaminated by an estrogenic receive the
substance, it would mask the contaminant.
 Negative
effect of the BPA.
control. The
In two of the studies heavily animals that are
cited by industry, there is treated with
strong evidence for this only the
contamination. Both these 'vehicle,' e.g.,
water, used to
studies, (Ashby et al.
deliver the
1999; Cagen et al.
contaminant to
1999) included positive
controls in their studies (see
column to right). In both these
experiments, a known estrogen
used for the positive control
failed to produce a result.
The graph below compares the
1997 data from Nagel et al.
(Missouri) with that of Ashby.
Ashby's (negative) controls
have prostates as heavy as
Missouri's treated animals
(BPA and DES). And his
positive control (DES) has no
effect. Missouri's BPA and
DES groups differed
significantly from the
Missouri's negative control
group.
adapted from vom Saal and
Welshons 2006
Despite the failure of the positive control the scientists
who conducted the research concluded bisphenol A had
the experimental
group
 Positive control.
Animals that
receive an agent
known to cause
an effect similar
to the one being
tested for in the
contaminant.
The main comparison is
between the
experimental group and
the negative control.
This comparison
reveals the effect of
treatment.
If, however, there is no
difference, the positive
control becomes
crucial. If the positive
control also shows no
difference, then the
experiment failed, not
because the
contaminant didn't
produce an effect but
because the controls
were already
contaminated by
something that made
them the same as the
positive control group.
When the positive
control fails, no
conclusion can be
reached about the effect
of the contaminant
because the experiment
has failed.
More on positive
controls...
 no effect, and chemical industry representatives continue
to cite these papers as evidence supporting their position.

It is also important to note that the Ashby and Cagen

studies were presented by the chemical industry as exact
replicas of the Missouri work. That is factually incorrect,
as they used different types of feed and these feed types
could be the source of the contamination evident above.

A similar difference in controls was evident comparing

Ashby et al.'s efforts to replicate a study by Sakaue
et al. showing low-dose effects of BPA on sperm
production. As with the Missouri comparison, above,
Ashby et al.'s controls were similar to the animals treated
by Sakaue et al. with bisphenol A, indicating
contamination in Ashby's experiments.

3. The experiments used an insensitive strain of

animal. Two studies frequently cited by industry (Ema
et al. 2001, Tyl et al. 2002) used a strain of inbred
rat, the Charles River Sprague-Dawley strain, that has
become highly insensitive to any form of estrogen. The
experimental design did not include a positive control;
without one, it is impossible to conclude whether the lack
of a BPA effect was because BPA had no effect, or
because the rat strain was unable to respond to any
estrogen (see above re positive controls). Hence their
conclusion that bisphenol A did not have an effect cannot
be accepted. None of the 6 government-funded studies
with this rat strain found effects of bisphenol A, either.
Nonetheless, the chemical industry holds up the Tyl study
as strong evidence that BPA has no effect. vom Saal and
Hughes 2005 examine the strain issue in greater depth.

What do vom Saal and Welshons conclude?

To recap, current US government standards are based upon

experiments conducted in the 1980s. No 'no-adverse-observed-
effect' level was ever determined experimentally during those early
experiments; instead it was assumed the NAOEL was near the
lowest level used, which had an effect.

Over 100 studies now show adverse effects at levels beneath the
'lowest observed effect' level found in those experiments, some
2,000,000 times beneath that level.

Industry maintains that low dose effects cannot be replicated. It does

this by (1) focusing on one experiment showing effects and insisting
that it cannot be replicated; (2) ignoring replications of that work in
 the peer reviewed literature; (3) promoting studies with clear biases
and flaws; and (4) maintaining that human exposure are "millions of
times lower than levels shown to be safe in experiments" with
animals. The wealth of data from many independent laboratories,
along with biomonitoring data from the CDC, show clearly that
most Americans are exposed to BPA at levels well within the range
that is biologically active.

vom Saal and Welshons conclude by stating: "The weight of

evidence based on examination of the published studies
concerning low-dose effects of BPA in experimental animals
demonstrates the need for a re-evaluation of the prior estimate
of the acceptable limit of daily human exposure to BPA, which is
currently 50 µg/kg/day in the US."

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Human Health & Safety >> Product Safety Product Safe
Polycarbonate Plastics and Bisphenol A Release Polycarbonat
Summary Epoxy Can C
Migration Studies
Potential Exposure and Margin of Safety Dental Sealan
Conclusion
References

Summary

Polycarbonate plastic is a lightweight, high-performance plastic

that possesses a unique balance of toughness, dimensional
stability, optical clarity, high heat resistance and excellent
electrical resistance. Because of these attributes, polycarbonate
is used in a wide variety of common products including digital
media (e.g. CDs, DVDs), electronic equipment, automobiles,
construction glazing, sports safety equipment and medical
devices. The durability, shatter-resistance and heat-resistance of
polycarbonate also make it an ideal choice for tableware as well
as reusable bottles and food storage containers that can be
conveniently used in the refrigerator and microwave (APME).

Bisphenol A (BPA) is a key building block of polycarbonate

plastic. In recent years a number of researchers from
government agencies, academia and industry worldwide have
studied the potential for low levels of BPA to migrate from
polycarbonate products into foods and beverages. These studies
consistently show that the potential migration of BPA into food
is extremely low, generally less than 5 parts per billion, under
conditions typical for uses of polycarbonate products.
Using these results, the estimated dietary intake of BPA from
polycarbonate is less than 0.0000125 milligrams per kilogram
body weight per day. This level is more than 4000 times lower
than the maximum acceptable or "reference" dose for BPA of
0.05 milligrams per kilogram body weight per day established
by the U.S. Environmental Protection Agency.

Stated another way, an average adult consumer would have to

ingest more than 600 kilograms (about 1,300 pounds) of food
and beverages in contact with polycarbonate every day for an
entire lifetime to exceed the level of BPA that the U.S.
Environmental Protection Agency has set as safe.

The European Commission's Scientific Committee on Food

(SCF) has also recently confirmed the safety of polycarbonate
plastic products for contact with foods and beverages. The SCF
estimated total dietary intake of BPA from all food contact
sources, including polycarbonate plastic products and epoxy
resin coatings, to be in the range of 0.00048 to 0.0016
milligrams per kilogram body weight per day, which is below
the Tolerable Daily Intake set by the SCF of 0.01 milligrams per
kilogram body weight per day.

The study data and analyses show that potential human exposure
to BPA from polycarbonate products in contact with foods and
beverages is very low and poses no known risk to human health.
The use of polycarbonate plastic for food contact applications
continues to be recognized as safe by the U.S. Food and Drug
Administration, the European Commission Scientific
Committee on Food, the United Kingdom Food Standards
Agency, the Japan Ministry for Health and Welfare and other
regulatory authorities worldwide.

Polycarbonate Migration Studies

Studies Show Very Low Migration of BPA from Polycarbonate

Polycarbonate is a lightweight plastic with a unique

combination of attributes that make it an ideal material for use
in a wide variety of applications. Included are a number of home
and kitchen applications involving direct contact with food and
beverages that take advantage of polycarbonate's inherent
shatter-resistance, optical clarity, and heat-resistance. Common
examples include reusable 5-gallon water bottles, baby bottles,
tableware such as plates and cups, and containers for storing
food and reheating in a microwave oven.

The primary building block used to make polycarbonate plastic

is bisphenol A (BPA). Many researchers have studied the
potential for trace levels of BPA to migrate from polycarbonate
into food and beverages under conditions typical for uses of
polycarbonate products. These studies include ones conducted
by government agencies in the US, Europe and Japan, as well as
studies conducted by academic researchers and by industry.
These studies generally show that, under typical use conditions,
the potential migration of BPA into food is extremely low.

Some of the most notable examples include studies conducted

by the:

1. U.S. Food and Drug Administration (FDA) on baby

bottles, water bottles and cut portions of baby bottles
under "typical/normal use" conditions (Biles et al, 1997);

2. U.K. Ministry of Agriculture, Fisheries and Food

(MAFF) on baby bottles subjected to as many as 30
cycles of cleaning, sterilizing and simulated use
(Mountfort et al, 1997; MAFF, 1997);

3. U.K. Department of Trade and Industry (DTI),

Consumer Affairs Directorate on baby bottles handled
under "realistic worst-case conditions of use" (Earls et
al, 2000);

4. Japanese National Institute of Health Sciences (NIHS)

on tableware and baby bottles under conditions
representative of normal consumer use (Kawamura et al,
1998); and

5. Society of the Plastics Industry, Inc. (SPI) on

polycarbonate discs under the most rigorous conditions
recommended by FDA (Howe and Borodinsky, 1998).

These studies are not identical in design but all aimed to

measure the potential migration of BPA into foods and
beverages under temperature and time conditions considered to
be typical of how polycarbonate products are actually used.
Study design aspects that vary among the studies are the type of
polycarbonate product or article tested (i.e., baby bottles, water
bottles, tableware, molded discs or cut pieces), the nature of the
"food" in contact with polycarbonate (i.e., an actual food such as
water, fruit juice or infant formula, or a solvent such as 10%
ethanol to simulate food), and the specific time/temperature
conditions used. Considered together, these studies cover a
complete range of polycarbonate food contact products and use
conditions, which provides reassurance that the collective results
fully represent the potential migration of BPA into foods and
beverages. The results of these studies are briefly summarized
below in reference to the type of polycarbonate product or
article that was tested.

Baby Bottles

Each of the studies conducted by the government agencies

included or focused entirely on baby bottles. In most cases, new
baby bottles were studied under well-characterized laboratory
conditions. In each case, migration of BPA from new baby
bottles, when detected, was less than 5 parts per billion.

The Japanese National Institute of Health Sciences (Kawamura

et al, 1998) conducted the most sensitive study on 4
commercially available baby bottles. Because of the use of food
simulants (i.e., water, 20% ethanol, 4% acetic acid, heptane),
which facilitate the analytical measurement of BPA, the limit of
detection was 0.5 parts per billion. Temperature and time
conditions as severe as 30 minutes at 95oC followed by 24 hours
at room temperature were examined. With the exception of one
data point, migration of BPA was less than 1 part per billion for
all test conditions and, for the majority of samples, no BPA was
detected at the 0.5 part per billion limit of detection. The one
exception involved a new unwashed bottle, which resulted in
migration of 3.9 parts per billion. After washing, migration from
this bottle decreased to the limit of detection.

A similar study was sponsored by the United Kingdom's

Department of Trade and Industry (DTI), Consumer Affairs
Directorate, Consumer Safety Research program and conducted
by LGC Ltd (Earls et al, 2000). The study examined 21 new
baby bottles purchased from various retail outlets in the London
area and tested under "realistic worst-case conditions of use."
The bottles were washed and sterilized, filled with either boiling
water or 3% acetic acid solution, capped, and placed in a
refrigerator for 24 hours at 1-5oC. After warming briefly, the
contents were analyzed using a method with a 10 part per billion
limit of detection. In every case, no BPA was detected.

The U.S. Food and Drug Administration and the U.K. Ministry
of Agriculture, Fisheries and Food (MAFF) both measured
migration of BPA from polycarbonate baby bottles into infant
formula or fruit juice. In the FDA study (Biles et al, 1997),
bottles were washed, sterilized, filled with apple juice or infant
formula and refrigerated for 72 hours. These conditions were
characterized as typical or normal. No BPA was found in any
sample with a 100 part per billion limit of detection.

Likewise, in the extensive UK MAFF study (Mountfort et al,

1997; MAFF, 1997), baby bottles were repeatedly processed
through a sequence in which the bottles were washed, sterilized
(three methods tested), filled with fruit juice or infant formula,
warmed in a microwave oven, cooled, and analyzed. After as
many as 30 cycles, BPA was not detected in any sample with a
30 part per billion limit of detection. In addition, no detectable
levels of BPA were found when the bottles were periodically
filled with water and held at 40oC for 10 days.

In the UK DTI study, a small number of used baby bottles of

uncertain age and history were also tested under the same
conditions as the new bottles. For both water and 3% acetic acid
solution, no migration was detected in 8 of the 12 bottles tested.
In 4 bottles, migration of BPA was detected at levels of 20 to 50
parts per billion. However, the results were inconsistent and
there was no correlation between migration levels and the food
simulant, estimated age of the bottles or sterilization method
reported to have been used. After reviewing all available
migration data on new and used bottles as well as other
polycarbonate articles, the European Commission's Scientific
Committee on Food concluded, "There is no significant effect
from repeated-use, abrasion, heating, or chemical sterilization of
these plastic articles." (SCF, 2002)

Water Bottles

In the US FDA study, water from several 5-gallon

polycarbonate bottles from a bottled water supplier was
analyzed with a detection limit of 0.05 parts per billion. In water
that had been stored in the bottles for up to 39 weeks, BPA was
found only at very low levels ranging from 0.1 to 4.7 parts per
billion.

Tableware

The Japanese NIHS study evaluated several mugs and ricebowls

along with a measuring cup. As with baby bottles, water and
20% ethanol were used as food simulants, which allowed a 0.5
part per billion limit of detection. No BPA was detected after 3
of 5 articles were exposed to either water (95oC for 30 minutes)
or 20% ethanol (60oC for 30 minutes). Migration of BPA was
observed from the other 2 articles, but only at levels below 5
parts per billion.

Molded Discs or Cut Pieces

In addition to evaluation of whole baby bottles, the US FDA

study also tested migration from baby bottles that had been cut
into pieces. The pieces were immersed in a simulant (either
water or 10% ethanol), heated to 100oC for 30 minutes and
refrigerated for 72 hours. For both simulants, the amount of
BPA detected was estimated to be equivalent to migration of
approximately 2 ng/ml (equal to 2 parts per billion) from a
whole baby bottle. The authors of the US FDA study concluded,
"When whole PC baby bottles were tested by using typical fill
conditions and less severe, normal use conditions, neither BPA
migration nor hydrolysis were observed (limit of detection was
2 ng/ml)."

The Society of the Plastics Industry, Inc. conducted a study

(Howe and Borodinsky, 1998) to measure migration from
molded discs that were prepared from a blend of polycarbonate
resin from three American manufacturers. The three resins were
blended and pressed into small discs such that all surfaces were
similar to that of a finished polycarbonate product. The study
was conducted according to procedures developed by the US
FDA (FDA, 1995, revised 2002) and performed using storage
time and temperature conditions recommended by the US FDA.

The discs were immersed in food simulating solvents (water,

3% acetic acid, 10% ethanol, coconut oil) and held at 212oF for
6 hours or at 120oF for 10 days. No BPA migration was
detected in any of the samples with a 5 part per billion limit of
detection.

Potential Exposure and Margin of Safety

The potential dietary exposure to BPA from polycarbonate

products that contact food and beverage can be estimated using
procedures recommended by the US FDA (FDA, 2002):

dietary concentration = CF x [(fwater-based x Mwater-based) + (facidic x

Macidic)
+ (flow alcohol x Mlow alcohol) + (ffatty x Mfatty)]

In this equation, "CF" is the "consumption factor," the fraction

of the average individual's diet that is likely to contact a specific
type of food-contact material, such as polycarbonate plastic.
Also in this equation, "f" is the "food-type distribution factor",
the fraction of each food or beverage type that contacts the
material, "M" is the migration value for that type of food in
contact with the material, and the type is indicated by the
subscript description (water-based, acidic, low (<15%) alcohol
or fatty).

Migration testing under conditions that are typical of how

polycarbonate products are actually used indicates that
migration of BPA, when it is detected at all, is generally less
than 5 parts per billion. This value (<5 parts per billion) can then
be used as the M value for each food type. Standard or "default"
values for CF and f are prescribed by the US FDA (FDA, 2002)
for food-contact materials for which actual consumer usage data
is not available. The default f values for polycarbonate are 0.97,
0.01, 0.01 and 0.01 for water-based, acidic, low alcohol and
fatty foods and beverages, respectively. With these parameters,
the average concentration of BPA in all food and beverages that
contact polycarbonate is <5 parts per billion.

Polycarbonate plastic is classified in the "all other" category for

which the CF value is 0.05, corresponding to the estimate that a
maximum of 5% of the food and beverages consumed in an
average diet are in contact with polycarbonate. Thus, the
potential concentration of BPA in the entire diet from food and
beverages that contact polycarbonate is <0.25 parts per billion.

According to FDA, the average individual consumes 3000

grams of food and beverages per day. Based on this value, the
potential dietary concentration of <0.25 parts per billion
corresponds to a potential daily intake of <0.00075 milligrams
per person per day. Based on FDA's estimate that a typical
individual weighs 60 kilograms, the estimated dietary intake of
BPA is <0.0000125 milligrams per kilogram body weight per
day.

This level is more than 4000 times lower than the maximum
acceptable or "reference" dose for BPA of 0.05 milligrams per
kilogram body weight per day established by the U.S.
Environmental Protection Agency (EPA, 1993). When the
dietary intake of BPA from polycarbonate is combined with
other sources of dietary exposure to BPA, the total dietary
intake of BPA (<0.00012 milligrams per kilogram body weight
per day) from all sources is still more than 400 times lower than
the reference dose (BPA INFO, 2002). The reference dose is
defined by the US EPA as an estimate of a daily oral exposure
to the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious effects
during a lifetime.

With an average concentration of BPA in all food and beverages

that contact polycarbonate of <5 parts per billion (equal to
<0.005 milligrams BPA per kilogram food/beverage), an
average adult consumer weighing 60 kilograms would have to
consume more than 600 kilograms (or about 1300 pounds) of
food and beverages in contact with polycarbonate every day for
an entire lifetime to exceed the reference dose of 0.05
milligrams per kilogram body weight per day.

The reference dose for BPA has recently been confirmed by a

three-generation study in rats (Tyl et al, 2002), which found no
adverse effects on reproduction from BPA at doses of 50
milligrams per kilogram body weight per day and lower. The
US EPA calculated the reference dose by dividing the Lowest-
Observed-Adverse-Effect-Level (LOAEL, 50 milligrams per
kilogram body weight per day) from an earlier chronic toxicity
study by an uncertainty factor of 1000. Applying that same
uncertainty factor to the No-Observed-Adverse-Effect-Level
(NOAEL, 50 milligrams per kilogram body weight per day)
from the Tyl study confirms the safety of the reference dose,
0.05 milligrams BPA per kilogram body weight per day. Since
the maximum estimate of BPA exposure from polycarbonate
products in contact with food and beverages is over 4000-fold
lower than the reference dose, the potential human exposure to
BPA from polycarbonate products is minimal and poses no
known risk to human health.

The Scientific Committee on Food (SCF), which is an

independent advisory committee to the European Commission
on food safety matters, has recently evaluated the safety of BPA
from all food contact sources (SCF, 2002). The SCF set a
Tolerable Daily Intake (TDI) for BPA of 0.01 milligrams per
kilogram body weight per day after a comprehensive review of
all robust scientific data covering all aspects of toxicity.

Similar to the US EPA reference dose, the TDI represents a

lifetime exposure level that is considered to be safe. Based on
the existing migraition data, total exposure to BPA from all food
contact sources, including polycarbonate plastic and epoxy resin
coatings, was estimated to be in the range of 0.00048 to 0.0016
milligrams per kilogram body weight per day for adults and
infants respectively, which is below the TDI value set by the
SCF. Only a small portion of the exposure was estimated to be
from polycarbonate plastic. This assessment confirms that
polycarbonate products are safe for use in contact with food and
beverage and pose no known risk to human health.

Conclusion

Human exposure to BPA from food-contact use of

polycarbonate plastic is very low and poses no known risk to
human health. The use of polycarbonate plastic for food contact
applications has been and continues to be recognized as safe by
the U.S. Food and Drug Administration, the European
Commission's Scientific Committee on Food, the United
Kingdom Food Standards Agency, the Japanese Ministry of
Health, Labor and Welfare, and other regulatory authorities
worldwide.

References

APME (Association of Plastics Manufacturers in Europe).

Additional information on the versatility and many uses of
polycarbonate plastic is http://www.apme.org/polycarbonate.

Biles, J.A., T.P. McNeal, T.H. Begley and H.C. Hollifield,

1997, Journal of Agricultural and Food Chemistry, vol. 45,
pages 3541-3544.

BPA INFO (Bisphenol A: Information Sheet), 2002, "Human

Safety: An Overview." http://www.bisphenol-
a.org/pdf/humanSafetyAnOverview.pdf

Earls, A. O., C. A. Clay, and J. H. Braybrook, 2000,

"Preliminary Investigation into the Migration of Bisphenol A
from Commercially-Available Polycarbonate Baby Feeding
Bottles," Final Report prepared by LGC Consumer Safety Team
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EPA (U.S. Environmental Protection Agency), Bisphenol A,

CASRN 80-05-7, IRIS, Integrated Risk Information System, on-
line, 1993. http://www.epa.gov/iriswebp/iris/subst/0356.htm.

FDA (U.S. Food and Drug Administration), 2002, "Preparation

of Food Contact Notifications and Food Additive Petitions for
Food Contact Substances: Chemistry Recommendations,"
Center for Food Safety and Applied Nutrition, Office of Food
Additive Safety, FDA, Washington, D.C., April 2002.
http://www.cfsan.fda.gov/~dms/opa2pmnc.html.

Howe, S.R. and L. Borodinsky, 1998, "Potential Exposure to

Bisphenol A from Food-Contact Use of Polycarbonate Resins,"
Food Additives and Contaminants, vol. 15, pages 370-375.

Kawamura, Y., Y. Koyama, Y. Takeda and T. Yamada, 1998,

"Migration of Bisphenol A from Polycarbonate Products,"
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Schreiber Translations, Rockville, MD. http://www.bisphenol-
a.org/pdf/migration.pdf

MAFF, 1997, "Investigations into the Potential Degradation of

Polycarbonate Baby Bottles During Sterilization with
Consequent Release of Bisphenol A," Central Science
Laboratory Report FD 97/08, MAFF R&D and Surveillance
Report 253, Ministry of Agriculture, Fisheries and Food
Library, Noble House, London.

Mountfort, K.A., J. Kelly, S.M. Jickells and L. Castle, 1997,

Food Additives and Contaminants, vol. 14, pages 737-740.

SCF, 2002, "Opinion of the Scientific Committee on Food on

Bisphenol A", April 17.
http://europa.eu.int/comm/food/fs/sc/scf/out128_en.pdf

Tyl, R. W., C. B. Myers, M. C. Marr, B. F. Thomas, A. R.

Keimowitz, D. R. Brine, M. M. Veselica, P. A. Fail, T. Y.
Chang, J. C. Seely, R. L. Joiner, J. H. Butala, S. S. Dimond, S.
Z. Cagen, R. N. Shiotsuka, G. D. Stropp, and J. M. Waechter,
2002, "Three-Generation Reproductive Toxicity Study of
Dietary Bisphenol A in CD Sprague-Dawley Rats,"
Toxicological Sciences, vol. 68, pages 121-146.

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