Endocrine Activity Studies on Bisphenol A
Background on Endocrine Disruption
Endocrine Disruption and Bisphenol A
Estrogenic Activity of Bisphenol A
Low-Dose Endocrine Effects
on Endocrine Disruption
Our Stolen Future, a book published in 1996, popularized
the theory that natural and man-made substances that
exhibit hormone-like properties in the laboratory can
affect wildlife populations, thus speculating that humans
may be at risk of "hormone disruption." While
this theory has been widely discussed in the open scientific
literature, it caught the public's attention resulting
in a U.S. Congressional mandate to test man-made chemicals
for any hormonal properties.
Since that time there have been hundreds of published
studies testing the hypothesis, including assays that
show a positive response. These assays are often misused
to label certain substances "endocrine disrupters,"
although a more accurate term, "hormonally active
agents," was recently coined by the U.S.
National Academy of Sciences.
To date, the mechanisms through which hormonally active
agents act in a living organism have not been documented,
although a number of theories have been proposed. The
research community in cooperation with government agencies
and industry are working to clarify and characterize
any risks posed by hormonally active agents in the environment.
Disruption and Bisphenol A
There is no known risk from environmentally relevant
exposures of bisphenol A to humans, wildlife or the
Bisphenol A exhibits extremely weak hormonal activity
in test tube assays, such as those utilizing yeast or
human breast cancer cells. Effects have also been observed
in compromised laboratory animals at high doses of bisphenol
A. However, reproduction and development are not affected
by relatively high levels of bisphenol A in multi-generational
studies, which are designed to detect disruptions in
normal hormone activity (doses are compared to the extremely
low levels of possible consumer exposure).
Activity of Bisphenol A
The estrogenic activity of bisphenol A (BPA) has been
identified over the past several decades. The earliest
reference noted for the estrogenic action of BPA was
a report of a bioassay for a positive estrus response,
as measured by cornification in vaginal smears, that
occurred in ovariectomized rats dosed (route unspecified)
twice daily with 100 mg BPA dissolved or suspended in
sesame oil on three successive days (Dodds and Lawson,
1936). In this study, the effective estimated daily
dose was 800 mg/kg/day (100 mg/250 grams body weight/twice
A more comprehensive study was reported in 1970 (Bitman
and Cecil, 1970) in which DDT and 52 structurally related
compounds, including BPA, were injected subcutaneously
into immature rats. Estrogenic activity was measured
18 hours following dosing by measuring uterine glycogen
content. The minimally effective dose of BPA to produce
an increase in uterine glycogen content was 0.25 mg/rat,
or about 5 mg/kg/day.
A series of similar studies were undertaken in rats
by the National Institute for Occupational Safety and
Health (NIOSH) (Bond et al., 1980); also personal communication
from NIOSH to Morrissey, et al. mentioned in Morrissey,
et al., (1987). In these studies ovariectomized rats
were administered BPA: intraperitoneally (50-130 mg/kg),
orally (1250 mg/kg, dermally (8000 mg/kg), or via inhalation
(156 mg/m3 for 6 hours), and, following various times,
estrogenic activity was confirmed by measuring changes
in percentage uterine water.
An example of a more recent reference demonstrating
estrogenic activity of BPA is an in vitro study where
levels of BPA were found to induce progesterone receptors
in cultured human mammary cancer cells (MCF-7) at a
potency of 5000 times less than estradiol. BPA also
increased the rate of proliferation of MCF-7 cells,
and competed with estradiol for estrogen receptor binding
sites (Krishnan, et al., 1993).
These studies have shown that BPA possesses estrogenic
activity in special experimental systems. However, it
is not at all clear how these results can be related
to specific toxicologic endpoints that are relevant
to human health. For example, estrogenic activity was
mainly identified in ovariectomozed rats or in even
less relevant in vitro models. In addition, estrogenic
activity was seen in animals administered large doses
of BPA or animals exposed via only experimental routes
of exposure, such as intraperitoneally or subcutaneously.
For a discussion of bisphenol A and low-dose endocrine effects research, click here.