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

380 CHAPIN ET AL.
from other suppliers, there are no data supporting this
assertion.
4.4.1 Human. Human reproductive studies are
summarized in Table 100. A study of 42 men occupationally
exposed to an epoxy hardening agent containing
bisphenol A diglycidyl ether found higher urinary
bisphenol A concentrations, corrected for creatinine,
than were found in 42 men who worked in the same
factory but did not have known exposure to the
hardening agent (Hanaoka et al., 2002). Differences were
not detected between the worker groups in plasma
testosterone or LH, but plasma FSH was significantly
lower in exposed workers [BPA: 0.043 mg/kg bw] than in
workers not exposed to the hardening agent [BPA:
0.021 mg/kg bw]. A significant correlation was noted
between total urinary bisphenol A concentration and
decreased FSH when adjusted for age and alcohol intake
(r 5 0.23, P 5 0.045).
Two studies from Takeuchi and Tsutsumi (2002) and
Takeuchi et al. (2004a) suggested a relationship between
serum bisphenol A concentration and serum testosterone
(total and free). The first study (Takeuchi and Tsutsumi,
2002) included women with and without polycystic
ovary syndrome (POS), and healthy men. Statistically
significant positive correlations were observed for
women with and without POS (0.559 for total testosterone
and 0.598 for free testosterone, Po0.01), and with all
participants (0.595 and 0.609, respectively, Po0.001). The
second study (Takeuchi et al., 2004a) reported only
cycling women with and without obesity and women
with POC, with and without obesity, hyperprolactinemia
and hypothalamic amenorrhea. Statistically significant
positive correlations were found for bisphenol A and
total testosterone (r 5 0.391, Po0.001), free testosterone
(r 5 0.504, Po0.001), androstenedione (r 5 0.684,
Po0.001), and dehydroepiandrosterone sulfate (DHEAS,
r 5 0.514, Po0.001). Although these studies used ELISA,
which may overestimate bisphenol A compared to
HPLC, significant correlations between bisphenol A
levels and higher serum testosterone levels were found.
The authors speculated that androgens either may affect
bisphenol A metabolism or the reverse.
A study of 37 women found differences in bisphenol A
concentrations by health status. Significantly lower mean
bisphenol A concentrations were found among women
with endometrial cancer (1.4 ng/ml, n 5 7) and complex
endometrial hyperplasia (1.4 ng/ml, n 5 9) compared to
healthy women (2.5 ng/ml, n 5 11) and women with
simple hyperplasia (2.9 ng/ml, n 5 10) (Hiroi, 2004).
4.4.2 Experimental Animal.
Reproductive toxicity studies of high and limited
utility are summarized in Table 101 and Table 102
respectively.(single and multiple dose level studies in
the same utility category are combined within a table).
Based on reproductive studies using a single dose level,
the lowest dose level at which an effect was seen in these
studies was 0.04 mg/kg/day fed to female rats during
pregnancy and lactation and resulting in a decreased
duration of licking/grooming pups (Della Seta et al.,
2005). This study of neural and behavioral effects is
shown here for convenience but has been included with
other studies focused on these endpoints for further
discussion in Section 3.
For high utility female reproductive studies using
multiple doses, the lowest effect level, for altered estrous
cycle, was Z600 mg/kg bw/day by gavage in rat for 28
days (Yamasaki et al., 2002a). For high utility male
reproductive studies, the lowest effect level, for histologic
alterations in the testis, was 235 mg/kg bw/day by
gavage in rat for 28 days (Takahashi and Oishi, 2001). The
value of the histologic observations may be limited due
to the fixation and embedding techniques employed,
raising some concern over the validity of this endpoint.
The reproductive assessments by continuous breeding
included a study using very high-dose levels (NTP,
1985a), and this study is not the most informative for
reproductive risk assessment. In a multigeneration study,
CD rats did not show statistically significant or doserelated
reproductive effects over 2 generations with
bisphenol A gavage doses of 0.0002, 0.002, 0.020, or
0.200 mg/kg bw/day (Ema et al., 2001). In Sprague–
Dawley rats treated for 3 generations, adverse reproductive
effects consisted of decreased F 1 epididymal sperm
concentration, decreased F3 daily sperm production,
decreased live pups/litter, decreased pup body weight,
and delayed vaginal opening at an average dose level of
475 mg/kg bw/day. Delayed preputial separation was
seen in F 1 and F 2 males at an average dose level of
47.5 mg/kg bw/day (Tyl et al., 2000a, 2002b). In CD-1
mice given bisphenol A for 2 generations in the diet at
dose levels as low as B0.003 mg/kg bw/day, the most
sensitive effect was a reduction in F2 seminal vesicle
weight relative to brain weight at 50 mg/kg bw/day.
Effects on F0 epididymal sperm concentration, gestation
length, and relative testis weight occurred at 600 mg/kg/
day, the next highest dose level (Tyl et al., 2006).
A summary of LH and testosterone effects observed in
bisphenol A-exposed experimental animals and in humans
are included in Table 103.
Data sufficiency statement for human data: In
summary, there are insufficient data to evaluate whether
bisphenol A causes male or female reproductive toxicity
in humans. However, several studies collectively suggest
hormonal effects, including one study of exposed male
workers likely to have multiple routes of exposure
including inhalation (Hanaoka et al., 2002).
Data sufficiency statement for animal data: In
summary, the experimental animal literature was assessed
for its utility (high utility, limited utility, or no
utility) based on the criteria established by this Expert
Panel, including an evaluation of experimental design
and statistical procedures. Studies with high and limited
utility were further grouped according to female and
male reproductive toxicity, their use of single or multiple
dose levels, a multigenerational exposure paradigm, and
the measurement of various hormonal endpoints. Greater
weight was given to studies using the oral route of
exposure, because of evidence that oral exposure
predominates in humans and that target tissue exposure
to parent compound (bisphenol A) is very low after oral
exposure and first-pass metabolism as compared to
subcutaneous or other routes of exposure.
There is sufficient evidence in rats and mice
that bisphenol A causes female reproductive toxicity,
characterized as delayed vaginal opening with subchronic
or chronic oral exposure NOAELs of 47.5 mg/kg bw/
day and a LOAEL of 475 mg/kg bw/day (Tyl et al.,
2002b).
Birth Defects Research (Part B) 83:157–395, 2008