Monograph on the Potential Human Reproductive and ... - OEHHA

182 CHAPIN ET AL.
2.0 GENERAL TOXICOLOGY AND
BIOLOGICAL EFFECTS
As discussed in Section 1.4, the quantified amount of
free bisphenol A present in biological samples may be
affected by contamination with bisphenol A in plastic
laboratory ware and in reagents (Tsukioka et al., 2004;
Völkel et al., 2005). In addition, the accuracy may also be
affected by measurement technique, particularly at the
very low concentrations that can now be measured.
ELISA have the potential to overestimate bisphenol A in
biologic samples due to lack of specificity of the antibody
and effects of the biologic matrix (Inoue et al., 2002;
Fukata et al., 2006). High performance liquid chromatography
(HPLC) with ultraviolet, fluorescence, or electrochemical
detection is unable to make definitive
identification of bisphenol A or bisphenol A glucuronides,
because similar retention times may occur for the
metabolites of other endogenous and exogenous compounds
(Völkel et al., 2005). Use of LC-tandem mass
spectrometry (MS/MS) with and without hydrolysis of
bisphenol A glucuronide permits determination of free
and total bisphenol A with a limit of quantification of
1 mg/L (Völkel et al., 2005). Gas chromatography (GC)/
MS/MS has been used with solid phase extraction after
treatment with glucuronidase and derivatization to
measure total bisphenol A with a limit of detection of
0.1 mg/L (Calafat et al., 2005). Bisphenol A glucuronidate
has been shown to be unstable and can be hydrolyzed to
free bisphenol A at neutral pH and room temperature in
diluted urine of rats and in rat placental and fetal tissue
homogenates at room temperature. Bisphenol A glucuronide
can also be hydrolyzed and in some cases
degraded to unknown components either in acidic or
basic pH solutions of diluted urine, adding another
potential source of error in the measurement of sample
levels of bisphenol A and its conjugates (Waechter et al.,
2007). These considerations taken together, suggest that it
is possible that free bisphenol A concentrations measured
in biological samples may be overestimated.
2.1 Toxicokinetics and Metabolism
The studies presented in this section demonstrate that
bisphenol A is absorbed in humans and experimental
animals following oral exposure. In humans and experimental
animals, most of the dose is present in blood as
the main metabolite, bisphenol A glucuronide, and
smaller percentages are present as the parent compound.
Bisphenol A and its metabolites are widely distributed in
humans and animals. More than 90% of unmetabolized
bisphenol A is reportedly bound to plasma protein.
Bisphenol A is distributed to fetal fluids in humans and
experimental animals, and a limited number of studies in
humans demonstrate fetal concentrations of bisphenol A
within an order of magnitude of concentrations in
maternal blood. None of the studies detected bisphenol
A glucuronide in fetal fluids. Transfer of bisphenol A to
milk was demonstrated in humans and experimental
animals. One study in humans reported bisphenol A in
milk at concentrations exceeding maternal blood concentrations.
In humans and experimental animals, most
of a bisphenol A dose is metabolized to bisphenol A
glucuronide before absorption. Studies in humans and
experimental animals demonstrated that glucuronidation
of bisphenol A can occur in the liver, and one study in
rats demonstrated that bisphenol A is glucuronidated
upon passage through the intestine. Bisphenol A
glucuronide is excreted in the bile of rats, and enterohepatic
cycling is thought to occur in rats but not
humans. In humans, most of a bisphenol A dose is
eliminated through urine as bisphenol A glucuronide. In
rats, bisphenol A is eliminated through feces as bisphenol
A and in urine as bisphenol A glucuronide.
2.1.1 Humans. Human toxicokinetics studies that
were judged potentially important to interpret developmental
and reproductive toxicity were reviewed in full.
These studies include reports of potential exposure of
fetuses during pregnancy or of infants through human
milk and reports of toxicokinetics or metabolism following
low-dose exposure of humans. Information from
secondary sources was included if the information was
not considered to be critical to the interpretation of
developmental and reproductive toxicity data.
2.1.1.1 Absorption: Two studies described here examined
oral absorption of bisphenol A from dental
sealants, and one study examined in vitro dermal
absorption. Bisphenol A (as parent or the monoglucuronide)
is absorbed in humans as indicated by the
detection of bisphenol A (and metabolites) in blood from
the general population (Section 1) and in maternal and
fetal fluids (Table 9).
Fung et al. (2000) examined the toxicokinetics of
bisphenol A leaching from dental sealant. Volunteers
included 18 men and 22 non-pregnant women (20–55
years of age) who did not have dental disease, existing
composite resin restorations or pit and fissure sealants,
or a history of resin exposure. Volunteers were treated
with a widely used commercial dental sealant (Delton
Opaque Light-cure Pit and Fissure Sealant). Components
of the sealant were analyzed by HPLC. The low-dose
group (n 5 7 men, 11 women) received 8 mg dental sealant
on 1 tooth, and the high-dose group (11 men, 11 women)
received 32 mg sealant on 4 teeth. Saliva and blood
samples were collected before the procedure and at 1 and
3 hr and 1, 3, and 5 days after the procedure. Blood and
saliva were analyzed by HPLC. Statistical analyses of data
were conducted by nonparametric test, Wilcoxon signed
rank test, and w 2 test. Analysis of the dental sealant
revealed that bisphenol A concentrations were below the
detection limit of 5 ppb. At 1 hr following treatment,
bisphenol A was detected in samples from 3 of 18
volunteers in the low-dose group and 13 of 22 samples
from volunteers in the high-dose group. At 3-hr posttreatment,
bisphenol A was detected in samples from 1 of
18 volunteers in the low-dose group and 7 of 22 volunteers
in the high-dose group. Concentrations of bisphenol A in
saliva at 1 and 3 hr following exposure were reported at
5.8–105.6 ppb [lg/L]. No bisphenol A was detected in
saliva samples at 24 hr or in serum samples at any time
point. Differences between the low-dose and high-dose
groups in bisphenol A saliva concentrations and in the
proportion of bisphenol A-positive saliva samples at 1 and
3 hr achieved statistical significance. In the high-dose
group, a significant difference in ‘‘readings’’ was observed
between 1 and 3 hr. [The data as presented did not
illustrate possible quantitative differences in saliva
bisphenol A concentrations from the 2 dose groups or
at different sampling times.]
Joskow et al. (2006) examined bisphenol A in urine and
saliva of 14 adults (19–42 years old) treated with dental
Birth Defects Research (Part B) 83:157–395, 2008