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

0.002, 0.02, and 2 mg/kg bw/day for 6 days. Epididymal
sperm were collected 22 days after the end of bisphenol
A treatment and multicolor fluorescent in situ hybridization
was used to evaluate decondensed sperm for
aneuploidy. Sperm count was decreased by bisphenol
A 0.002 mg/kg bw/day, but there was no increase in the
frequency of hyperhaploidy or diploidy. Bisphenol A was
negative in a bone marrow micronucleus test at dose
levels up to 2 mg/kg/day for 2 days.
2.4. Carcinogenicity
No human data examining the carcinogenicity of
bisphenol A were identified.
NTP (1982) and Huff (2001) examined carcinogenicity
of bisphenol A in F344 rats and B6C3F1 mice. Animals
were randomly assigned to treatment groups. Bisphenol
A(o98.2% purity) was administered through feed for
103 weeks to 50 rats/sex/dose at 0, 1000, or 2000 ppm, 50
male mice/group at 0, 1000, or 5000 ppm, and 50 female
mice/group at 0, 5000, or 10,000 ppm. NTP estimated
mean bisphenol A intakes of 74 and 148 mg/kg bw/day
for male rats and 74 and 135 mg/kg bw/day for female
rats. [Data on bisphenol A intake, food intake, and
body weights were not provided for mice.] Using
default values, the European Union (2003) estimated
bisphenol A intakes of 120 and 600 mg/kg bw/day in
male mice and 650 and 1300 mg/kg bw/day in female
mice. Concentration and stability of bisphenol A in feed
were verified. Body weights and clinical signs were
observed during the study. Following the exposure
period, animals were killed and necropsied. Organs,
including seminal vesicle, prostate, testis, ovary, and
uterus, were preserved in 10% neutral buffered formalin
and examined histologically. Statistical analyses included
Cox and Tarone methods, 1-tailed Fisher exact test,
Bonferroni inequality criterion, Cochran-Armitage test,
and life table methods for linear trend.
In rats, body weights of males and females from both
dose groups were lower than controls throughout the
study. Feed intake was decreased in females of both dose
groups beginning at Week 12. No adverse effects on
survival were observed. There were no non-neoplastic
lesions [including in male and female reproductive
organs] that appeared to be treatment-related. The
incidence of leukemia was increased in males (13 of 50,
12 of 50, and 23 of 50 in control and each respective dose
group) and females (7 of 50, 13 of 50, and 12 of 50). In
males the trend for leukemia was significant by Cochran-
Armitage test, but statistical significance was not shown
by life table analysis for trend or incidence in the highdose
group, according to the unpublished version of the
study. The published version of the study indicated
statistical significance at the high-dose. Statistical significance
was not attained for leukemia incidence in
female rats. An increased incidence of testicular interstitial
cell tumors (35 of 49, 48 of 50, 46 of 49) was
statistically significant in both dose groups. An increased
incidence of mammary fibroadenomas in males of the
high-dose group (0 of 50, 0 of 50, and 4 of 50) achieved
statistical significance for trend by Cochran-Armitage
test but not by Fisher exact test. In bisphenol A groups,
there were decreased incidences of adrenal pheochromocytomas
in males, adrenal cortical adenomas in
females, and uterine endometrial stromal polyps. The
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NTP concluded that none of the increases in tumor
incidence in rats was clearly associated with bisphenol A
exposure.
In mice, body weights were lower in high-dose males
and in females of both dose groups. Feed intake could
not be accurately determined because of spillage. Bisphenol
A did not affect the survival of mice. Incidence
of multinucleated hepatocellular giant cells was increased
in treated males (1 of 49, 41 of 49, and 41 of
50). [A review of the data indicated no increases in
incidence of non-neoplastic lesions in the reproductive
organs of male or female mice.] The incidence of
leukemia or lymphoma in male mice by dose group (2
of 49, 9 of 50, and 5 of 50) was not statistically significant.
The published version of the report indicated an
increasing trend for lymphoma. The linear trend for
increased pituitary chromophobe carcinomas in male
mice (0 of 37, 0 of 36, 3 of 42) was reported to be
statistically significant by Cochran-Armitage test but
statistical significance was not shown by Fisher exact
test. The study authors concluded that none of the
increases in tumor incidence in mice could be unequivocally
associated with bisphenol A exposure.
NTP concluded that under the conditions of this study,
there was no convincing evidence the bisphenol A was
carcinogenic in F344 rats or B6C3F 1 mice. However,
study authors stated that there was suggestive evidence
of increased cancer in the hematopoietic system based on
marginally significant increases in leukemia in male rats,
non-statistically significant increases in leukemia in
female rats, and a marginally significant increase in
combined incidence of lymphoma and leukemia in male
mice. A statistically significant increase in testicular
interstitial cell tumors in aging F344 rats was also
considered suggestive evidence of carcinogenesis. The
effect was not considered conclusive evidence because of
the high incidence of the testicular neoplasm in aging
F344 rats (88% incidence in historical controls).
The NTP study was reviewed by the European Union
(2003) and Haighton et al. (2002). For increases in
leukemia, mammary gland fibroadenoma, and Leydig
cell tumors in male rats, both groups noted the lack of
statistical significance using the appropriate analyses and
the common occurrence of these tumor types in F344 rats.
The European Union (2003) concluded, ‘‘Overall, all of
these [tumor] findings in rats and mice are not considered
toxicologically significant. Consequently, it is concluded
that bisphenol A was not carcinogenic in this study in both
species.’’ Haighton et al. (2002) concluded, ‘‘Overall, the
results of this bioassay did not provide any compelling
evidence to indicate that [bisphenol A] was carcinogenic
in F344 rats or in B6C3F 1 mice.’’ Based on the experimental
animal data, the European Union concluded that
‘‘ythe evidence suggests that bisphenol A does not have
carcinogenic potential.’’ Using a weight of evidence
approach, Haighton et al. (2002) concluded that bisphenol
A was not likely to be carcinogenic to humans. This
conclusion was based on NTP study results; lack of
activity at noncytotoxic concentrations in both in vitro
genetic toxicity tests and in an in vivo mouse micronucleus
test; and data from metabolism studies that show
rapid glucuronidation and no formation of possibly
reactive intermediates, with the possible exception of
reactive intermediates potentially generated as a result of
saturated detoxification pathways at high-doses.