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

1988 mg/kg bw/day in females during the prebreeding
period, and 0, 870, and 1716 mg/kg bw/day in females
during the gestation period. [Intake values were
obtained from the Results section and study summary
tables. They differed from values reported in text Table
C, which were assumed to be in error.] Homogeneity
and stability of bisphenol A in feed were verified.
Parameters evaluated during the study included clinical
signs, body weight, and feed intake. Reproductive
endpoints evaluated included implantation loss and
indices of mating, fertility, pregnancy, and gestation. F 0
Males were killed at the end of the breeding period; liver
and kidney were weighed. At birth, pups were counted,
sexed, weighed, and evaluated for viability and external
alterations. F0 females and F1 pups were killed on the day
of parturition (PND 0). Dams were assessed for clinical
chemistry parameters of liver and kidney function;
corpora lutea and implantation sites; uterus, ovary,
kidney, and liver weight; and liver and kidney histopathology.
The male, female, pregnant female, or the
litter were considered statistical units. Statistical analyses
included ANOVA, Levene test, GLM procedure, Dunnett
test, w 2 test, Cochran–Armitage test, and Fisher exact
probability test.
Treatment-related effects in F 0 animals are summarized
in Table 97. There were no treatment-related changes
in clinical signs, body weight gain, feed intake, or food
efficiency in males or in females during the prebreeding
period. A transient increase in food intake occurring in
females of the low-dose group on study stays 0–7 did not
appear to be treatment-related. Gestational body weight
gain was decreased in the high-dose group, beginning on
GD 7 and in the low dose group beginning on GD 10.
Body weights of live F 0 females were significantly lower
in the high-dose group on PND 0, but no significant
differences were observed during necropsy conducted
later in the day. A significant decrease in feed intake was
reported for the high-dose group on GD 14–17, only
when the values were expressed as g/day. [The results
section indicated that food efficiency during gestation
was not significantly affected, but a downward trend
was observed. Table 10 of the study reported a
significant decrease in food efficiency.] Significant
necropsy findings observed in males included increased
absolute and relative liver weight at both doses and
increased absolute paired kidney weight at the low dose.
Absolute and relative liver and paired kidney weight
were increased significantly in females from both dose
groups. Histopathological observations in females included
dose-related increases in incidence and severity
of hepatocyte hypertrophy and increased kidney lesions
(renal tubular epithelial necrosis, degeneration, and
regeneration) in both dose groups. Significant clinical
chemistry findings in females included increased blood
urea nitrogen in the high-dose group and decreased
sodium, potassium, and chloride levels in the low-dose
group.
Treatment-related reproductive or developmental effects
are summarized in Table 97. No significant effects
were observed for mating, fertility, or pregnancy indices;
time to insemination; numbers of ovarian lutea or
implantation sites; or implantation loss. Gestation duration
was extended by B10 hr in both dose groups; the
study authors stated that the biological significance of
the finding is not known. Total and live pup numbers
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
369
were decreased in the high-dose group. No significant
effects on pup weight were observed but a downward
trend was statistically identified for female pup weight.
The study authors concluded that their study confirmed
the NTP (1985a) finding of reduced litter size in
mice fed 10,000 ppm bisphenol A in feed. The NTP
finding of decreased litter size at 5000 ppm bisphenol A
was not confirmed in this study, likely due, according to
the authors, to the shorter exposure duration in the
current study than in the NTP study. The study authors
concluded that the litter size decreases in their study
were likely caused by the compromised status of dams.
Strengths/Weaknesses: Strengths of this report include
the comprehensive design with the assessment of multiple
relevant endpoints. There were adequate numbers of
animals, the doses and stability of the compound were
verified, and the oral route of exposure was used.
Weaknesses include the limited number of doses examined
and the relatively high-doses studied.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and useful for the evaluation
process.
Tyl et al. (2006), sponsored by the American Plastics
Council, conducted a two-generation study of bisphenol
A in mice. The study was conducted accorded to GLP.
CD-1 mice were received in two cohorts approximately 2
weeks apart and data from the two cohorts were
combined. Mice were fed Purina Certified Ground
Rodent Diet No. 5002. The supplier provided information
about phytoestrogen content of feed (177–213 ppm
genistein, 173–181 ppm daidzein, and 39–55 ppm glycitein).
Mice were housed in polypropylene cages with
Sani-Chip bedding. Assignment of F 0 animals to groups
involved randomization stratified by weight. F 0 and F 1
mice (28 sex/group/generation) were fed diets containing
bisphenol A (99.70–99.76% purity) at 0.018, 0.18, 1.8,
30, 300, or 3500 ppm. Target intakes were 0.003, 0.03, 0.3,
5, 50, or 600 mg/kg bw/day, respectively. Based on
measured feed intake, the study authors estimated
bisphenol A intake in males at 0.0024–0.0038, 0.024–
0.037, 0.24–0.37, 3.98–6.13, 39.1–60.8, or 529–782 mg/kg
bw/day. Bisphenol A intakes (in mg/kg bw/day) by
females were estimated at 0.0030–0.0041, 0.030–0.042,
0.32–0.43, 5.12–7.12, 54.2–67.8, 653–910 during the premating
period; 0.0027–0.0029, 0.027–0.028, 0.28–0.29,
4.65–4.80, 47.0–48.6, 552–598 during the gestation period;
and 0.0063–0.0087, 0.062–0.091, 0.61–0.89, 10.4–15.1,
103.2–146.4, 1264–1667 during the lactation period. In
each generation, there were 2 vehicle control groups with
28 mice/sex/group. A positive control group was given
feed containing 17b-estradiol at 0.5 ppm (target intake of
0.08 mg/kg bw/day). Estimated intakes for 17b-estradiol
(in mg/kg bw/day) were 0.074–0.104 in males, 0.093–
0.12 in females during the pre-mating period, 0.08–0.081
in females during the gestation period, and 0.160–0.25 in
females during the lactation period. Dose selections were
based on observations from several studies. [The Expert
Panel notes that a separate 2-generation study was used
to characterize the dose–response relationship for 17bestradiol.]
Homogeneity, stability, and concentration of
bisphenol A in feed were verified. Exposure of F 0 mice
began at B6 weeks of age. Exposure of F1 animals began at
weaning, although it was noted that pups began eating the
dosed feed in the late lactation period. F0 and F1 mice were
fed the bisphenol A-containing diets for a minimum of 8