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

348 CHAPIN ET AL.
the bisphenol A versus control group, but there were no
effects on testis, seminal vesicle, or right epididymis
weight. [Relative reproductive organ weights were not
reported.] Epididymal sperm counts were reduced
significantly [by B10%] in the bisphenol A group, but
there was no significant effect on sperm motility. The
study authors concluded that bisphenol A exposure can
affect basal and gonadotropin-releasing hormone-stimulated
LH production and reduced daily sperm production
in rats.
Strengths/Weaknesses: This study appears to have
been relatively well conducted. A major weakness of this
study is the inconsistency in the hormone data (control
data after 2 weeks were dramatically different than after
5 weeks even though both are from sexually mature rats).
The subcutaneous route of administration with the use of
DMSO as vehicle are weaknesses.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate and not useful for the evaluation
process primarily due to the significant inconsistencies in
the hormone data from control animals.
Toyama et al. (2004), supported in part by the Japanese
Ministry of Environment and Ministry of Education,
Science, Sports, and Culture, examined the effects of
bisphenol A exposure on the reproductive system of
male rats and mice. [No information was provided
about feed, caging, or bedding materials. The mouse
portion of the study is discussed in Section 4.2.2.2.]
Adult male Wistar rats (n 5 12/group) were s.c. injected
with bisphenol A [purity not indicated] at 0.020 or
0.200 mg/kg bw/day for 6 consecutive days. Three
control animals were s.c. injected with the DMSO/olive
oil vehicle for 6 days. Ten animals/bisphenol A group
and 2 controls were killed the day following treatment
and perfused with glutaraldehyde. Testes were weighed
and examined by light and electron microscopy. Epididymis,
preputial gland, ventral prostate, and seminal
vesicle with coagulating glands were also weighed. The
remaining animals, 2 in each bisphenol A group and 1 in
the control group, were held an additional 2 months and
then subjected to fertility tests. In fertility testing, each
male was mated to 2 untreated females. One of the 2
mated females was kept until parturition. [The males
were apparently killed for an examination of reproductive
organs following fertility testing.] Results were
qualitatively reported, and statistical analyses were not
conducted.
The description of the results was limited primarily to
rats in the 0.020 mg/kg bw/day group. Body and male
accessory reproductive organ weights were not affected
by bisphenol A treatment. [Data were not shown by
study authors.] In the bisphenol A group, examination
by light microscopy revealed exfoliation of round
spermatids, deformed heads of mature spermatids, and
multinucleated giant cells in seminiferous epithelium.
Testicular effects observed by electron microscopy
included abnormal acrosomal caps and invagination
and/or vacuole formation in nuclei of spermatids
beyond Step 1. Ectoplasmic specialization around Sertoli
cells was also affected by bisphenol A treatment. No
histological or ultrastructural abnormalities were observed
in the testis 2 months following exposure. Sexual
behavior was observed to be normal in treated males.
Females delivered normal pups and litter sizes were
similar between groups. The study authors concluded
that bisphenol A exposure did not affect fertility in rats
and that adverse effects were transient.
Strengths/Weaknesses: Definite conclusions cannot be
drawn from such a limited data set; the fertility
assessment was not meaningful due to the sample size
(2/group). The background incidence of the electron
microscope findings was not discussed. Another weakness
is the subcutaneous route with DMSO as a vehicle.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate and not useful in the evaluation.
4.2.2.2 Mouse: Takao et al. (1999), support not
indicated, examined the effects of bisphenol A exposure
on the reproductive system of mice. Five-week-old male
C57BL/6 mice were exposed to bisphenol A [purity not
indicated] in drinking water at 0 (0.005% ethanol in
water vehicle), 0.0005, or 0.050 g/L for 4 or 8 weeks.
[Based on daily water intakes and body weights
reported in the study, bisphenol A intake was estimated
by CERHR at 0.14 and 13 mg/kg bw/day.] To
maintain bisphenol A at a stable concentration, drinking
water was changed twice a week, but the stability of
bisphenol A was not verified. Mice were killed, and both
testes and spleen were removed and weighed. One testis
was processed for histopathological evaluation. Plasma
testosterone, corticosterone, and LH levels were measured
in 7 mice/group using RIA or enzyme immunoassay.
[No information was provided on the purity of
bisphenol A, time between last dose and sacrifice, or
the type of chow, caging, or bedding materials used.
Very few details were provided on the methods,
including histopathological evaluation.] Statistical analyses
included ANOVA followed by Fisher protected
least significant difference test.
Water intake was reduced significantly [by 8%] in the
high-dose group exposed for 4 weeks. There were no
effects on body weight or absolute or relative (to body
weight) testis or spleen weight. Plasma testosterone
levels were reduced [by 87–89%] in the high-dose group,
but statistical significance was attained only in the group
exposed for 8 weeks. No statistically significant changes
were reported for plasma corticosterone or LH levels.
The number of multinucleated cells in the seminiferous
tubules was increased in high-dose mice treated for 8
weeks. The study authors concluded that exposure to
bisphenol A around the peripubertal period may disrupt
the reproductive tracts of male mice.
Strengths/Weaknesses: This study lacks important
experimental details on methodology, including
numbers of treated animals. Although it appears that
bisphenol A in the drinking water results in a doserelated
decrease in plasma testosterone, this endpoint is
highly variable because testosterone is secreted in a
pulsatile manner, and controls for Weeks 4 and 8 varied
by B30%.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate and not useful for the
evaluation process due to the paucity of important
experimental details and the variability of the testosterone
data.
Al-Hiyasat et al. (2002), supported by the Deanship of
Scientific Research at Jordan University of Science and
Technology, examined the effect of bisphenol A exposure
on fertility of male mice. [No information was provided
about composition of chow, bedding, or caging.] Ten 60day-old
male Swiss mice/group were gavaged with the
Birth Defects Research (Part B) 83:157–395, 2008