Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

120
greater, and in a 26-week study with atrazine at doses of 3.65 mg/kg bw per day and greater. Consistent
with attenuation of the LH surge, disruption of the estrous cycle was seen in a 3-week study with
atrazine at doses of 75 mg/kg bw per day and greater, and in a 26-week study at doses of 3.65 mg/
kg bw per day and greater. Owing to the failure to ovulate and the subsequent persistent exposure
to endogenous estrogen and prolactin, hyperstimulation of the mammary gland (increase in acinarlobular
development indicative of increased exposure to estrogen; increase in secretory activity and
galactocoele formation indicative of increased exposure to prolactin) was observed with atrazine at
doses of 20 mg/kg bw per day and greater, while increased incidences of mammary tumours were
found at doses of 3.1 mg/kg bw per day and greater.
Generally, there was a good correlation between the doses causing attenuation of the LH surge
and those causing an earlier onset and/or an increased incidence of mammary tumours.
5. Temporal association
The key events, such as attenuation of the LH surge and disruption of the estrous cycle were
observed after a single high dose of atrazine at 300 mg/kg bw, after a 3-day or 3-week exposure at
doses of 50 or 75 mg/kg bw per day and greater, respectively, and after a 26-week exposure at doses
of 3.65 mg/kg bw per day and greater. In 2-year studies in rats, the onset-time for initial palpation of
mammary masses was decreased when compared with controls (14 weeks at approximately 20 mg/kg
bw per day vs 29 weeks in controls), while the incidence of palpable mammary masses was increased
at interim kill (weeks 52–54) after exposure to atrazine at approximately 20 mg/kg bw per day. Thus,
there is a logical temporal response with all key events preceding tumour formation.
6. Strength, consistency and specificity of association of tumour response with key events
The key events were observed consistently in a number of studies with differing experimental
designs. On the basis of information from the studies described in the monograph, there is sufficient
weight of evidence that the key events (attenuation of the LH surge, disruption of the estrous cycle)
are linked to the morphological changes in the mammary gland indicative of stimulation of estrogen
and prolactin (increase in acinar-lobular development, increase in secretory activity and galactocoele
formation) which precede the occurrence of tumours. In addition, there is a substantial independent
literature on the role of estrogen and prolactin in the pathogenesis of mammary tumours in rats. There
are no significant contradictory data.
7. Biological plausibility and coherence
The relationship between sustained perturbation of the hypothalamic–pituitary axis (change of
the regulation of GnRH pulsatility, attenuation of the LH surge), disruption of the estrous cycle, persistent
secretion of estrogen and prolactin, prolonged stimulation of the mammary gland by endogenous
estrogen and prolactin, and the development of mammary gland tumours is considered to be
biologically plausible and has been shown in several studies in laboratory rats.
In long-term bioassays with natural and synthetic estrogens, it has been established that prolonged
stimulation of the mammary gland with estrogen leads to development of adenocarcinomas.
In contrast, high-level stimulation of the mammary gland with prolactin has been shown to be linked
to the development of fibroadenoma.
The tumour response elicited by atrazine is typical of a rodent mammary-gland carcinogen
in that mammary tumours are found in female Sprague-Dawley rats but not in male rats or mice.
Rats tend to be more sensitive to mammary-gland carcinogenesis than mice, and female rats are
frequently found to be more sensitive than male rats with respect to the proportion of chemicals
that induce mammary tumours. Consistent with this, concentrations of estrogen and prolactin are
typically higher in female rats than in males.
ATRAZINE 37–138 JMPR 2007