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

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From the rats in the supplementary study of carcinogenicity described above (Thakur, 1991a), the
ovaries, uterus, vagina, mammary gland and pituitary were re-evaluated microscopically for specific
indications of reproductive senescence, which might relate to the onset-time of hormonally-mediated
mammary tumours.
The histomorphological evaluation of the reproductive organs and mammary and pituitary
glands revealed no evidence of any exogenous estrogenic effect associated with atrazine. This observation
was on the basis of the absence of histomorphological changes which occur with administration
of exogenous estrogen. Vaginal epithelial morphology in treated and control groups was similar.
There was no increased mitotic activity in the basal layer, no significant increase in cornification (an
estrogenic response), no suppression of mucification, and no increase in exaggerated rete pegs in
treated animals when compared with that in controls. The lack of exogenous estrogenicity was also
evident in senescent rats that had progressed into the phase of extended diestrus (pseudopregnancy)
when increased endogenous progesterone activity is expressed. E2 directly antagonizes progesterone
and if exogenous estrogenicity associated with atrazine had been present, extended diestrus would
have been suppressed or inhibited.
Ovarian histomorphology showed that anovulatory cycles (ovaries without corpora lutea) were
slightly increased at 400 ppm at 3 months and were present in all rats at 9 months. A similar trend
in anovulatory cycles was present in rats in the control group and at 70 ppm but was less frequent.
Thus, the period between 3 and 9 months was critical in the development of irregular estrous cycles
and development of the first stages of reproductive senescence. Morphological alterations in ovarian
follicular and corpora lutea development and interstitial clear cells of rats at 400 ppm indicated a
treatment-related interference of the LH surge and prolonged exposure of LH-responsive cells in the
interstitial gland to endogenous LH. These changes, exacerbated in rats at 400 ppm between 9 and
12 months, suggested that atrazine had modulated LH secretion.
Changes in the mammary glands, characterized by increased acinar/lobular development,
secretory activity with duct ectasia, and galactocoele formation, occurred as early as 3 months and
were more frequent and severe at 400 ppm than at 70 ppm or in the control group for 1 year. After
1 year, the mammary changes were balanced in all groups. The mammary-gland changes in rats
treated with atrazine were similar in type and degree to those observed during early and later phases
of reproductive senescence in rats in the control group. They have been shown to occur by imbalances
of endogenous estrogen, progesterone and prolactin.
The Meeting concluded that atrazine induced the earlier appearance of reproductive senescence
in Sprage-Dawley rats by gradually interfering with ovulation and causing estrous cycles
characterized by extended periods of proestrus/estrus. Although changes characteristic of reproductive
senescence occurred earlier in rats at 400 ppm, the stages of senescence tended to equalize with
those of the rats at 70 ppm and in the control group after 1 year of treatment (McConnell, 1995).
In a supplementary study of carcinogenicity designed to evaluate the oncogenic potential of
atrazine in the ovaries, pituitary, uterus and mammary gland, groups of 60 female Sprague-Dawley
rats were fed diets containing atrazine (purity, 97%) at a concentration of 0, 70 and 400 ppm, equivalent
to 0, 3.5 and 20 mg/kg bw per day, for 104 weeks. At termination, all surviving rats were killed
and uterus, ovary, pituitary, and mammary glands from all rats were examined microscopically for
oncogenic effects. The study was conducted in compliance with GLP guidelines.
No treatment-related increases in clinical signs were noted in the study. A slight reduction in
survival was found in the group at the highest dose. Body-weight gains were statistically significantly
reduced relative to controls (12–13%) at 400 ppm during weeks 0–76. Non-neoplastic lesion findings
were comparable in controls and treatment groups. At 400 ppm, the onset-time for palpable masses
in the mammary region (confirmed histologically as mammary fibroadenomas and/or carcinomas)
ATRAZINE 37–138 JMPR 2007