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

consistent effects on the levels of these hormones have
been seen (Ema et al., 2001).
Fertility and ability to raise pups to weaning following
developmental exposure: Multigenerational studies in
both rats and mice have shown that BPA over a
wide dose range does not compromise the ability of
animals exposed during development to successfully
produce offspring, raise them to weaning and for those
offspring to successfully give rise to a subsequent
generation of animals (Ema et al., 2001; Tyl et al.,
2002b, 2006).
Neural and Behavioral Endpoints Following Oral
Administration: Several studies addressing effects on
neural and behavioral endpoints have been conducted
following gestational and lactational exposure
[rats: (Funabashi et al., 2004a; Negishi et al., 2004a;
Della Seta et al., 2005)]; mice: [(Palanza et al., 2002;
Nishizawa et al., 2003, 2005b; Laviola et al., 2005; Ryan
and Vandenbergh, 2006)], pubertal exposure [rat: (Akingbemi
et al., 2004; Della Seta et al., 2006; Ceccarelli et al.,
2007)], and exposure during adulthood [gerbils: (Razzoli
et al., 2005)].
Gestational and lactational exposures in rats have
reported subtle effects on sexually-dimorphic brain
nuclei (Funabashi et al., 2004a), hormonal receptors in
brain (Nishizawa et al., 2003, 2005b), and certain
sexually-dimorphic or reproductively relevant behaviors
(Negishi et al., 2004a; Ryan and Vandenbergh, 2006).
Most of this work has utilized single doses across the
range of 2–40 mg/kg, and none has been confirmed or
linked to other functional or clearly adverse effects. No
effects on the volume of the SDN-POA of the hypothalamus
were observed in offspring of rats orally exposed
to bisphenol A doses ranging from 3.2–320 mg/kg bw/
day during the gestation and lactation period (Kwon
et al., 2000). Single dose level rat studies demonstrated
reduced sexually dimorphic difference in corticotropinreleasing
hormone neurons in anterior stria terminalis at
2.5 mg/kg bw/day (Funabashi et al., 2004a). No changes
in sexual behavior were reported for female rats exposed
to 0.3–320 mg/kg bw/day or males exposed to r0.3 mg/
kg bw/day during the gestation and/or lactation period
(Kwon et al., 2000).
Maternal behavior of dams has also been suggested to
be altered in two studies of dams exposed during
gestation and lactation (Palanza et al., 2002; Della Seta
et al., 2005).
One study involving exposures during puberty (Della
Seta et al., 2005) suggested alterations in exploratory and
sexual behavior of males following 40 mg/kg on PND
23–30. Certain changes in hypothalamic estrogen receptors
(Ceccarelli et al., 2007) following 40 mg/kg exposures
on PND 23–30 have been reported. Akingbemi et al.
(2004) reported effects on gonadal hormonal and
receptor endpoints in the pituitary following 2.4 mg/kg/
day on PND 21–35.
Other endpoints: Following oral exposure of mice
to bisphenol A during gestation, changes were
observed for mRNA expression of arylhydrocarbon
receptors, receptor repressor, or nuclear translocator
and retinoic acid and retinoid X receptors in brain,
testes, and/or ovary at 0.00002–20 mg/kg bw/day
(Nishizawa et al., 2003, 2005a,b). The strongest
effects were found at the lowest doses following
exposures during organogenesis (GD 6.5–13.5 or
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BISPHENOL A
329
6.5–17.5) (Nishizawa et al., 2005a,b). The study authors
suggested those changes as possible mechanisms for
bisphenol A-induced toxicity.
A summary of LH and testosterone effects observed in
humans and in bisphenol A-exposed experimental
animals is included in Section 4.4.
Summary and Conclusion of Developmental
Hazards: There are sufficient data to conclude that
bisphenol A does not cause malformations or birth
defects in fetuses exposed during gestation at levels up to
640 mg/kg/day (rats) and 1000 mg/kg/day (mice) (Morrissey
et al., 1987). This is consistent with the lack of
malformations seen in offspring in multigenerational
studies (Tyl et al., 2002b, 2006).
There are sufficient data to conclude that bisphenol A
does not alter male or female fertility in rats or mice after
gestational exposure up to doses of 450 mg/kg/day
(Cagen et al., 1999b; Tyl et al., 2000a, 2002b; Ema et al.,
2001).
There are sufficient data to conclude that bisphenol A
does not change the age of puberty in male or female rats
[NOAELs of 0.2 mg/kg/day (Ema et al., 2001) and
1823 mg/kg/day (Tyl et al., 2002b)]. While limited data
available suggest an effect on the onset of female puberty
in mice [LOAEL 0.2 mg/kg/day (Ryan and Vandenbergh,
2006), 0.002 mg/kg/day, (Howdeshell et al.,
1999)], the data are insufficient to conclude that bisphenol
A accelerates puberty in female mice. The
limited data available suggest, but are insufficient to
conclude, that bisphenol A slightly delays the age of
puberty in male mice at a LOAEL of ca. 550–800 mg/kg/
day (Tyl et al., 2006).
There are sufficient data to conclude that bisphenol A
exposure during development does not permanently
affect prostate weight in adult rats or mice [NOAELs of:
1823 mg/kg/day (Tyl et al., 2002b), 600 mg/kg/day (Tyl
et al., 2006), 4 mg/kg/day (Cagen et al., 1999b), 0.2 mg/
kg/day (Ema et al., 2001), 50 mg/kg/day (Tinwell et al.,
2002), and 320 mg/kg/day (Kwon et al., 2000). There are
sufficient data to conclude that bisphenol A does not
cause prostate cancer in rats or mice after adult
exposure [calculated dose ranges of 25–400 mg/kg/day
for rats, 600–3000 mg/kg/day, mice (NTP, 1982)]. There
are slight suggestions, but insufficient data to conclude,
that bisphenol A might predispose toward prostate
cancer in rats in later life following developmental
exposure [at 10 mg/kg (Ho et al., 2006a)]. There are
slight suggestions, but insufficient evidence to conclude,
that fetal exposure to bisphenol A can contribute to
urinary tract deformations in mice [10 mg/kg (Timms
et al., 2005)].
There are sufficient data to suggest that developmental
exposure to bisphenol A causes neural and behavioral
alterations related to sexual dimorphism in rats and mice
(ca. 2.5 mg/kg/day, gestation and lactation in rats,
(Funabashi et al., 2004a); LOEL 0.00002 mg/kg/day, fetal
mice, (Nishizawa et al., 2005a); 0.0002 mg/kg/day, fetal
mice, (Nishizawa et al., 2003), 0.04 mg/kg/day, weaning
to puberty, rats, (Ceccarelli et al., 2007); 0.1 mg/kg/day,
GD 3–PND 20, rats, (Negishi et al., 2004a); 0.2 mg/kg/
day, GD 3–PND 20, mice, (Ryan and Vandenbergh, 2006);
0.01 mg/kg/day, GD 11–18, mice, (Laviola et al., 2005),
although other studies report no change in a related
measure, the size of the sexually dimorphic nucleus of
the pre-optic area (SDN-POA) [300 mg/kg/day, rats