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The relationship between increased concentrations of estradiol (E2) and prolactin and
tumours of the mammary gland in female rats is further supported by the fact that tumours of the
mammary gland tumours do not occur in female Sprague-Dawley rats ovariectomized at an early
age and treated with atrazine, as concentrations of E2 and prolactin are both minimal in these
females.
8. Other modes of action
Genotoxicity is always one possible MOA to consider, but in a large range of in studies of
genotoxicity in vitro and in vivo with atrazine, mostly negative results were obtained in tests using
standard methods. The weight of evidence suggests that it is unlikely that atrazine is genotoxic.
This conclusion is also supported by the fact that atrazine did not induce a tumorigenic response in
ovariectomized rats, while genotoxic carcinogens like dimethylbenz[a]anthracene and N-methyl-Nnitrosourea
are capable of inducing mammary tumours in ovariectomized rats.
In addition, a possible intrinsic estrogenic activity of atrazine was considered. However, the
majority of in-vitro studies reported that atrazine did not competitively bind to the rat cytosolic
estrogen or progesterone receptors. Also, exposure to atrazine in vivo did not induce uterine growth
nor increase the number of progesterone receptors in ovariectomized rats. Thus, the development of
tumours of the mammary gland in female rats exposed to atrazine does not seem to be related to any
intrinsic estrogenic activity of the compound.
Furthermore, studies in rats indicated no evidence for any atrazine-induced upregulation of
aromatase expression in the brain, testes, or mammary gland.
9. Uncertainties, inconsistencies, and data gaps
No inconsistencies were identified in the database for atrazine with regard to the postulated
MOA for mammary-gland tumours in female rats.
However, the precise mechanism by which atrazine disrupts the neuronal control of hypothalamic
GnRH secretion in the rat remains to be determined.
10. Assessment of postulated MOA
There is sufficient experimental evidence that atrazine disrupts the neuroendocrine control of
ovarian function in Sprague-Dawley rats, which leads to premature reproductive senescence (i.e. constant
estrus) and a hormonal milieu conducive to the development of mammary gland tumours. The
strength, consistency, and specificity of the available MOA information for female Sprague-Dawley
rats is further confirmed by data showing that Fischer 344 rats, which have a different reproductive
senescence, do not develop atrazine-related mammary tumours. Alternative hypotheses have been
ruled out, such as genotoxicity, estrogenic activity or upregulation of aromatase expression, further
showing the strength and specificity of the proposed MOA
II.
Can human relevance of the MOA be reasonably excluded on the basis of fundamental,
qualitative differences in key events between experimental animals and humans?
The MOA for the formation of mammary tumours in female Sprague-Dawley rats after exposure
to atrazine depends on the rat-specific nature of the reproductive cycle and reproductive senescence.
Because of the fundamental differences between female Sprague-Dawley rats and humans with
regard to both the normal regulation of the pre-ovulatory LH surge and the reproductive senescence,
the mammary tumorigenic effects of atrazine in female Sprague-Dawley rats are not expected to
occur in humans.
ATRAZINE 37–138 JMPR 2007