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

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The NOAEL was 25 ppm, equal to 1.8 mg/kg bw per day, on the basis of estrous cycle alterations
and attenuation of the LH surge at 50 ppm (Morseth, 1996c).
In a study on the effects of atrazine on the hypothalamic control of pituitary-ovarian function in
the rat, the estrogen-induced surges of LH and prolactin were examined in ovariectomized Sprague-
Dawley and LE rats treated with atrazine (purity, 97.1%) by gavage for 1, 3 or 21 days. Rats treated
for 1 day were ovariectomized and received a subcutaneous estrogen implant on day 0, and then
atrazine at a dose of 0, 50, 100, 200 or 300 mg/kg bw on day 3, and were killed at 0, 1, 3 or 6 h after
treatment. Rats treated for 3 days were ovariectomized and received a subcutaneous estrogen implant
on day 0, and then atrazine at a dose of 0, 50, 100, 200 or 300 mg/kg bw per day on days 1–3, and
were killed at 0, 1, 3 or 6 h after treatment on day 3. Rats treated for 21 days were ovariectomized on
day 0, and then received atrazine at a dose of 0, 75, 150 or 300 mg/kg bw per day on days 1–21, followed
by a subcutaneous estrogen implant on day 21 and were killed on day 24 at the time of expected
peak LH concentration.
Atrazine at the highest single dose (300 mg/kg bw) significantly suppressed the LH and prolactin
surge in ovariectomized LE rats, but not in Sprague-Dawley rats. Treatment with atrazine on three
consecutive days suppressed the estrogen-induced LH and prolactin surges in ovariectomized LE
females in a dose-dependent manner at 50 mg/kg bw and greater, but this same treatment was without
effect on serum LH and prolactin in Sprague-Dawley females. Also in LE females, exposure to atrazine
at a dose of 50 mg/kg bw and greater inhibited the decrease in pituitary prolactin concentration
that was observed in rats in the control group. After 21 days of treatment with atrazine, there was a
significant dose-dependent suppression of serum LH and prolactin in both strains at all doses, while
the concentration of prolactin in the pituitary was significantly increased in both strains at all doses.
In a further experiment conducted to determine the effect of a single dose of atrazine on ovulation
and ovarian cycling, intact female LE rats displaying regular 4-day estrous cycles received
atrazine at a dose of 0, 75, 150 or 300 mg/kg bw on the day of vaginal proestrus, and vaginal smears
were examined for 3 weeks in half of the rats in each group, while in the remaining rats, oocytes
were collected and quantified on the day of vaginal estrus. Atrazine administered at the highest dose
of 300 mg/kg bw induced a pseudopregnancy in seven of nine females, but was without effect on
ovulation.
Three further experiments were performed to determine whether the brain, pituitary or both
organs were target sites for atrazine. These included examination of the ability of: (a) the pituitary
lactotrophs to secrete prolactin, using hypophysectomized females bearing pituitary autotransplants
(ectopic pituitaries) in female LE rats receiving atrazine as a single dose at 300 mg/kg bw; (b) the
synthetic GnRH to induce LH secretion in ovariectomized LE rats treated with atrazine at a dose of
300 mg/kg bw for 3 days; and (c) atrazine (administered in vivo or in vitro) to suppress LH and prolactin
secretion from pituitaries, using a flow-through perfusion procedure. The results indicated that:
(a) the secretion of prolactin by the pituitary was not altered by atrazine if the gland was removed
from the influence of central nervous sytem factors; (b) the effect of atrazine on LH secretion was
not a result of a direct impairment of LH release from the pituitary; and (c) direct exposure of the
pituitary had no effect on the release of LH and prolactin.
In summary, the experiments demonstrated a clear effect of atrazine on the estrogen-induced
LH and prolactin surge in female LE and Sprague-Dawley rats. LE rats appeared to be more sensitive
to the hormone-suppressive effects of atrazine than Sprague-Dawley rats. The results support the
hypothesis that the effects of atrazine on LH and prolactin secretion are mediated via a hypothalamic
site of action (Cooper et al., 2000).
In a study designed to compare the effects of atrazine and its metabolite DACT on the the
pre-ovulatory LH surge, groups of 20 female Sprague-Dawley [Crl:CD BR] rats were given atrazine
(purity, 97.1%) or DACT (purity, 96.8%) at a dose of 2,5, 5, 40 or 200 mg/kg bw per day by oral
ATRAZINE 37–138 JMPR 2007