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

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0, 75, 150 or 300 mg/kg bw per day by gavage for 21 days. Only rats that displayed regular 4-day
estrous cycles for 2 weeks were used in the study. Blood for serum hormone concentrations (E2,
progesterone) was taken from rats that displayed a pattern of vaginal diestrus for 10 days. After the
21-day treatment period, all females were ovariectomized (the day of ovariectomy was selected by
using the vaginal smear pattern) and the ovaries were examined microscopically.
In both strains, dosing at 75 mg/kg bw per day disrupted the 4-day ovarian cycle; however, no
distinct alteration (i.e. irregular cycles but not persistent estrus or diestrus) was apparent at this dose.
At 150 mg/kg bw per day, atrazine induced repetitive pseudopregnancies in females of both strains.
The highest dose tested (300 mg/kg bw per day) also induced repetitive pseudopregnancies in the
Sprague-Dawley females, while the ovaries of the LE hooded females appeared regressed and the
smear cytology was indicative of the anestrous condition.
A NOAEL was not identified; however, the doses employed were in excess of those used in
long-term feeding studies in which an early onset of mammary gland tumours was noted. These data
demonstrate that atrazine can disrupt ovarian function and bring about major changes in the endocrine
profile of the female rat (Cooper et al., 1996).
In a pilot study designed to determine the validity of a proposed protocol for testing the effect
of exposure to atrazine on the proestrous afternoon LH surge, E2 as estradiol benzoate was given to
70 ovariectomized female Sprague-Dawley rats (Crl:CD BR) through a subcutaneously surgically
implanted capsule. Serum concentrations of LH, E2, and prolactin were measured 3 days later at 2-h
intervals. The results showed that nearly all of the rats had E2 concentrations within the desired range
of 75–150 pg/ml in the hour preceeding and during the rise of LH. There was a peak in LH secretion
at 16:00 biological time, while prolaction showed a peak at 14:00 biological time and a return
to baseline values by 24:00 biological time. The results were consistent with numerous published
reports of LH and prolactin surges in intact cycling female rats, thus demonstrating the validity of the
experimental method (Morseth, 1996a).
In a study of method validation designed to determine the optimum experimental methods
to be used for testing the integrity of the LH surge in atrazine-treated female rats, E2 (as estradiol
benzoate) was given to 20 ovariectomized female Sprague-Dawley (Crl:CD BR) rats through a subcutaneously
surgically implanted capsule. Ten rats were used as a control group for the vehicle (0.5%
aqueous carboxymethyl-cellulose), and ten rats were given atrazine (purity, 97.1%) by oral gavage
for 3 days, beginning the day after surgery. The rats were subsequently bled at designated intervals
(11:00, 13:00, 15:00, 18:00 and 22:00 biological time), and serum LH and prolactin concentrations
were measured. Results indicated that the LH surge was attenuated in rats treated with atrazine at
15:00, the time range in which the peak LH surge is expected to occur in young intact rats. Prolactin
concentrations rose over the course of the day, but failed to return to the expected baseline level late
in the day in the control group and in the rats treated with atrazine, which was considered to be a
response to the stress of repeated jugular bleeding (Morseth, 1996b).
In a study designed to evaluate the effects of atrazine on the pre-ovulatory LH surge and on the
estrous cycle, groups of 90 female Sprague-Dawley (Crl:CD BR) rats received diets containing atrazine
(purity, 97.1%) at a concentration of 0, 25, 50 or 400 ppm (equal to 0, 1.8, 3.65 and 29.44 mg/kg bw per
day) for 26 weeks. The study was conducted in compliance with GLP guidelines. Vaginal smears were
evaluated for 2-week periods each 4 weeks. Ten days before beng killed, the rats were ovariectomized,
and 3 days before being killed a capsule releasing E2 was implanted subcutaneously. The rats were
killed by decapitation in groups of 10 or 15 at designated intervals (11:00, 14:00, 16:00, 18:00, 20:00
and 23:00 biological time), and blood samples were analysed for LH, prolactin and E2. Serial blood
samples were drawn without anaesthesia at the same time-point from an additional group of 10 rats and
ATRAZINE 37–138 JMPR 2007