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

eproductive success were only 7-fold lower than the 96hr
median lethal concentration, and concluded that the
reproductive effects may have been the result of
sublethal generalized toxicity rather than effects
mediated through the endocrine axis.
Strengths/Weaknesses: This study was well-conducted
with multiple dose levels and concentrations in
the test water were confirmed. ‘‘General toxicity’’ was
identified and good histology was used. The conclusions
regarding weak estrogenic activity were appropriate at
160 mg/L and higher. Other effects were likely due to
general toxicity. A classic dose response was noted.
Utility (Adequacy) for CERHR Evaluation Process:
Fish are apparently a sensitive model for assessment of
responses to weak estrogenic compounds. Given that this
study evaluated a fish species, it is not useful in the
evaluation.
Kang et al. (2002), supported by the Japanese Ministry
of the Environment, exposed adult (4-month-old) breeding
pairs of medaka (Oryzias latipes) to bisphenol A
(499% purity) in the water at 0, 1000, or 4000 mg/L for 3
weeks [culture ware not discussed]. Bisphenol A
concentrations during the exposure period were 78–
86% of nominal concentrations. Thirty-two pairs of fish
had been selected for exposure during an acclimatization
period based on their capacity to spawn daily, with the
production of Z15 eggs/day and 90% fertility. During
the exposure period, eggs were collected daily and
assessed for fertility. Fertilized eggs collected on the last
3 days of the exposure period were permitted to develop
in untreated water, and 60 larvae/group were grown for
60 days after hatching to assess normalcy of development.
The parent fish were killed at the end of the
treatment period for evaluation of external sex characteristics
and for histologic assessment of the gonads.
Hepatic vitellogenin was also assessed. Statistical comparisons
of egg number were made using ANCOVA with
female body weight as a covariate. Fertility, growth
endpoints, and hepatic vitellogenin data were analyzed
with ANOVA or Kruskal–Wallis test with post-hoc
Dunnett or Mann–Whitney U test. There were no
treatment effects on egg number, fertility, mortality,
relative gonad weight, or relative liver weight in the
adult fish. Ovarian tissue was found in the testis in some
males in all bisphenol A-treated groups, although normal
testicular tissue with apparently normal spermatogenesis
was also found. Hepatic vitellogenin was increased in
male fish in the high-dose group to control female levels.
There were no treatment-related alterations in hepatic
vitellogenin in female fish. Offspring at 60 days of age
did not demonstrate treatment-related alterations in
survival, growth, or secondary sex characteristics. The
sex ratio was not significantly different in offspring of
parents exposed to bisphenol A, although the authors
noted that the low-dose group had a numerical deficit of
males (41% males compared to 50% in the controls). The
authors concluded that although bisphenol A increased
hepatic vitellogenin in males and produced an intersex
gonad, there were no adverse effects on reproductive
capacity or the normalcy of offspring.
Strengths/Weaknesses: This appears to have been a
well conducted study. The bisphenol A findings are
consistent with the work of others, using sensitive
endpoints in fish such as vitellogenin production. Given
the nature of the intersex gonad observation, it should be
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
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considered as adverse even though the severity was not
sufficient to induce decreases in reproductive capacity
under the conditions tested.
Utility (Adequacy) for CERHR Evaluation Process:
This study indicates that bisphenol A is able to induce
vitellogenin in male fish and intersex gonads. This study
exhibited classic dose responses in the affected endpoints.
Because this study was conducted in fish, it is not
useful in the evaluation.
Lahnsteiner et al. (2005), supported by the Austrian
Federal Ministry of Agriculture, Forestry, Environment,
and Water Management, examined the effects of bisphenol
A exposure on reproduction of male and female
brown trout (Salmo trutta f. fario). Fish were caught and
acclimated for 2 weeks before starting the study. Ten
males/group and 6 females/group were exposed in a
flow-through system to bisphenol A at 0 (DMSO vehicle),
1.75, 2.4, or 5.00 mg/L beginning in the late prespawning
period and continuing through the remainder of the
spawning season [No information on purity or culture
ware was provided]. The bisphenol A concentrations
selected were said to occur in the Austrian water system.
Endpoints examined included time point of spawning,
sperm count and motility, ability of sperm to fertilize
eggs from non-treated females, and numbers and
viability of eggs produced by treated females. Statistical
analyses included ANOVA and Tukey b post-hoc test.
Throughout the entire spawning period, only 1 male in
the high bisphenol A dose group produced semen and it
was of low quality as indicated by significantly reduced
sperm density, motility rate, swimming velocity, and
fertility. In the low- and mid-dose groups, sperm density
was significantly reduced in the early spawning period
but was not affected in the mid or end part of the
spawning period. Additional significant effects observed
in the low-dose group included decreased sperm motility
in the early spawning period, reduced swimming
velocity in the early and middle spawning period, and
increased circular motion and decreased linear motion in
the middle of the spawning period. In the mid-dose
group, sperm motility and swimming velocity were
significantly decreased in the early and mid-spawning
period, and a significant increase in circular motion and
a decrease in linear motion occurred in the mid and late
part of the spawning period. The study authors
interpreted the sperm effects as representing a 4-week
delay in spawning. Fertility of males in the low- and middose
group was not affected by bisphenol A treatment.
In females, no eggs were produced by fish in the highdose
group. In all other dose groups, there were no
significant effects on egg volume, viability, mass, mass
increase during hardening, or on numbers of eggs
produced by females. However, ovulation was delayed
by 2 weeks in the low-dose group and by 3 weeks in the
mid-dose group. The study authors concluded that
exposure of trout to bisphenol A resulted in negative
effects on semen and egg quality.
Strengths/Weaknesses: In this study of fish, alterations
in sperm motility were observed consistent with
those observed in mice. Fertility effects in the female
were also similar to those observed in other species.
Weaknesses include a failure to determine the actual
bisphenol A concentrations in the test system, the narrow
dose range examined (1.75 to 5 mg/L), and the small
number of fish/dose level assessed.