Pharmacokinetic Studies and Bisphenol A Metabolism
A "pharmacokinetic" study answers
the question of what happens to a chemical in the body,
including how it is metabolized and eliminated or whether
it accumulates in certain types of tissues.
Bisphenol A is rapidly metabolized in live animals
and extensively excreted in urine and feces. A study
conducted by The Society of the Plastics Industry shows
that levels of bisphenol A in the blood were much lower
for oral doses than for other routes of administration,
such as injection in the abdominal cavity or under the
skin. Bisphenol A has not been shown to accumulate in
test animals.
Pharmacokinetics Study
Pharmacokinetics Study Design
Pharmacokinetics Study Key Findings
Pharmacokinetics Study Conclusions
 Pharmacokinetics
Study
One of the questions that can be asked about any chemical
is: what happens to that chemical in the body? A “pharmacokinetic”
study is how that question is answered. Pharmacokinetic
studies measure how much of the chemical is absorbed
and distributed into the body, metabolized to other
compounds, and eliminated or retained. These measurements
can provide key information to perform a safety assessment
of the chemical.
Recently, a pharmacokinetic study (Pottenger et al,
2000) was conducted on bisphenol A in rats. Bisphenol
A is used in the manufacture of polycarbonate plastic
and epoxy resins. The study demonstrated that bisphenol
A was rapidly metabolized to a hormonally inactive form
and excreted. Another study that compared bisphenol
A metabolism in rat, mice and human liver cells showed
similar metabolism across the species (Pritchett et al, 2001). Taken all together, the studies indicate
that rapid metabolism and excretion would also occur
following any possible human exposure.
The pharmacokinetic study also showed that concentrations
of bisphenol A in the blood were much lower for oral
doses than for other routes of administration, such
as injection in the abdominal cavity (intraperitoneal)
or under the skin (subcutaneous). The oral route of
exposure is the most relevant route of possible human
exposure. Consequently, safety assessments comparing
possible levels of human exposure to no-effect or lowest
effect levels should be based on laboratory animal studies
using the oral route of exposure. Studies based on other
routes of exposure, such as intraperitoneal or subcutaneous
injection, will not be comparable to possible human
exposures and will not produce realistic safety assessments.
Pharmacokinetic
Study Design
Groups of healthy, adult laboratory rats (Fisher 344
rats, five males and five females per dose per route
of administration) were given a single dose of bisphenol
A, and absorption, metabolism, excretion and retention
were measured over a seven-day period. The bisphenol
A used was custom synthesized with radioactive carbon-14
(radiolabeled) to allow easy tracking of intact material
and any metabolites. An analytical method specifically
developed for this study was used to measure bisphenol
A concentrations in blood.
Two doses of bisphenol A were studied: a high dose (100
milligrams bisphenol A per kilogram of test animal body
weight) and a ten-fold lower dose (10 milligrams per
kilogram body weight). Each dose was mixed in an edible
oil (corn oil) to provide bisphenol A in an easily administered
and readily absorbable form.
Three routes of administration were examined: oral,
where bisphenol A was given using a feeding tube (gavage);
intraperitoneal, where the dose was injected into the
abdominal cavity; and subcutaneous, where the dose was
injected directly under the skin.
Concentrations of bisphenol A and metabolites were
measured in blood, feces and urine collected from the
test animals over a 7-day period. The animals were then
sacrificed and residual concentrations of bisphenol
A and metabolites in tissues were determined.
Results were calculated for each group (sex, dose level
and route of administration) of test animals.
Pharmacokinetic
Study Key Findings
The highest bisphenol A concentrations in blood were
observed in the first hour following administration
of oral or intraperitoneal doses and within four hours
following subcutaneous doses.
Bisphenol A was rapidly cleared from the blood (below
the limit of quantitation) within 72 hours for intraperitoneal
or subcutaneous injection and within approximately 18
hours for oral gavage. The limit of quantitation was
0.1% of the initial dose administered, which is equal
to 0.01 and 0.1 micrograms bisphenol A per gram of blood
for blood samples from low and high doses, respectively.
Metabolites of bisphenol A were detected in the blood
of test animals. Highest concentrations of metabolites
in blood were reached within one hour of dosing. Metabolite
concentrations in blood were below the limit of quantitation
within 7 days for intraperitoneal or subcutaneous injection
and within 72 hours for oral gavage.
Fecal excretion was the major route of elimination
with urinary excretion as a secondary route. Total excretion
was similar for male and female rats (86-96%) but males
excreted more bisphenol A in the feces (74-83%) than
females (52-72%) while females excreted more bisphenol
A in the urine (21-34%) than males (13-16%).
Bisphenol A was excreted in the feces mostly as unmetabolized
bisphenol A (86-99% of the radiolabeled material in
the feces). The major forms of bisphenol A in urine
were the monoglucuronide of bisphenol A (69-87% and
57-68% of the radiolabeled material in the urine from
females and males, respectively) and bisphenol A itself
(8-10% of the radiolabeled material). A glucuronide
is a common type of metabolite formed by liver metabolism.
Bisphenol A monoglucuronide is inactive in a short-term
test (uterotrophic assay) in which bisphenol A is active,
indicating that metabolism of bisphenol A results in
a metabolite that is hormonally inactive (Fennell et al, 2000; Matthews et al, 2001).
A number of other metabolites of bisphenol A were detected
in feces and urine. None of these metabolites represented
more than 10% of the radiolabeled material in feces
or urine.
After the 7-day observation period, residual amounts
of bisphenol A and metabolites in the animals were quite
low, ranging from a maximum of 1.3% of the test dose
for subcutaneous injection, 0.8% for intraperitoneal
injection and 0.4% for oral gavage. Residual concentrations
in body fat and sex organs were no higher than in other
tissues.
Recent data from the University of Arizona with liver
cells from rats, mice and humans show similar metabolism
of bisphenol A across the species (Pritchett et al,
2002). Consequently, bisphenol A intake from any possible
human exposure would be rapidly metabolized to a hormonally
inactive form and excreted from the body (Fennell et al, 2000; Matthews et al, 2001; Pottenger et al, 2000).
The metabolism and toxicokinetics of BPA in humans
has also been measured directly by exposing human volunteers
to oral doses of 5 mg of deuterated BPA (d16-BPA). The
glucuronide was the only metabolite detected in urine
and blood, and free d16-BPA was not detected in either
urine or blood. The applied doses were completely recovered
in urine as the glucuronide and the clearance of the
glucuronide from blood to urine proceeded with a terminal
half-life of less than 6 hours (Völkel et al, 2002).
Pharmacokinetic
Study Conclusions
Bisphenol A was rapidly adsorbed into the blood and
metabolized following intraperitoneal or subcutaneous
injection, or oral exposure (gavage). Bisphenol A was
efficiently excreted from the bodies of both female
and male laboratory rats. The excreted material is primarily
bisphenol A itself and bisphenol A monoglucuronide,
a metabolite that is biologically inactive.
Bisphenol A did not accumulate in body fat or sex organs
of either male or female test animals given either 10
or 100 milligrams per kilogram body weight of bisphenol
A administered by oral exposure, or intraperitoneal
or subcutaneous injection.
The results of a study comparing rat, mice and human
liver cells (Pritchett et al, 2002) demonstrate that
the results of the pharmacokinetic study in rats also
apply to humans. Consequently, bisphenol A intake from
any possible human exposure would be rapidly metabolized
to a hormonally inactive form and excreted from the
body.
The rapid metabolism of BPA to the glucuronide and
clearance from the body in humans has been confirmed
in a test on human volunteers.
In the pharmacokinetic study of Pottenger et al (2000),
lowest concentrations of bisphenol A in blood were observed
following oral exposure, the most relevant route of
administration for a safety assessment of bisphenol
A. Consistent with this observation, lower bioactivity
of bisphenol A following oral exposure has also been
observed (Ashby and Tinwell, 1998; Jekat et al, 2000,
Matthews et al, 2001).
This finding of different levels of bioavailability
and bioactivity of bisphenol A depending on the route
of exposure provides important guidance for conducting
a safety assessment of bisphenol A. Specifically, safety
assessments comparing possible levels of human exposure
to no-effect or lowest effect levels should be based
on laboratory animal studies using oral routes of exposure
since this is the most relevant route of human exposure.
Studies based on other routes of exposure, such as intraperitoneal
or subcutaneous injection, will not be comparable to
possible human exposures and will not produce realistic
safety assessments.
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