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

Endpoint
BISPHENOL A
Table 30
Toxicokinetic Endpoints in Lactating Rats Infused With Bisphenol A a
0.13
Bisphenol
A infusion rate, mg/hr
Systemic clearance, mL/min/kg 119.2723.8 142.4745.3 154.1744.6
Steady state serum bisphenol A concentration, ng/mL 66.1715.5 120.0734.7 217.1765.0
Steady state milk bisphenol A concentration, ng/mL 173.1743.3 317.47154.4 493.97142.2
Milk/serum ratio 2.770.9 2.671.2 2.470.6
Data presented as mean7SD.
a Yoo et al. (2001).
5 min after injection, 50% of total bisphenol A 20 min
after injection, and B10% of total bisphenol A 6 hr after
the injection. The half-life of free bisphenol A in the
dam’s blood was 0.34 hr, and the half-life of total
bisphenol A was 0.58 hr. Bisphenol A in fetal tissues
peaked 20–30 min after maternal injection at 4.0 mg/kg in
placenta, 3.4 mg/kg in fetal liver, and 2.4 mg/kg in
remaining fetal tissues. Peak maternal blood bisphenol A
had been 3.8 mg/L shortly after injection.
Rapid distribution of bisphenol A was observed in
placenta, fetus, and amniotic fluid. Bisphenol A concentrations
in placenta and fetus remained higher than those
in maternal serum over most of the sampling period.
Amniotic fluid contained the lowest concentration of
bisphenol A. Decay curves in amniotic fluid, fetus, and
placenta paralleled decay curves in maternal serum.
Transfer rate constants and clearance rates are summarized
in Table 29. Transfer rate constants were greater in
the direction of amniotic fluid to fetus or placenta than in
the opposite direction. The elimination rate constant and
clearance rate from the fetal compartment were much
lower than for the maternal central compartment. The
clearance rate from placenta to fetus was higher than
clearance rate from fetus to placenta. The authors
calculated that 65.4% of the bisphenol A dose was
delivered to the fetus, 33.2% to the maternal central
compartment, and 1.4% to amniotic fluid. According to
the study authors, the low transfer rate from the fetal to
amniotic compartment suggested minimal fetal excretion
of unchanged bisphenol A through urine and feces into
the amniotic fluid. They also noted that the small fetal
compartment transfer constant compared to the relative
fetal–placental transfer constant indicated minimal metabolism
by the fetus. Authors estimated that 100% of
bisphenol A was eliminated from the fetus via the
placental route and concluded that fetal elimination
represents 0.05% of total elimination from the maternal–
fetal unit.
Moors et al. (2006) evaluated the kinetics of bisphenol
A in pregnant rats on GD 18 after a single i.v. dose of
10 mg/kg bw. Unconjugated bisphenol A represented
almost 80% of total bisphenol A 5 min after injection, 50%
of total bisphenol A 20 min after injection, and B10% of
total bisphenol A 6 hr after the injection. The half-life of
free bisphenol A in the dam’s blood was 0.34 hr, and the
half-life of total bisphenol A was 0.58 hr. Bisphenol A in
fetal tissues peaked 20–30 min after maternal injection at
4.0 mg/kg in placenta, 3.4 mg/kg in fetal liver, and
2.4 mg/kg in remaining fetal tissues. Peak maternal
blood bisphenol A had been 3.8 mg/L shortly after
injection.
Birth Defects Research (Part B) 83:157–395, 2008
0.27
0.54
191
Yoo et al. (2001) examined mammary excretion of
bisphenol A in rats. At 4–6 days postpartum, 4–6
lactating female Sprague–Dawley rats/group were i.v.
injected with bisphenol A at 0.47, 0.94, or 1.88 mg/kg bw
and then infused with bisphenol A over a 4-hr period at
rates of 0.13, 0.27, or 0.54 mg/hour. Blood samples were
collected at 2, 3, and 4 hr, and milk was collected at 4 hr
following initiation of infusion. Before collection of milk,
rats were injected with oxytocin to increase milk
production. HPLC was used to measure bisphenol A
concentrations in serum. Differences in data for mean
systemic clearance were analyzed by analysis of variance
(ANOVA). Results are summarized in Table 30. The
study authors noted extensive excretion of bisphenol A
into milk, with milk concentrations exceeding serum
concentrations. No significant differences were reported
for systemic clearance rates between the 3 doses. Steady
state concentrations of bisphenol A in maternal serum
and milk increased linearly according to dose.
Kabuto et al. (2004) reported bisphenol A concentrations
in mice indirectly exposed to bisphenol A during
gestation and lactation. The focus of the study was
oxidative stress; more details are presented in Section
3.2.7. Six ICR mouse dams were given drinking water
containing 1% ethanol vehicle or bisphenol A at 5 or
10 mg/L. [Based on the reported water intake of 5 mL/
day and an assumed body weight of 0.02 kg (USEPA,
1988), it is estimated that bisphenol A intakes in mice at
the start of pregnancy were 0.0013 and 0.0025 mg/kg bw/
day.] Mice gave birth about 3 weeks following mating
and pups were housed with dams for 4 weeks. [Based on
an assumed body weight of 0.0085 kg and assumed
water intake rate of 0.003 L/day (USEPA, 1988), it is
estimated that intake of bisphenol A in weanling males
was 0.0018 and 0.0035 mg/kg bw/day.] At 4 weeks of age,
male pups were killed and a GC/MS technique was used
to measure bisphenol A concentrations in brain, kidney,
liver, and testis in an unspecified number of control pups
and in four pups from the 10 mg/L group. Study authors
reported that they could not detect bisphenol A in control
pups. In pups from the 10 mg/L group, the highest
concentration of bisphenol A was detected in kidney
(B24 mg/kg wet weight), followed by testis (B20 mg/kg
wet weight), brain (B18 mg/kg wet weight), and liver
(B11 mg/kg wet weight).
Zalko et al. (2003) examined metabolism and distribution
of bisphenol A in pregnant CD-1 mice. A series of
studies was conducted in which mice were treated with
3 H-bisphenol A (499.9% purity)/unlabeled bisphenol A
(499% purity). Mice were exposed to different regimens;
biological samples examined included blood, liver, fat,