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

and left ovary weight in the mid-dose group
[25–27% lower]. No treatment effects were observed for
uterine or ovarian histology. There were no effects of
bisphenol A treatment on hematological endpoints in
females. Blood urea nitrogen levels were decreased
significantly [by 28–32%] in females of all dose groups.
The study authors did not report conclusions regarding
study findings.
Strengths/Weaknesses: The study design regarding
frequency and route of administration and the lack of an
appropriate positive control are weaknesses.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate though of limited utility for the
evaluation process.
Berger et al. (2007), supported by the Natural Sciences
and Engineering Research Council of Canada, examined
the effect of bisphenol A exposure on blastocyst
implantation in mice. CF-1 mice were housed in
polypropylene cages and were fed Harlan Teklad 22/5
rodent chow, which was stated to contain soy. [No
information was provided about bedding materials.]
On GD 1–4 or 5 [described as GD 1–5 in Methods
section and GD 1–4 in study figures and tables] (GD
0 5 day of vaginal plug), 8–9 mice/group were s.c.
injected with peanut oil vehicle or bisphenol A (97%
purity) at 10.125 mg/animal/day. [Assuming that the
mice weighed 0.02 kg at the start of gestation (USEPA,
1988), CERHR estimated bisphenol A intake at 500 mg/
kg bw/day.] Mice were killed on GD 6 for an examination
of implantation sites. Data were analyzed by w 2 test or 2sample
t-test. The number of implantation sites was
reduced significantly in the treated animals (mean of
B2.5 compared to B15 in controls). Implantation sites
were observed in 8 of 8 control females at a range of 12–
17/female. Six of 9 females in the bisphenol group had
no implantation sites. The study authors concluded that
pregnancy disruption occurred during the period of
implantation.
Strengths/Weaknesses: Weaknesses include lack of
experimental details for examining the uteri, use of a
single high-dose, number of corpora lutea were not
recorded.
Utility (Adequacy) for CERHR Evaluation Process:
Due to the absence of key information and faulty
methodology, this study is inadequate for evaluation
process.
Al-Hiyasat et al. (2004), supported by Jordan University
of Science and Technology, examined the effect of
bisphenol A and dental composite leachate on fertility of
female mice. In this study, Swiss mice were fed a
standard laboratory feed containing soy protein. [No
information was provided on caging and bedding
materials.] At 60 days of age, 11 mice/group were
gavaged with distilled water or composite leachate for 28
days. Components of the composite leachate were
identified by HPLC and included tri-(ethylene glycol)dimethacrylate
(5945 mg/L), bisphenol A glycerolate
dimethacrylate (2097 mg/L), and bisphenol A (78 mg/
L). [Based on the reported volume of administration
of 0.2 mL and a body weight of 34.4 g, CERHR
estimated bisphenol A intake from leachate at
0.45 mg/kg bw/day.] Additional 60-day-old mice
(n 5 15/group) were gavaged with bisphenol A (97%
purity), at doses of 0 (ethanol/distilled water vehicle),
0.005, 0.025, or 0.1 mg/kg bw/day for 28 days. Five
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mice/group in the bisphenol A study were killed at the
end of the dosing period for measurement of body,
uterus, and ovary weights. All mice in the leachate
study and 10 mice/group in the bisphenol A study were
mated to untreated males (2 females to 1 male) for 10
days. One week following the end of the mating period,
the mice were killed and examined for pregnancy,
implantations, viable fetuses, and resorptions. Body,
ovary, and uterus weights were measured in mice from
the leachate study. Data were analyzed by Student t-test
or Fisher exact test.
Effects in the leachate group included increased
relative (to body weight) ovarian weight and decreased
percentages of pregnant mice. In mice exposed to
bisphenol A, body weights were decreased at all dose
levels. Effects observed in mice exposed to the mid- and
high-dose of bisphenol A included increased uterine
weight, increased percentages of resorptions/implantations,
and increased percentages of mice with resorptions.
Ovarian weight was increased in mice of the highdose
bisphenol A group. [Although the effects were not
statistically significant, the percentages of pregnant
females were 90, 77.7, 80, and 60% pregnant mice in the
control and each respective dose group.] In both the
composite leachate and bisphenol A groups, there were
no statistically significant effects on implantations or
viable fetuses. The study authors concluded that bisphenol
A and components leached from dental composite
have adverse effect on fertility and the reproductive
system of mice.
Strengths/Weaknesses: With only 5–10/group,
this study was underpowered for determination of
potential bisphenol A-related effects on fertility and
other endpoints. Confirmation of mating was not
performed (cohabitation was for 10 days; if the mice
mated on day 10, the necropsy would have been
performed on GD 7. Mean body weight and reproductive
organ weights of bisphenol A-treated animals were
only collected from 5 mice/dose level. Moreover,
the normal body weight range for 10-week-old female
Swiss mice is 28–35 g. Given that there are only 5 mice/
group, it is hard to draw any meaningful conclusions
from these data.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation based on
small sample size.
Matsumoto et al. (2004), support not indicated,
examined the effect of maternal bisphenol A exposure
on growth of offspring in mice; this study was discussed
in Section 3.2.7. Because the results of this study bear on
lactation competence in treated dams, the study will also
be considered here. Mice were fed standard rodent chow
(CE-2, Japan Clea). [No information was provided on
caging and bedding materials.] Mice of the ddY strain
were exposed to bisphenol A (Z97% purity) through
feed at 0 or 1% from GD 14–PND 7. The study authors
stated that the bisphenol A dose was equivalent to
1000 mg/kg bw/day. [The numbers of dams treated was
not indicated. Day of vaginal plug and day of birth
were not defined.] Mice delivered pups on PND 21.
Body weight of pups were monitored during the
postnatal period in 31 pups from the control group and
61–89 pups from the bisphenol A group. Serum prolactin
levels were measured by RIA in 3 dams/group 4 days
following delivery. Pups were killed on PND 7, and