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

200 CHAPIN ET AL.
Table 43
Biliary Excretion in Male and Female Rats Exposed to
0.1 mg/kg bw 14 C-Bisphenol A Through the Oral or
Intravenous Route a
Male Female
Parameters I.V. Oral I.V. Oral
Biliary excretion, %
0–2 hr
0–4 hr
0–6 hr
Radioactivity in bile
represented by glucuronide, %
Dose excreted as glucuronide
in bile, %
a
Kurebayashi et al. (2003).
48
61
66
84
55
32
44
50
86
43
35
50
58
87
50
28
39
45
88
observed following oral exposure. A compound tentatively
identified as a sulfate conjugate was observed
following i.p. exposure and represented a small portion
of radioactivity. An unresolved peak of 3 compounds
was observed following i.p. or s.c. exposure, at the time
when parent compound was not quantifiable and
represented that major percent of radioactivity for that
time point. Three additional unidentified, minor peaks
were observed following i.p. or s.c. but not oral exposure.
The major sex differences observed were higher Cmax
values for bisphenol A and bisphenol A glucuronide in
females than males, especially following i.p. administration.
A review by the European Union (2003) noted that
the substantially higher concentrations of parent compound
with i.p. and s.c. compared to oral exposure
indicated the occurrence of first-pass metabolism following
oral intake.
Elsby et al. (2001) examined bisphenol A metabolism
by rat hepatocytes. In the hepatocyte metabolism study,
hepatocytes were isolated from livers of adult female
Wistar rats and incubated in dimethyl sulfoxide (DMSO)
vehicle or bisphenol A 100 or 500 mM [23 or 114 mg/L] for
2 hr. Metabolites were identified by HPLC or LC/MS.
Data were obtained from 4 experiments conducted in
duplicate. At both concentrations, the major metabolite
was identified as bisphenol A glucuronide, which was
the only metabolite identified following incubation with
100 mM bisphenol A. Two additional minor metabolites
identified at the 500 mM concentration included 5-hydroxy-bisphenol
A-sulfate and bisphenol A sulfate. Another
part of the study comparing metabolism of bisphenol A
by rat and human metabolites is discussed in Section
2.1.1.3. Another study (Pritchett et al., 2002) comparing
metabolism of bisphenol A in humans, rats, and mice is
also summarized in Section 2.1.1.3.
In neonatal rats gavaged with 1 or 10 mg/kg bw
14 C-bisphenol A on PND 4, 7, and 21 and adult rats
gavaged with 10 mg/kg bw bisphenol A, the major
compounds detected in plasma were bisphenol A
glucuronide and bisphenol A (Domoradzki et al., 2004).
Up to 13 radioactive peaks were identified in neonatal
rats dosed with 10 mg/kg bw and 2 were identified in
neonates dosed with 1 mg/kg bw/day. At the 10 mg/kg
bw dose, the concentration of bisphenol A glucuronide
detected in plasma increased with age. Metabolic
profiles were generally similar in males and
40
females. The study authors noted that metabolism of
bisphenol A to its glucuronide conjugate occurs as
early as PND 4 in rats. However, age-dependent
differences were observed in neonatal rats, as noted by
a larger fraction of the lower dose being metabolized to
the glucuronide. More details from this study are
included in Section 2.1.2.2.
Kurebayashi et al. (2005) used a thin layer chromatography
technique to examine metabolite profiles in
blood, urine, and feces of 3 male rats orally dosed with
0.5 mg/kg bw 14 C-bisphenol A. [The procedure did not
identify metabolites.] Parent bisphenol A represented
B2% of the dose in plasma at 0.25 and 6 hr post-dosing
and B0.3% of the dose at 24 hr after exposure.
Unmetabolized bisphenol A represented 1.6% of compounds
in urine and 77.2% of compounds in feces
collected over a 24-hr period. Free bisphenol A represented
47.1% of compounds in urine following bglucuronidase
hydrolysis of urine, and there was an
almost equivalent decrease in a metabolite the study
authors identified as ‘‘M2.’’ Therefore, the study authors
stated that M2 was most likely bisphenol A glucuronide.
M2 was the major metabolite identified in plasma (B74–
77%) and urine (B40%).
The European Union (2003) reviewed studies by
Atkinson and Roy ([1995a,b) that reported two major and
several minor adducts in DNA obtained from the liver of
CD-1 rats dosed orally or i.p. with 200 mg/kg bw bisphenol
A. Chromatographic mobility of the two major adducts was
the same as that observed when bisphenol A was incubated
with purified DNA and a peroxidase or microsomal P450
activation system. The profile closely matched that of
adducts formed with the interaction between bisphenol Oquinone
and purified rat DNA deoxyguanosine 3 0 -monophosphate.
Formation of the adduct appeared to be
inhibited by known inhibiters of cytochrome P (CYP) 450.
It was concluded that bisphenol A is possibly metabolized
to bisphenol O-quinone by CYP450.
Biliary excretion of bisphenol A and its metabolites
following oral or i.v. dosing with bisphenol A was
examined by Kurebayashi et al. (2003). Bile ducts of 3
rats/sex/group were cannulated, and the rats were
dosed with 0.1 mg/kg bw 14 C-bisphenol A (499%
radiochemical purity) in phosphate buffer vehicle by
oral gavage or i.v. injection. Biliary fluid was collected
every 2 hr over a 6-hr period to determine percent total
biliary excretion and percent of dose represented by
bisphenol A glucuronide. Results are summarized in
Table 43. The study authors noted that the importance of
biliary excretion following oral or i.v. dosing. 14 Cbisphenol
A-glucuronide was the predominant metabolite
in bile.
In another study by Kurebayashi et al. (2003), biliary,
fecal, and urinary metabolites were examined in male
rats gavaged with 100 mg/kg bw bisphenol A or D16bisphenol
A in corn oil. Bile was collected over an 18-hr
period, and urine and feces were collected over a 72-hr
period. The primary metabolite detected in urine was
bisphenol A glucuronide, which represented 6.5% of the
dose. Lower percentages of the dose (r1.1%) were
present in urine as bisphenol A and bisphenol A sulfate.
In feces, the primary compound detected was bisphenol
A, which represented 61% of the dose. No glucuronide or
sulfate conjugated metabolites of bisphenol A were
detected in feces. Most of the dose in bile consisted of
Birth Defects Research (Part B) 83:157–395, 2008