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

206 CHAPIN ET AL.
scaling and species-invariant time methods were used to
predict values for a 70-kg human, and those values are
summarized in Table 49. Regression analyses of estimates
using the species-invariant time methods demonstrated
that data from the 4 animal species were superimposable
(r 5 0.94–0.949).
Teeguarden et al. (2005) developed a physiologically
based pharmacokinetic (PBPK) model for bisphenol A.
Rat toxicokinetic data for the model were obtained from
the studies by Pottenger et al. (2000) and Upmeier et al.
(2000). Human toxicokinetic data were obtained from the
study by Völkel et al. (2002). The model was developed to
simulate blood and uterine concentrations of bisphenol A
following exposure of humans through relevant routes.
Correlations were determined for simulated bisphenol A
binding to uterine receptors and increases in uterine wet
weight, as determined by an unpublished study by
Twomey. Although intestinal metabolism of bisphenol A
to the glucuronide metabolite had been demonstrated
recently, the model attributed bisphenol A metabolism
entirely to the liver. Plasma protein binding was
considered in both the rat and human model. The model
accurately simulated plasma bisphenol A glucuronide
concentrations in humans orally administered 5 mg
bisphenol A, with the exception of underpredicting
bisphenol A glucuronide concentrations at the 24–48-hr
period following exposures. Cumulative urinary elimination
of bisphenol A glucuronide in human males and
females was simulated accurately. Less accurate simulations
were observed for toxicokinetics in orally exposed
rats, and the study authors indicated that a likely cause
was oversimplification of the rat gastrointestinal compartment.
Comparisons in metabolic clearance rates for
i.v. and oral exposure suggested significant intestinal
glucuronidation of bisphenol A. Enterohepatic recirculation
strongly affected terminal elimination in rats but not
humans. Consideration of bound versus unbound bisphenol
A was found to be important in simulating
occupancy of the estrogen receptor (ER) and uterine
weight response. No increase in uterine weight was
reported with simulated receptor occupancy of B1–15%.
An increase in uterine weight was reported with B25%
receptor occupancy, and doubling of uterine weight was
reported with 63% receptor occupancy.
Shin et al. (2004) developed a PBPK model to predict
the tissue distribution (lung, liver, spleen, kidneys, heart,
testes, muscle, brain, adipose tissue, stomach, and small
intestine) and blood pharmacokinetics of bisphenol A in
rats and humans. The model was based on experimentally
determined steady state blood-to-serum and tissueto-blood
partition ratios and does not include parameters
to account for elimination via glucuronidation or
differences in metabolism between rats and humans
(e.g., enterohepatic circulation). Predicted concentrationtime
profiles were then compared to actual rat toxicokinetic
data and to a profile for a simulated 70-kg human.
Rat toxicokinetic information was obtained by administering
multiple i.v. injections of bisphenol A (0.5 mg/kg)
to adult male rats to achieve steady state. Bisphenol A
concentrations were determined by a modified HPLC
method with fluorescence detection. The authors noted
good agreement between predicted and observed
concentration-time profiles for blood and all tissues but
did not present any statistical analysis or evaluate
the performance of alternative models in order to
Table 50
LD50 s for Bisphenol A
Species Exposure route LD50 (mg/kg bw)
Rat Oral 3300–4100 a
5000 b
3250 c
Inhalation 4170 mg/m 3b
Mouse Oral 4100–5200 a
2400 c
Intraperitoneally 150 c
Guinea pig Oral 4000 c
Rabbit Oral 2230 b,c
Dermal 42000 b
3 mL/kg c
a National Toxicology Program (NTP, 1982).
b Reviewed by the European Union (2003).
c Reviewed in ChemIDplus (2006).
establish goodness of fit. Based on the figures presented
in the article, the PBPK model appeared to more
accurately predict concentrations of bisphenol A in some
tissues (e.g., blood, lung, and liver) better than others
such as the small intestine and adipose tissue. The model
was then applied to predict blood and tissue levels of
bisphenol A in a 70 kg human after single i.v. injection
(5-mg dose) and multiple oral administrations to
steady state (100-mg doses every 24 hr). Tissue volumes
and blood flow rates for a 70 kg human were taken
from the literature. The authors concluded that
simulated steady-state human blood levels (0.9–1.6 ng/
ml) were comparable to blood levels of bisphenol A
reported in the literature (1.49 ng/ml). In addition, the
authors noted the similarity of predicted toxicokinetic
endpoints obtained from their PBPK model to those
predicted by Cho et al. (2002) based on simple allometric
scaling on rat data.
2.2 General Toxicity, Estrogenicity, and
Androgenicity
This section includes information on general toxicity as
well as information on estrogenicity and androgenicity;
however, results of estrogenicity and androgenicity
testing are not considered a priori evidence of toxicity.
2.2.1 General toxicity. The European Union (2003)
reported there were no adequate studies for assessing
acute toxicity of bisphenol A in humans.
In an acute toxicity study in rats orally dosed with
bisphenol A at Z2000 mg/kg bw, clinical signs included
lethargy, prostration, hunched posture, and piloerection
[reviewed by (European-Union, 2003)]. Gross signs in
animals that died included pale livers and hemorrhage in
the gastrointestinal tract. In a study in which male and
female rats were subjected to whole body inhalation
exposure to 170 mg/m 3 bisphenol A dust for 6 hr, there
were no gross signs of toxicity [reviewed by (European-
Union, 2003)]. Effects observed in the respiratory tract at
2 but not 14 days following exposure included slight
inflammation of nasal epithelium and slight ulceration of
the oronasal duct. LD50 reported in studies with oral,
dermal, inhalation, or i.p. exposure are summarized in
Table 50. The European Union (2003) concluded that
bisphenol A is of low acute toxicity through all exposure
routes relevant to humans.
Birth Defects Research (Part B) 83:157–395, 2008