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

BISPHENOL A
Table 104
Estimates of U.S. General Population Intake of Bisphenol A
Exposure source Population BPA mg/kg bw/day Notes Source
Formula Infant
Breast milk Infant
Food Infant (0–4 months old)
Infant (6–12 months old)
Child (4–6 years old)
Adult
Aggregate Child (1.5–5 years old)
Estimates based on urinary metabolites
Aggregate Child
Adult
0.001
0.001
0.0016
0.0008–0.00165
0.0012
0.00037 (canned food)
0.00048 (canned
food 1 wine)
0.00004-0.00007
0.00007
0.000026
between urinary levels of bisphenol A and plasma LH,
FSH, and free testosterone, found reduced FSH levels
among the exposed men. No fertility endpoints were
evaluated. Three studies were considered to have low
utility in the evaluation process due to limitations in
design and analysis but suggest directions for future
research. Two of these studies measured serum bisphenol
A in healthy women, women with polycystic ovary
syndrome and healthy men and evaluated correlations
with serum gonadotropins, prolactin, testosterone, and
other androgens. No fertility endpoints were included in
these studies. The third study of 37 women found
significantly lower bisphenol A concentrations among
women with endometrial cancer and complex endometrial
hyperplasia compared to healthy women and
women with simple hyperplasia.
4.3.2 Experimental animal. Female reproductive
toxicity testing using multiple dose levels has been
evaluated in 2 rat, 1 mouse, and 1 gerbil study. Endpoints
affected in these studies included brain progesterone
receptor, estrous cyclicity, resorptions, and social sniffing.
Male reproductive toxicity testing using multiple
dose levels has been evaluated in 7 rat and 2 mouse
studies. Affected endpoints in males included reproductive
organ weight and histology, serum testosterone,
daily sperm production, sperm motility, sperm concentration,
percent pregnant females after mating, and
females with resorptions after mating. There are 4
multigeneration tests, 2 in rats and 2 in mice, involving
gavage or dietary treatments with bisphenol A with dose
levels as low as 0.0009 mg/kg bw/day. There are also 2
reproductive assessments by continuous breeding, 1 of
which involved subcutaneous implants for bisphenol A
delivery and 1 of which used dietary administration in
which the lowest dose level was B437.5 mg/kg bw/day.
4.4 Summary of Reproductive Toxicity Data
The hypothesis has been advanced that the Charles
River Sprague-Dawley (SD) rat is insensitive to estrogens
and other EDCs and therefore it should not be used for
Birth Defects Research (Part B) 83:157–395, 2008
Assumes 4.5 kg bw, 700 ml
formula at 6 mg/L
BPA (U.S. canned formula max)
Assumes 4.5 kg bw, 700 ml at 6.3 mg/L
(U.S. breast milk max)
European Commission
European Commission
European Commission
Max 5 0.00007–0.00157
Assumes 50% absorption
U.S. 6–8-year-old girls
(max 5 0.00217)
U.S. population 95th
percentile 0.0.00159
Expert Panel
Expert Panel
Table 11 Table 14
Table 11 Table 14
Table 11 Table 14
Wilson et al.
(2003, 2006)
Table 15
Table 15
379
developmental EDC studies and the studies of the effects
of BPA that used this strain should be discounted. In
order to address this important issue Expert Panel
members reviewed the literature on estrogen-sensitivity
among rat strains and the following is a summary of our
findings.
Different strains of rats show clear, robust reproducible
differences in responses to potent estrogens and
antiandrogens. Several traits have been shown to be
estrogen sensitive in rats including prolactin regulation
in the pituitary, thymic involution, uterine pyometra, and
liver carcinogenesis to name a few. It is evident that the
SD rat and other rat strains are less sensitive to the effects
of estrogens than the F344 rat. However, for some traits,
the reverse is true. In addition, while the SD was less
sensitive than the F344 to estrogen, the reverse was true
for sensitivity to tamoxifen.
The sensitivity to estrogens has been mapped to
specific chromosomes for several traits. In no case has
it been demonstrated that the SD strain is completely
insensitive to any known estrogen. It is evident that
different traits map to different chromosomes and the
degree of estrogen sensitivity varies from tissue to tissue,
likely depending on the tissue-specific gene regulated by
ER on the chromosome.
Therefore, one cannot conclude that the SD is
insensitive to estrogens and the results of BPA studies
with BPA should be ignored. In fact, there are several
studies reporting low dose effects that used the SD rat. A
comparison of the uterotrophic data from the OECD
study with EE, BPA, and other estrogens does not
indicate that the SD rat is less sensitive to any estrogen
versus the Wistar. In this study, oral EE at 1 mg/kg/day
for 3 days stimulated uterine weight whereas 0.3 mg/kg/
day was uterotrophic when administered s.c. In addition,
in the pubertal female rat assay, EE, the antiestrogen
tamoxifen and the estrogenic pesticide methoxychlor
produced equivalent responses in the Long–Evans and
SD female rats.
Although some have hypothesized that the Crl: CD
(SD) rat is more insensitive to estrogens than SD rats