FACTORS AFFECTING MAMMARY-TUMOR INCIDENCE IN CHLOROTRIAZINE-TREATED FEMALE RATS - HORMONAL PROPERTIES, DOSAGE, AND ANIMAL STRAIN

Chlorotriazines are widely used in agriculture as broadleaf herbicides. The compounds specifically inhibit photosynthesis, and, as such, display little interaction with animal systems. However, a 24-month feeding study with atrazine (ATR) revealed a significant dose-related increase of mammary tumors in female Sprague-Dawley (SD) rats. Because numerous studies indicated that ATR had a low mutagenic and oncogenic potential, it was decided to test a hypothesis that the herbicide possessed endocrine activity. Among tests for estrogenic action, oral dosing of ATR up to 300 mg/kg did not stimulate uterine weight of ovariectomized rats. However, ATR administration did reduce estrogen-stimulated uterine weight gain. Further evidence of inhibition came from measures of [H-3]-thymidine incorporation into uterine DNA of ATR-treated immature rats. Again, no intrinsic estrogenic activity was observed up to a 300-mg/kg dose. In vitro, ATR competed poorly against estradiol binding to cytosolic receptors, with an approximate IC50 or 10(-5) M. Atrazine administration to SD and Fischer-344 (F-344) rats for 12 months, up to 400 ppm in food, was correlated with significant alterations of estrous cycling activity, but there was a divergent strain response. SD rats showed an increased number of days in vaginal estrus, increased plasma estradiol, and decreased plasma progesterone by 9 to 12 months of treatment. F-344 rats rdid not demonstrate treatment-related affects, A study of ultrastructure in the hypothalamic arcuate nucleus of female SD rats that were fed diaminochlorotriazine (DACT), an ATR metabolite, suggested that age-associated glial pathology was enhanced by treatment. It is proposed that antiestrogenic actions of ATR are able to disrupt critical hormone-mediated functions at very high dose levels. In SD rats, this disruption delays ovulation. maintains estrogen secretion from ovarian follicles, and produces a hormonal milieu more conducive to mammary tumors. Aging in F-344 rats promotes higher progesterone secretion, and ii is predicted that mammary tumors would not be increased in ATR-fed F-344 animals. It is also concluded that the risk of ATR-related mammary tumors in humans would be quite low because of the unique response oi the SD rat estrous cycle, the nature of stimulated mammary tumors in rats, and the extremely high dose levels and concentrations required for ATR to express activity in vivo and in vitro.