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

234 CHAPIN ET AL.
Table 68
Toxicokinetic Values for Free Bisphenol A in Lactating
Rats a
Endpoint Blood value Milk value
Systemic clearance, 119.2/142.4/154.1 b
mL/min/kg
Steady state 66.1/120.0/217.1 b
bisphenol
A concentration,
ng/mL
Milk/serum ratio 2.7/2.6/2.4 b
173.1/317.4/493.9 b
Rats were i.v. injected 0.47, 0.94, or 1.88 mg/kg bw and then
infused over a 4-hr time period with 0.13, 0.27, 0.54 mg/hr.
a Yoo et al. (2001).
b Effect at each dose, from low to high dose.
Table 69
Toxicokinetic Values for Radioactive Dose in Lactating
Rats (Total Bisphenol A) a
Endpoint Blood value Milk value
Cmax, mg – eq/L 27.2 4.46
Tmax, hr 4 8
Elimination half-life, hr 31 26
AUC (0–48 hr), mg –eq � hr/L) 689 156
a Kurebayashi et al. (2005).
Rats were orally dosed with 0.5 mg/kg bw on PND 11.
day) or high-doses (10–100 mg/kg bw/day) were similar.
In contrast to rodents and similar to humans, most of the
dose in orally- or i.v.-exposed monkeys was eliminated
through urine.
Toxicokinetics of bisphenol A were examined in
pregnant rats and are summarized in Table 66 for free
bisphenol A and Table 67 for total dose. One study
demonstrated similar disposition, metabolism, and elimination
of bisphenol A in pregnant and non-pregnant rats
(Domoradzki et al., 2003). A number of rodent studies
demonstrated distribution of bisphenol A or radioactive
dose to fetuses following oral dosing of the dam
(Miyakoda et al., 1999; Takahashi and Oishi, 2000;
Domoradzki et al., 2003; Kim and Hwang, 2003; Kabuto
et al., 2004; Kurebayashi et al., 2005). Bisphenol A
distribution to fetus was also demonstrated with i.v.
dosing of rats (Shin et al., 2002) and s.c. dosing of mice or
monkeys (Uchida et al., 2002; Zalko et al., 2003). In a
study in which bisphenol A was orally administered to
rats on GD 19, bisphenol A glucuronide was not detected
in fetuses (Miyakoda et al., 2000); study authors noted
the possibilities that bisphenol A glucuronide was not
likely transferred from dams to fetuses and that fetuses
do not likely possess glucuronidation ability. Some of the
studies demonstrated slower elimination of bisphenol A
from fetuses than maternal blood following oral dosing
(Miyakoda et al., 1999; Takahashi and Oishi, 2000).
Toxicokinetics data in lactating rats are summarized in
Table 68 for free bisphenol A and Table 69 for total dose.
Distribution of bisphenol A to milk and/or nursing pups
was demonstrated in rodent studies with oral or i.v.
exposures (Snyder et al., 2000; Yoo et al., 2001;
Kurebayashi et al., 2005). One study reported that most of
the bisphenol A dose is present as bisphenol A glucuronide
in milk of lactating rats (Snyder et al., 2000). In a study that
compared bisphenol A concentrations in maternal serum,
milk, and offspring after rat dams were administered low
oral doses (0.006 or 6 mg/kg bw/day), a significant
increase in bisphenol A concentration was only observed
in the serum of dams from the high-dose group on PND 21;
no increase was observed in milk or pups (Yoshida et al.,
2004). Another study demonstrated higher concentrations
of bisphenol A in milk compared to maternal serum after
i.v. dosing of rat dams (Yoo et al., 2001).
A number of in vitro studies compared bisphenol A
metabolic velocity rates in microsomes or hepatocytes
from rodents and humans. Generally, faster rates were
demonstrated by rodent than human hepatocytes and
microsomes (Elsby et al., 2001; Pritchett et al., 2002)
[reviewed in (European-Union, 2003)]. One of the studies
noted that adjustment for total hepatocyte number in
vivo resulted in higher predicted rates for humans than
rodents (Pritchett et al., 2002). The European Union
(2003) noted that the interpretation of such studies
should included knowledge about in vivo conditions
such as varying metabolic capacity of hepatic cells,
relationship of hepatic size to body size, and possibly
important physiological endpoints such as blood flow.
2.6.2 General toxicity. Gross signs of toxicity
observed in rats acutely exposed to bisphenol A included
pale livers and gastrointestinal hemorrhage [reviewed by
the (European-Union, 2003)]. Acute effects of inhalation
exposure in rats included transient and slight inflammation
of nasal epithelium and ulceration of the oronasal
duct. Based on LD50 observed in animals, the European
Union (2003) concluded that bisphenol A is of low acute
toxicity through all exposure routes relevant to humans.
According to the European Union (2003), there is evidence
that bisphenol A is irritating and damaging to the eye and
is irritating to the respiratory tract and possibly the skin.
Findings regarding sensitization potential were not clear.
Possible target organs or systems of toxicity identified
in repeat-dose animal studies with oral dosing included
intestine, liver, kidney, and male, and female reproductive
systems [reviewed in (NTP, 1982; Yamasaki et al., 2002a;
European-Union, 2003)]. Intestinal findings (effect levels)
in rats included cecal enlargement (Z25 mg/kg bw/day)
and cecal mucosal hyperplasia (Z200 mg/kg bw/day).
Hepatic effects included prominent hepatocyte nuclei or
inflammation in rats (Z500 mg/kg bw/day), multinucleated
giant hepatocytes in mice (Z120 mg/kg bw/day),
and increased weight with no evidence of histopathology
in dogs (Z270 mg/kg bw/day). Renal tubule degeneration
or necrosis was observed in rats dosed with
Z500 mg/kg bw/day. Reproductive findings are discussed
in Section 4.0. Effects in subchronic inhalation
studies in rats included cecal enlargement resulting from
distention by food and transient, slight hyperplasia and
inflammation of epithelium in the anterior nasal cavity;
both effects occurred at (Z50 mg/m 3 ).
2.6.3 Estrogenicity. Estrogenicity of bisphenol A
has been evaluated using in vitro (Table 52) and in vivo
(Table 53) assays. In those studies estrogenic potency was
compared to 17b-estradiol, ethinyl estradiol, diethylstilbestrol,
and, in one study, estrone. There is considerable
variability in the results of these studies with the estrogenic
potency of bisphenol A ranging over about 8 orders of
magnitude (Fig. 2). On the other hand, the average potency
only differs by 1 order of magnitude and there is very little
difference between rat and mouse means.
Birth Defects Research (Part B) 83:157–395, 2008