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

204 CHAPIN ET AL.
low following oral exposure, absorption was considered
to be complete. The authors also noted that there were no
obvious route or sex differences in excretion of radioactivity.
The study authors concluded that terminal
elimination half-lives were longer following i.v. than oral
exposure. A limited amount of information was presented
for the fast phase, defined as the 2 hr following i.v.
injection. Fast-phase elimination half-life of bisphenol A
following i.v. exposure was significantly lower in females
(0.39 hr) than males (0.57 hr). There were no sex-related
differences in fast-phase half-life for bisphenol A
glucuronide (0.79–0.82 hr) or total radioactivity (0.61–
0.67 hr).
2.1.3 Comparison of humans and experimental
animals. Studies comparing toxicokinetics and metabolism
of bisphenol A in humans and laboratory animals
were reviewed and are summarized below. In most cases
the data were from original sources, but information
from secondary sources was included if the information
was not new or critical to the evaluation of developmental
or reproductive toxicity.
Elsby et al. (2001) compared bisphenol A metabolism
by rat and human microsomes. Microsomes were
obtained from 8 immature Wistar rats (21–25 days old)
and histologically normal livers from 4 male (25–57 years
old) and 4 female (35–65 years old) Caucasian donors
who were killed in accidents. Human microsomes were
pooled according to sex of the donor. Glucuronidation
Table 45
Glucuronidation Kinetics in Microsomes From Immature
Rats and Adult Humans a
Sex/species
Male/human
Female/human
Female/immature rat
Data presented as mean7SEM.
a Elsby et al. (Elsby et al., 2001).
Vmax, nmol/minute/
mg protein Km, mM
5.970.4
5.270.3
31.678.1
77.578.3
66.377.5
27.071.2
was examined following exposure of microsomes to
bisphenol A concentrations of 0–1000 mM [0–228 mg/L]
for 30 min with human microsomes and 10 min with rat
microsomes. Metabolites were identified by HPLC or
LC/MS. Data were obtained from 4 experiments conducted
in duplicate. Data were analyzed by Mann–
Whitney test. Maximum velocity (Vmax) and the rate
constant (Km) values are summarized in Table 45. The
study authors reported a significant difference between
the V max for glucuronidation in immature rats and
humans. No sex-related difference was reported for
glucuronidation by human microsomes. As a result of
less extensive glucuronidation by human than rat
microsomes, the study authors noted that estrogen target
tissues in humans may receive higher exposure to
bisphenol A than tissues of immature female rats used
in estrogenicity studies. Lastly, oxidation of bisphenol A
by female rat or human microsomes was examined
following incubation with 200 mM [46 mg/L] bisphenol A
and NADPH. The only metabolite identified was 5hydroxybisphenol
A.
The European Union (2003) reviewed a series of
studies by Sipes that compared metabolism of bisphenol
A in microsomes from male and female humans (15
pooled samples/sex and 3–5 individual samples/sex),
rats (4/sex), and mice (4/sex). It was concluded that the
studies generally agreed with the findings of Elsby et al.
(2001). Clearance rates (V max/Km) in human microsomes
(0.4–0.9 mL/min/mg for pooled samples and 0.3–0.5
mL/min/mg in individual samples) were lower than
those observed in rats (1.0–1.7 mL/min/mg) and mice
(1.3–3.0 mL/min/mg).
Pritchett et al. (2002) compared metabolism of bisphenol
A in hepatocyte cultures from humans, rats, and
mice. Cell cultures were prepared from adult male and
female F344 rats, Sprague–Dawley rats, and CF1 mice.
Human hepatocyte cultures were obtained from 3
females and 2 males. [No information was provided
about the age of human donors.] Cells were exposed to
14 C-bisphenol A (99.3% purity)/bisphenol A (499%
purity) in a DMSO vehicle. In a cytotoxicity assessment,
Table 46
Metabolites Obtained From Incubation of Human, Rat, and Mouse Hepatocyte Cultures With 20 mM [4.6 mg/L]
Bisphenol A a
Percentage of parent compound or metabolites
Sex and species Glucuronide/sulfate Sulfate Glucuronide Bisphenol A
Human samples
Female–1 4 0 93 0
Female–2 2 0 84 2
Female–3 43 2 55 0
Male–1 1 0 85 0
Male–2 0 7.5 75 0
Rodent samples
Male F344 rat 70 0 30 0
Female F344 rat 10 0 86 0
Male Sprague–Dawley rat 30 2 58 0
Female Sprague–Dawley rat 0 0 100 0
Male CF1 Mouse 0 0 100 0
Female CF1 mouse 0 0 93 0
Human cells were incubated for 3 hr, and animal cells were incubated for 6 hr.
a Pritchett et al. (2002).
Birth Defects Research (Part B) 83:157–395, 2008