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

orn to 1 dam in that group died by PND 2. Maternal
body weight gain during pregnancy was reduced in the
400 mg/kg bw/day group. A transient decrease in body
weight gain was observed early in the lactation period in
dams of the 40 mg/kg bw/day group. In offspring from
the 4 and 40 mg/kg bw/day group, no statistically
significant effects were observed for body or organ
weights, anogenital distance, anogenital distance/g body
weight, or anogenital distance/body weight cubed at any
time point in the study. At 9 weeks of age, plasma
testosterone levels were significantly increased by 88% in
the 4 mg/kg bw/day group and by 123% in the 40 mg/
kg bw/day group. [Benchmark dose was not calculated
because the SD was provided only graphically.] The
study authors stated that there was a tendency for
plasma testosterone to increase with dose at 36 weeks,
but neither of the values were significantly increased
compared to control. Testis testosterone was not statistically
different from control at either dose at 9 or 36
weeks of age. There were no significant effects on plasma
LH and FSH levels at 9 weeks of age. Plasma levels of
17b-estradiol were also unaffected by bisphenol A
exposure. [Data were not shown.] The study authors
concluded that gestational and lactational exposure to
bisphenol A did not affect somatic growth or anogenital
distance but did have a significant effect on testosterone
homeostasis in rat offspring.
Strengths/Weaknesses: The study appears better able
to address maternal toxicity than offspring outcomes, for
which it appears to be best considered a screening study.
Sample sizes are too small to reliably judge postnatal
endpoints.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation of bisphenol
A effects on postnatal outcome.
Yoshino et al. (2002), supported by the Japanese
Ministry of Health, Labor, and Welfare, examined the
effects of prenatal and lactational bisphenol A exposure
in the prostate and testis of rats. In this study, pregnant
and lactating dams were fed nMF feed and offspring
were fed MF feed (Oriental Yeast Co., Tokyo). The
animals were housed in an unspecified type of cage
containing wood chip bedding. F344 rat dams (n 5 19–
22/group) were gavaged with bisphenol A (99.9%
purity) at 0 (0.5% sodium carboxymethylcellulose vehicle),
7.5, or 120 mg/kg bw/day during mating, gestation,
and lactation periods. Doses were based on the result of
an NTP study (NTP, 1982). Clinical signs, food intake,
and body weight were monitored in dams during the
study. After birth, pups were counted and weighed. Pups
were randomly culled to 8/litter on PND 4 (day of birth
not defined). On PND 21, weaning occurred and female
pups were killed and discarded. Dams were killed at
weaning for examination of implantation sites. Male
pups were weighed during the post-weaning period. On
PND 23, 28, and 91, five male offspring/group were
killed. Ventral prostate weights were measured during
each evaluation period, and anterior and dorsolateral
prostate, testis, and epididymis weight were also
measured on PND 91. Reproductive organs were
preserved in 10% buffered formalin and examined
histologically. Sperm count, motility, and morphology
were examined on PND 91. The study was repeated with
evaluation of 10 male offspring/group. [The number of
dams treated/group in the repeat study was not
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
253
reported. Based on body weights reported for rats in
Experiment 2, it appears they were evaluated at
adulthood, but it was not specified if they were
evaluated on PND 91.] Data were analyzed by Student
t-test. [It appears that offspring were considered the
statistical unit.]
In the first experiment, bisphenol A exposure had no
effect on dam body weights during gestation or lactation,
duration of the gestation period, or number of implantation
sites. There were no effects on litter size, pup
viability, or sex ratio. On PND 21, relative dorsolateral
prostate weight was significantly higher [by 23%] in the
low-dose group than in controls. [It was not stated if
organ weights were relative to body weight.] There
were no effects on final body weight or weights of
anterior and ventral prostate, testis, or epididymis. There
were no increases in malformations of reproductive
organs. [Data were not shown by study authors.]
Testicular sperm counts were significantly lower [by
22%] in males of the high-dose group, but there were no
effects on epididymal sperm counts. There were also no
effects on sperm motility or abnormalities. [Data were
not shown by authors.] In the second experiment
examining 10 males/group, exposure to bisphenol A
had no effects on final body weights or relative weights
of testis, epididymis, or ventral, anterior, or dorsolateral
prostate. There were no adverse effects on testicular or
epididymal sperm count, motility, or morphology.
Morphologically abnormal sperm were reduced in rats
of the low-dose group. Study authors concluded that
under the conditions of their study, exposure of dams to
bisphenol A during the gestation and lactation periods
did not result in adverse effect on the reproductive
system of male offspring.
Strengths/Weaknesses: The number of dams used in
Experiment 1 appears adequate and 10 males/group
were used to examine various organ endpoints at
multiple time points. It is unfortunate that these data
were then analyzed by many t-tests rather than multivariate
analyses.
Utility (Adequacy) for CERHR Evaluation Process:
This study is considered inadequate due to statistical
insufficiencies.
Ichihara et al. (2003), supported by the Japanese
Ministry of Health, Labor, and Welfare, examined the
effects of prenatal and lactational exposure to bisphenol
A on the development of prostate cancer in rats. F344 rat
dams were fed nMF feed during pregnancy and lactation
and their offspring were fed MF (Oriental Yeast Co.)
following weaning. Rats were housed in cages containing
wood chip bedding. [No information was provided
about caging materials.] During pregnancy and lactation,
B8–15 dams/group were gavaged with bisphenol
A (99.9% purity) at 0 (0.5% carboxymethyl cellulose
sodium salt vehicle), 0.05, 7.5, 30, or 120 mg/kg bw/day.
Doses were based on findings from an NTP study
[citation not provided]. Dam body weight and food
intake were monitored during the study. Gestation
period duration and implantation sites were evaluated.
Pups were counted and sexed at birth. Litters were culled
randomly to 8 pups on PND 4, and pups were weaned
on PND 21 [day of birth not defined]. At 5 weeks of age,
21 male rats/group were injected s.c. with 50 mg/kg bw
3,2-dimethyl-4-aminobiphenyl 10 times at 2-week intervals.
An additional 12 rats/group in the 0, 0.05, 7.5, and