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

238 CHAPIN ET AL.
clinical signs, body weight gain, and food intake. Dams
were killed on GD 21 and examined for corpora lutea and
implantation sites. Fetuses were sexed, weighed, and
examined for viability and external abnormalities.
Anogenital distance was measured and alternate fetuses
were examined for visceral and skeletal malformations.
The dam or litter was considered the statistical unit. Data
were analyzed by ANOVA, Scheffé multiple comparison
test, Kruskal–Wallis nonparametric ANOVA, Mann–
Whitney U-test, and Fisher exact probability test.
Statistically significant effects are summarized in
Table 70. Dose-dependent clinical signs observed in
dams at the 2 highest doses included piloerection, dull
fur, reduced locomotor activity, emaciation, sedation,
red-colored tears, soft stool, diarrhea, urination, and
perineal soiling. Pregnancy failure, as observed by lack of
implantation sites, was increased in females from the
high-dose group. Maternal body weight, body weight
gain, and body weight corrected for gravid uterus weight
were reduced at the mid- and high-dose. GD 4 was the
only time period when food intake was significantly
reduced at the mid- and high-dose. Expansion and
congestion of stomach and/or intestines were observed
in dams from the high-dose group. Body weights of male
fetuses were decreased at the mid- and high-dose, and
body weights of female fetuses were reduced at the highdose.
Increases in fetal death, early resorption, and postimplantation
loss, accompanied by reduced number of
live fetuses, were observed at the high-dose. Anogenital
distance was significantly reduced in males from the
mid- and high-dose groups, but there were no differences
in anogenital distance of males or females when
the values were normalized by the cube root of body
weight. Significantly reduced ossification was observed
in the high-dose group. There were no treatment-related
differences in fetal sex ratio or external, visceral, or
skeletal malformations. Study authors concluded that
exposure of rats to a maternally toxic dose of bisphenol A
during the entire gestation period resulted in pregnancy
failure, post-implantation loss, reduced fetal body
weight, and retarded fetal ossification but not
dysmorphogenesis.
Strengths/Weaknesses: This report presents a fairly
standard embryo–fetal developmental toxicity study.
One strength is that the doses utilized incorporated both
a no-effect dose and a high maternally toxic dose,
revealing fetal effects only at the high-dose that showed
marked maternal toxicity. Measurement of anogenital
distance is another strength. Weaknesses include the
absence in all groups of information about postnatal
viability, and postnatal function. Further, a gross visceral
exam is likely insensitive to certain abnormalities of the
reproductive tract and brain. However, this type of study
does report on the ability of the exposure to cause
structural malformations, which are notably absent.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.
Kim et al. (2003), support not indicated, examined the
effects of prenatal bisphenol A exposure on postnatal
body and organ weights of Sprague–Dawley rats. Rats
were housed in polycarbonate cages. [No information
was provided on feed or bedding material.] Rats were
grouped according to body weight and randomly
assigned to dose groups. On GD 7–17 (GD 0 5 day of
vaginal sperm or plug), at least 10 rats/dose group were
gavaged with bisphenol A (499.7% purity) at doses of 0
(corn oil vehicle), 0.002, 0.020, 0.200, 2, or 20 mg/kg bw/
day. Dosing solution concentrations were verified. Dams
were weighed and observed for clinical signs of toxicity
during the study. Dams were killed on Day 21 of the
postpartum period. Corpora lutea, implantation sites,
resorptions, and fetal viability were assessed. Maternal
liver, kidney, spleen, ovary, and gravid uterus were
weighed. Live fetuses were weighed and examined for
external and visceral abnormalities. Fetal liver, kidneys,
spleen, and reproductive organs were weighed in half
the fetuses. [These methods are produced here as
written in the original; although dams were clearly
stated to have been killed on PND 21, the ‘‘fetal’’
examinations described appear more consistent with
killing of the dams on GD 21.] Data were analyzed by
ANOVA and Student t-test. [It was not clear if the litter
or fetus was considered the statistical unit in the
evaluation of developmental toxicity data.]
A significant but non-dose-related increase in dam
body weight occurred in the 0.2 mg/kg bw/day group
on GD 0–15. Dam body weight was significantly
increased on GD 21 in the 2 (by 53%) and 20 (by 43%)
mg/kg bw/day groups. No significant differences in
dam body weight were noted during the lactation period.
Significant changes in dam relative organ weights (dose
at which effects were observed) were: increased liver
(0.002, 0.020, and 20 mg/kg bw/day); decreased right
kidney (0.2 mg/kg bw/day); increased right kidney
(2 mg/kg bw/day), and increased uterine (0.2 mg/kg
bw/day). There was no effect on ovary weight of
dams. The majority of dams were in diestrus when
killed. One of 7 dams in the 0.2 mg/kg bw/day
group was in proestrus. One of 7 dams in the 0.2 mg/
kg bw/day, 1 of 6 dams in the 2 mg/kg bw/day
group, and 2 of 8 dams in the 20 mg/kg bw/day
group were in diestrus. Body weight effects in male
and female offspring were reported in most treatment
groups when evaluated at various time points between
birth and PND 22. In general, when body weights effects
were detected it was an increase in weight of B12–65%.
[Changes occurred at most dose levels but were not
consistent over time and there was little evidence of
dose–response relationships. In general, effects appeared
to be most pronounced in the lowest dose
group.] Relative weights for several tissues attained
statistical significance at 1 or more doses in offspring of
both sexes: liver, spleen and right kidney. In addition,
relative organ weights for were altered in males for the
left kidney, both testes, right epididymis, left seminal
vesicle, and prostate gland. There were no effects on
ovary or uterus weights. [In most cases, there was little
evidence of a dose–response relationship for organ
weights, including male reproductive organs, in offspring.]
Study authors concluded that bisphenol A had
estrogenic effects on rat dams and offspring exposed
during the gestation period.
Strengths/Weaknesses: While the verification of the
dosing solution is a strength, this study is of unclear
quality, to the point that there is real confusion about
what was actually done. It is indicated that 10 dams were
assigned to each dose group but numbers at sacrifice
were 7, 7, 6, and 8 across the 4 doses. It is unclear
whether fetal data were appropriately analyzed with
Birth Defects Research (Part B) 83:157–395, 2008