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

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There were no effects on clinical signs, survival or organ weights. A slight retardation of bodyweight
gain (82–89% of controls) and feed consumption (88–95% of controls) were seen at the
highest dose. The results of plasma hormone analyses were not reported. There were no statistically
significant differences in the incidence of mammary gland adenomas, fibroadenomas or adenocarcinomas
at up to 400 ppm. When the incidences of mammary adenomas, fibroadenomas and adenocarcinomas
were combined for analysis, a statistically significant increase in the incidence of rats
with mammary tumors was observed at 400 ppm (Table 8). There were no significant trends or group
differences for onset-time of mammary gland adenomas, fibroadenomas or adenocarcinomas. However,
a significant positive trend for onset-time existed when mammary gland adenomas and fibroadenomas
were combined or when adenomas, fibroadenomas and adenocarcinomas were combined. No
trend was evident when the group at the highest dose (400 ppm) was excluded from the analysis.
The NOAEL for incidence of mammary tumours and onset-time was 70 ppm, equal to 4.1 mg/kg
bw per day (Pettersen & Turnier, 1995).
In a supplementary study of carcinogenicity designed to determine the incidence and onset of
mammary tumours, groups of 80 ovariectomized or intact female Sprague-Dawley Crl:CD BR rats
were fed diets containing atrazine (purity, 97.1%) at a concentration of 0, 25, 50, 70 or 400 ppm,
equal to 0, 1.2, 2.5, 3.5 and 20.9 mg/kg bw per day in ovariectomized females and 0, 1.5, 3.1, 4.2 and
24.4 mg/kg bw per day in intact females, respectively. After 52 weeks of treatment, 20 rats in each
group were killed and necropsied, and the surviving rats were killed after 104 weeks of treatment.
Daily examinations for mortality, morbidity, and indications of toxic effects were performed. There
were no clinical pathology investigations. Palpation for tissue masses in rats was performed before
the initiation of dosing and weekly thereafter. Necropsies and complete histological examinations
were performed on all rats. The study was conducted in compliance with GLP guidelines.
Survival and body-weight gain of ovariectomized rats was markedly better than that of intact
rats, and there was no dose-related effect on survival among ovariectomized females. However, there
was significantly impaired survival among intact females at the highest dose. Body-weight gain at the
highest dose was impaired in intact and in ovariectomized rats, demonstrating a maximum tolerated
dose (MTD) to be achieved.
In the ovariectomized rats, there were no treatment-related increases in mammary-gland
proliferative changes and mammary tumours were not present in any of the rats. The lack of mammary
tumours in ovariectomized rats provides evidence that the mode of action of atrazine is neither
a direct genotoxic nor an estrogenic effect on the mammary gland. Rather, an indirect hormonallymediated
effect involving the ovary is implied.
In sexually intact rats, the incidence of palpable masses and of histological mammary neoplasia
was higher than in ovariectomized females, and a statistically significant increased incidence of
mammary neoplasia was seen at doses of 50 ppm and greater compared with the concurrent control
group. When compared with the data for historical controls from the same laboratory (on the basis
of 14 studies), only in the group at 400 ppm did incidences exceed the pooled incidence values for
either fibroadenoma or carcinoma. An earlier onset and increased incidence of mammary carcinoma
were observed only in the intact rats at 400 ppm (Table 9). The study authors therefore concluded
that increases in mammary tumours at 50 and 70 ppm did not represent part of a carcinogenic dose–
response trend.
However, the comparison with data for historical controls considers carcinoma and fibroadenoma
in isolation but not as a combined analysis (i.e. all rats bearing mammary tumours). Also, the
spacing of doses between the two intermediate doses (50 and 70 ppm) is small in terms of normal
design for studies of carcinogenicity, and is possibly too small to prudently allow for dose–response
differentiation. Were the groups at 50 and 70 ppm to be combined, this would result in a statistically
significantly increased incidence of tumours, which would be part of a clear trend.
ATRAZINE 37–138 JMPR 2007