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

study authors noted that no historical control database
was available at CIIT at the time of the analysis.
[The NTP Statistics Subpanel (NTP, 2001) reanalyzed
these data agreed with its results and conclusions
showed a consistent increase in ventral prostate weight
in the 2 replicates. Note that the NTP Statistics
Subpanel rejected the conclusions in Elswick et al.
(2000) that use of multiple pups per litter can decrease
false positive rates in these studies.]
Strengths/Weaknesses: This study demonstrated an
increase in ventral prostate weight. These data argue for
multiple pup/litter sampling, a characteristics that has
been uncommon in this literature. The fact that significant
effects were noted in only in 1 block raise the
question of a lack of experience or training among the
technicians. The study referred to in Elswick et al. (2000)
is unpublished and not peer-reviewed.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate because it is primarily a
discussion of results published previously and the new
data presented have inconsistencies in block replicates.
Rubin et al. (2001), supported by the Tufts Institute of
the Environment and NIH, examined the effects of
perinatal bisphenol A exposure on estrous cyclicity and
LH levels in rats. Uterotropic responses were examined
in a second group of rats, and those results are listed in
Table 53. Sprague–Dawley rats were fed Purina Rodent
Chow and provided drinking water in glass bottles. The
rats were housed in plastic cages; estrogenicity testing of
ethanol extracts indicated that estrogenic compounds did
not leach from cages at detectable levels. [No information
was provided about bedding.] Dams were weighed
and randomly assigned to treatment groups of 6 animals
given drinking water containing bisphenol A [purity not
reported] at 0 (1% ethanol vehicle), 1, or 10 mg/L from
GD 6 (plug day not indicated) through the lactation
period. Mean bisphenol A doses were estimated by study
authors at 0.1 and 1.2 mg/kg bw/day. At weaning, pups
were given untreated water. Dams were examined and
weighed during the studies. Offspring were sexed on
PND 2 and weighed beginning in the postnatal period
and continuing through adulthood (n 5 40–53/group
during the neonatal period and 19–27/sex/group during
adulthood). Anogenital distance was examined during
the neonatal period. [It was not clear how many time
points and animals were examined. According to 1
study author, anogenital distance was measured on
PND 2 (A. Soto, personal communication, March 2,
2007).] Genital tracts were examined for gross abnormalities
in males killed during the neonatal period, at 3
months, and at 5 months of age and in females killed
during the neonatal period, at 8 months, and at 12–16
months of age. [The total number of animals examined
at each time period was reported as 12–34, but it is not
known how many/dose group were examined.] Animals
were selected from as many different litters as possible at
each time point. Day of vaginal opening was monitored.
Estrous cyclicity was evaluated daily for 18 days at 4 and
6 months of age in 18–28 rats/group. Eight female
offspring/group were killed 3 months later following
ovariectomy to measure serum LH levels using an LH
assay kit; a total of 6–8 values/group were obtained.
Body and uterine weights and LH levels were analyzed
by ANOVA followed by t-test, Tukey test, or least
significant difference test. Mammary tumors were
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
251
analyzed by w 2 test, and estrous cyclicity data were
analyzed by Kruskall–Wallis test and Mann–Whitney Utest.
[It appears that offspring were considered the
statistical unit.]
On PND 4, 7, and 11, body weights were significantly
higher in pups from the bisphenol A groups than in the
control group; body weights were higher in animals of
the low compared to the high-dose group. Body weights
of low-dose females were higher than body weights of
control and high-dose females at PND 28 and beyond.
Although the percentage of control females with regular
estrous cycles was 83% at 4 months of age and 60% at 6
months of age, the values were reduced significantly in
the high-dose group to 21% at 4 months of age and 23%
at 6 months of age. There were no clear patterns of
estrous cycle changes. Periods of diestrus were extended
in some animals and other animals had extended
periods of proestrus and/or estrus. The mean number
of 4–5-day estrous cycles was reduced significantly in
rats of the high-dose group at 6 months of age. Serum
LH levels in the high-dose group were reduced significantly
by B19% compared to the control group
[BMD10 5 0.94, BMDL10 5 0.48, BMD1 SD 5 1.6, and
BMDL1 SD 5 0.78 mg/kg bw/day]. The treatment group
incidences of females with mammary tumors (10% in
controls, 20% in the low-dose group, and 28% in the
high-dose group) were not statistically different. The
study authors noted that the study was not designed to
detect mammary tumors and that the tumors were
detected during routine handling. No effects were
reported for mean number of pups/litter, sex ratio, day
of vaginal opening, or anogenital distance in the neonatal
period. [Data were not shown for anogenital distance.]
In comparing the effects on estrous cycles and LH levels
in animals exposed in the perinatal period to the lack of
uterotropic effects in animals exposed in the postpubertal
period, the study authors concluded that there
was evidence of increased sensitivity to bisphenol A
during the perinatal period.
Strengths/Weaknesses: This study incorporates a
range of basic developmental and gross functional
reproductive endpoints, but the sample sizes are small
(6 dams/group) and the statistical approach does not
appear to use litter as the unit. Actual exposures are
poorly defined, particularly postnatally. The plausibility
of the estrous cycle changes is a strength.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation process,
based on a lack of adequate control for litter effects
Takashima et al. (2001), supported by a Grant-in-Aid
for Health Sciences Research [sponsor not indicated],
examined the effect of bisphenol A exposure during
development on carcinogenicity induced by N-nitrosobis
(2-hydroxypropyl)amine. [No information was provided
about caging and bedding materials used in this study.]
Female Wistar rats were fed either MF diet or soybeandevoid
powder diet (Oriental Yeast Co.). In each dietary
group, 10–11 rats/group received bisphenol A [purity
not indicated] at 0 or 1.0% diet. Bisphenol A exposure
commenced 10 weeks before mating and was continued
through the mating, gestation, and lactation periods.
Total intakes of bisphenol A were reported at 21–22 g/rat.
[Assuming an exposure period of B16 weeks, mean
bisphenol A intake over the course of the study was
estimated at B200 mg/day. Based on reported body