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

[0.23 mg/L]. Bisphenol A dimethylacrylate was also
tested, and most results were similar to those observed
with bisphenol A. The study authors concluded that
ovarian steroidogenesis might be a target of bisphenol A
toxicity.
Strengths/Weaknesses: Potential estrogenic effects
were observed at 10 -5 M bisphenol A. Decreases in
responses observed at the 10 -4 M concentration are likely
due to nonspecific cytotoxicity. Bisphenol A-mediated
responses in progesterone endpoints appeared to reach a
near maximum at the lowest dose level examined. There
was no mention of whether phenol red-free media were
used or whether fetal bovine serum was charcoalstripped.
The serum likely contained steroids, which
would have been potential confounding factors. Also, it
appears that cell viability was not examined after the
incubation period. With exception of the highest dose
level, there was no dose response (inconsistent trends);
the statistical flags are potentially due to random chance.
Since this was an in vitro study, the potential effects of
metabolism could not be assessed.
Utility (Adequacy) for CERHR Evaluation Process:
Due the weaknesses and limitation in the experimental
design, this study is considered inadequate.
Mohri and Yoshida (2005), supported by the Japanese
Ministry of Education, Science, Sports, and Culture,
examined the effects of bisphenol A and 17b-estradiol
exposure on calcium oscillations in immature mouse
oocytes. Immature oocytes with intact germinal vesicles
were obtained from 8–12-week-old CD-1/ICR mice and
incubated in bisphenol A [purity not indicated] in a
DMSO vehicle at concentrations of 0 or 10 nM [2.3 lg/L]
to 100 mM [23 mg/L] for 60 min. Calcium oscillations
were measured using a Fura-2 dye and image analyzer.
Data were analyzed by Student t-test. At 100 mM [23 mg/
L] bisphenol A, the duration of calcium oscillations
was significantly shortened and the oscillations
became irregular. The same findings were observed
following exposure to 17b-estradiol at concentrations that
were 10,000-fold lower than that of bisphenol A,
producing the same effect. The study authors stated that
estrogens may affect the oocyte by regulating calcium
oscillations and that bisphenol A could affect oocyte
maturation.
Strengths/Weaknesses: This study appears to have
been well conducted; however, because this study used
an in vitro system, metabolism could not be assessed. It is
unclear if calcium oscillations play a role in oocyte
maturation in other species, including humans.
Utility (Adequacy) for CERHR Evaluation Process:
This study is not considered useful for the evaluation
process.
4.2.2 Male.. Studies on the androgenicity of bisphenol
A, including Hershberger assays, are discussed
in Section 2.2.3.
4.2.2.1 Rat: Yamasaki et al. (2002a), support not
indicated, conducted a 28-day exposure study that
provided some information on the reproductive organs
of male and female rats. [Complete details of this study
are included in Section 2. Results for males are
discussed in this section, and results for females are
discussed in Section 4.2.1.1.] CD rats were fed a
commercial diet (MF Oriental Yeast Co.) and housed in
stainless steel wire mesh cages. Ten 7-week-old rats/sex/
group were gavaged with bisphenol A [98% purity] at 0
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
341
(olive oil vehicle), 40, 200, or 1000 mg/kg bw/day for 28
days. Due to the death of 1 animal exhibiting clinical
signs in the 1000 mg/kg bw/day group, the high-dose
was reduced to 600 mg/kg bw/day on Day 8 of the
study. In an additional study, rats were exposed to
ethinyl estradiol at 0, 10, 50, or 200 mg/kg bw/day for 28
days. There were no treatment-related abnormalities in
sperm or alterations in blood levels of thyroid hormones,
FSH, LH, 17b-estradiol, prolactin, or testosterone.
Changes in relative reproductive organ weights [assumed
to be relative to body weight] included a 28%
decrease in relative ventral prostate weight and 21%
increase in relative testis weight in the high-dose group.
No gross or histopathological alterations were reported
for reproductive organs. The study authors concluded
that change in estrous cyclicity was the only useful
endpoint for evaluating the endocrine-mediated effects
of bisphenol A. In comparison, male rats exposed to the
mid and/or high doses of ethinyl estradiol experienced
decreased prostate, seminal vesicle, and pituitary
weights; increased testis weight; and histopathological
alterations in prostate, seminal vesicle, mammary gland,
and testis.
Strengths/Weaknesses: This study was well-conducted,
used an appropriate route of administration, a
positive control group, adequate sample sizes, a range of
doses, and evaluations of both sexes. A weaknesses
include an insufficient duration of exposure to examine
the full spermatogenic cycle.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.
Takahashi and Oishi (2001), support not indicated,
examined the effects of bisphenol A exposure on testis of
rats. F344 rats were fed standard, soy-containing diet
(CE-2; Clea Japan) and housed in stainless steel
suspended cages. Four-week-old male rats (n 5 8/group)
were administered bisphenol A (99.0% purity) through
diet at concentrations of 0, 0.25, 0.5, or 1.0% for 44 days.
The study authors estimated bisphenol A intake at 235,
466, and 950 mg/kg bw/day. The stability of bisphenol A
in the diet was verified. Food intake was measured, and
animals were weighed and observed daily for clinical
signs. Rats were killed when mean body weight of
controls reached B200 g. Testosterone levels were measured
in serum using an ELISA method. Preputial gland,
testes, epididymides, prostate, seminal vesicles, kidneys,
and liver were weighed. The testis was fixed in buffered
6% formaldehyde and examined histologically. Statistical
analyses included Bartlett test, ANOVA, Dunnett or
Scheffé parametric test, Kruskall–Wallis test, Dunnett
non-parametric test, Wilcoxon rank sum test, w 2 test,
Mantel–Haenzel test, and Fisher exact test.
Statistically significant findings are summarized in
Table 88. Body weight gain and terminal body weights
were reduced in males of the mid- and high-dose groups.
Food intake was said to be slightly decreased according
to dose. Absolute organ weight effects included decreased
weight of preputial glands at all doses; liver in
the mid- and high-dose group; and seminal vesicles with
coagulation glands, dorsal and lateral prostate, and
hypophysis at the high-dose. [The Expert Panel assumes
that by coagulation gland, the authors mean the
anterior prostate or coagulating gland.] Significant
organ weight effects relative to body weights are