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

isphenol A. Bisphenol A was detected in 1 of 23
endometrial samples; the median concentration was
reported at o1 mg/kg wet weight, and the range was
reported at 0–13 mg/kg. [It is not known why a median
value and range were reported when bisphenol A was
only detected in 1 sample.]
As part of a study to compare an ELISA and an LC/MS
method for biological monitoring of bisphenol A, Inoue
et al. (2002) measured concentrations of bisphenol A in
semen samples obtained from 41 healthy Japanese
volunteers (18–38 years old). Analysis by the ELISA
method indicated bisphenol A concentrations ranging
from concentrations below the detection limit (2.0 mg/L)
to 12.0 mg/L. The LC/MS method indicated that
the bisphenol A concentration in all samples was
o0.5 mg/L, the LOQ. The study authors concluded that
theLC/MS method wasmoreaccurateand sensitiveand
that the ELISA method overestimated bisphenol A
concentrations, possibly due in part to nonspecific antibody
interactions.
2.1.1.3 Metabolism: Völkel et al. (2005) measured
bisphenol A and metabolite concentrations in human
urine following exposure to a low bisphenol A dose. The
human volunteers consisted of 3 healthy females (25–32
years old) and 3 healthy males (37–49 years old) who were
asked to refrain from alcohol and medicine intake for 2
days before and during the study. Volunteers received
25 mg D 16-bisphenol A in drinking water [0.00028–
0.00063 mg/kg bw based on reported body weights], a
dose reported to represent a worst-case human exposure.
Urine samples were collected at 0, 1, 3, 5, and 7 hr
following exposure. Analyses for D16-bisphenol A and
D 16-bisphenol A-glucuronide were conducted by LC/MS
and HPLC. Recovery of D 16-bisphenol A-glucuronide in
urine within 5 hr of dosing was 85% of dose in males and
75% of dose in females. Analysis following treatment of
urine with glucuronidase resulted in recovery of 97% of
the dose in males and 84% of the dose in females. The
highest concentrations of bisphenol A glucuronide in
urine were measured at 1 hr (221–611 pmol [50–139 ng
bisphenol A eq]/mg creatinine) and 3 hr (117–345 pmol
[27–79 ng bisphenol A eq]/mg creatinine) following
exposure. Elimination half-life was estimated at 4 hr.
Bisphenol A concentrations exceeding the detection limit
were detected in only 2 urine samples at concentrations of
B10 pmol [2 ng]/mg creatinine.
Völkel et al. (2002) examined toxicokinetics and
metabolism of bisphenol A in humans administered a
low dose. Volunteers in this study consisted of 3 healthy
females (24–31 years of age) and 6 healthy males (28–54
years of age) who were non- or occasional smokers;
volunteers were asked to refrain from alcohol and
medicine intake for 2 days before and during the study.
In two different studies, D16-bisphenol A was orally
administered to volunteers via gelatin capsules at a dose
of 5 mg (0.054–0.090 mg/kg bw). The dose was reported
to be B10-fold higher than the estimated human
exposure level of 0.6 mg/day. In the first study, urine
samples were collected at 6-hr intervals until 42 hr
following exposure and blood samples were collected
at 4-hr intervals until 32 hr following exposure in 3 males
and 3 females. In a second, more detailed study
conducted in 4 of the male volunteers, blood samples
were collected at 30–60-min intervals until 381 min
following exposure. Samples were analyzed by GC/MS
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
185
and LC/MS. In the first study, a terminal half-life
of 5.3 hr was reported for D 16-bisphenol A glucuronide
clearance from blood. The half-life for urinary
elimination was reported at 5.4 hr. D16-Bisphenol A
glucuronide concentrations in plasma and urine fell
below LOD at 24–34 hr post-dosing. Complete urinary
recovery (100%) was reported for the D16-bisphenol
A glucuronide. In the second study, maximum
plasma concentration of D 16-bisphenol A glucuronide
(B800 pmol [183 ng bisphenol A eq]/mL) was obtained
80 min after oral administration. The half-life for
initial decline in plasma was reported at 89 min.
Free D16-bisphenol A was not detected in plasma.
According to study authors, the study demonstrated
rapid absorption of bisphenol A from the gastrointestinal
tract, conjugation with glucuronic acid in the liver, and
rapid elimination of the glucuronide in urine. Study
authors noted that the rapid and complete excretion of
bisphenol A glucuronide in urine suggested that in
contrast to rats, enterohepatic circulation did not occur in
humans.
Table 8 in Section 1 provides information on bisphenol
A and metabolites detected in human urine. A study
conducted in the U.S. used an HPLC method to examine
30 urine samples collected from a demographically
diverse adult population in 2000–2004 (Ye et al., 2005).
Mean urinary compound composition was 9.5% bisphenol
A, 69.5% bisphenol A glucuronide, and 21% bisphenol A
sulfate conjugate. A study conducted in Korea used an
HPLC method to examine urine collected from 15 men
(mean age 5 42.6 years) and 15 women (mean age 5 43.0
years) (Kim et al., 2003b). Sex-related differences were
observed for urinary metabolic profiles. Mean urinary
compound composition in men was reported at 29.1%
bisphenol A, 66.2% bisphenol A glucuronide, and 4.78%
bisphenol sulfate conjugate. The urinary metabolite
profile in females was 33.4% bisphenol A, 33.1% bisphenol
A glucuronide, and 33.5% bisphenol A sulfate conjugate.
The study authors concluded that women had a greater
ability for sulfation than men.
2.1.1.4 Excretion: As discussed in greater detail in
Section 2.1.1.3, two studies in which human volunteers
were administered low doses of D 16-bisphenol A
(B0.00028–0.090 mg/kg bw) demonstrated that most of
the dose (85–100%) was eliminated through urine (Völkel
et al., 2002, 2005). In those studies, the half-lives for
urinary elimination were reported at 4–5.4 hr. As discussed
in more detail in Section 2.1.1.3, examination of
human urine samples revealed that bisphenol A glucuronide
and sulfate conjugates are present at higher
concentrations than is the parent compound (Kim et al.,
2003b; Ye et al., 2005).
2.1.2 Experimental animal. Original animal studies
that were potentially important for the interpretation
of developmental and reproductive toxicity were
reviewed thoroughly. Examples included:
* Studies examining toxicokinetics or metabolism in
pregnant or lactating animals;
* Studies examining toxicokinetic difference observed
with different doses or exposure routes;
* Studies looking at age-related differences in toxicokinetics
or metabolism; and
* Studies in non-rodent species such as primates.