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

BISPHENOL A
Table 92
Effects Observed Following Gavage of Male Mice with Bisphenol A and Mating With Untreated Females a
Dose, mg/kg bw/day
Endpoint 0.005 0.025 0.1 BMD10 BMDL10 BMD1SD BMDL1SD
Body weight k18% k 21% k13%
Relative weight
Testis 2 m 26% 2
Seminal vesicle 2 k 27% 2
No. sperm/testis 2 k 17% k29% 0.035 0.029 0.036 0.028
No. sperm/mg testis 2 k 16% k37% 0.027 0.023 0.029 0.023
Daily sperm production 2 k 17% k29% 0.035 0.029 0.036 0.028
Efficiency of sperm production 2 k 16% k37% 0.027 0.023 0.029 0.023
No. sperm/epididymis k 14% k 25% k35% 0.033 0.026 0.040 0.030
Sperm/mg epididymis 2 k 17% k31% 0.033 0.025 0.053 0.038
Percent pregnant females 2 k 40% k33%
Resorptions/implantation site (3% control rate) 13% 15% 13%
Percent females with resorption sites m 2.5-fold m 3.8-fold m 3.4-fold
a Al-Hiyasat et al. (2002).
m,k Statistically significant increase, decrease, 2 no statistically significant effect.
ethanol/distilled water vehicle or bisphenol A (97%
purity) for 30 days. [The study listed the bisphenol A
doses as 5, 25, and 100 ng/kg bw. An erratum was later
released that indicated the correct units were lg/kg bw
(0.005, 0.025, and 0.1 mg/kg bw/day).] Following the
dosing period, each male was mated for 10 days with 2
untreated female mice, who were placed inside the cage
of the male during the same time period. The males were
then killed for an evaluation of testes, seminal vesicles,
and preputial gland weights. Sperm counts and daily
sperm production were determined. Mated females were
killed 10 days later to determine numbers of pregnancies,
implantation sites, viable fetuses, total resorptions, and
females with resorptions. [There was no indication that
mating was confirmed by checking for sperm in the
vagina.] Data were analyzed by Student t-test or Fisher
exact test.
Results that obtained statistical significance are summarized
in Table 92. Body weights were lower in all dose
groups compared to controls. There were no evident
dose–response relationships for organ weights. Absolute
testis weight was decreased at the low dose, and absolute
seminal vesicle weight was reduced at the mid and highdose.
Effects on relative organ weights are summarized
in Table 92. Decreases in testicular sperm counts and
daily sperm production were observed at the mid and
high-dose. Total sperm counts in the epididymis were
decreased at all dose levels, and sperm counts/mg
epididymis were decreased at the mid and high-dose.
The total number of resorptions and females with
resorptions were increased at all dose levels. The
percentage of pregnant females was reduced at the mid
and high-dose. The study authors concluded that bisphenol
A could adversely affect fertility and reproduction
of adult male mice.
The number of animals per group was too small
(n 5 10) for a definitive assessment of study endpoints.
The method of randomization (or initial body weights)
was not presented. There is also an absence of a dose
response in several of the endpoints assessed. Given that
mice usually have poor (relative to rats) fertility rates, the
confidence in control data is limited. The male mice were
killed shortly after the mating period, which may have
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influenced/confounded the number of sperm in the
epididymis. Student t-test is an inappropriate analysis
for organ weights (ANOVA with appropriate post-hoc
test would be appropriate). Statistical significance is
suspect, and the changes in organ weights are minimal in
magnitude.
Strengths/Weaknesses: Weaknesses include small
sample sizes for endpoints, inadequate coverage of the
full spermatogenesis cycle in dosing duration, measurement
of sperm counts without allowing adequate time
following mating, and inappropriate accounting of sire
influences on resorption rates in statistical analyses.
Sample sizes are small for fertility assessments.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate for inclusion. Data on tissue
weights are of limited utility for the evaluation process,
however fertility data are not useful.
Nagao et al. (2002), support not indicated, examined
the effects of bisphenol A in mice following exposure
during different life stages. An initial experiment,
described in more detail in Section 3.2.7, found that
C57BL/6N mice were more sensitive to 17b-estradiol
than ICR mice, and the study authors therefore used
C57BL/6N mice to examine the effects of bisphenol A.
Life stages examined included prenatal development,
adolescence, and adulthood. The study conducted in
adult mice is described here, while the studies conducted
during prenatal development and adolescence are
described in Section 3.2.7. C57BL/6N mice were fed
PLD (phytoestrogen-low diet; Oriental, Japan). They
were housed in polycarbonate cages with wood bedding.
Daidzein and genistein levels were analyzed in diet, tap
water, and bedding and found to be below 0.5 mg/100 g.
At 10 weeks of age, 20 male mice/group were gavaged
with bisphenol A (99.0% purity) at 0.002, 0.020, or
0.200 mg/kg bw/day for 6 days. Twenty control males/
group were given 0.5% carboxymethyl cellulose
[assumed to be the vehicle]. Six weeks after the final
dose was administered, the mice were weighed and 15
males/group were killed and necropsied. The testis,
epididymis, and seminal vesicles with coagulating
glands were weighed. The ventral prostate was not
weighed due to difficulties in obtaining only prostate