Factors affecting mammary tumor incidence in chlorotriazine-treated female rats: hormonal properties, dosage, and animal strain.

Abstract

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 [3H]-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 of 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 treatmentrelated 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 it 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 of 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. -Environ Health Perspect 1 02 (Suppl 11):29-36 (1994)

Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses

“…The possible common mechanism underlying the abnormal sexual development in the current study and reproductive abnormalities in reptiles and mammals has significant implications for environmental and public health. The effects observed in mammals were dismissed as a concern for public health because the exposure levels were very high (20)(21)(22)(23)(24)(25)(26)(32)(33)(34)(35)(36)(37)(38). The effective doses in the current study, however, demonstrate the sensitivity of amphibians relative to other taxa, validate the use of amphibians as sensitive environmental monitors͞sentinels, and raise real concern for amphibians in the wild.…”

“…Previous studies have suggested that atrazine is an endocrine disruptor, but these effects have been observed in a single strain of rat or were produced only at high doses (32)(33)(34)(35)(36)(37)(38). In fact, no published studies have addressed effects of atrazine at concentrations considered safe in drinking water or safe for limited human exposure-3 and 200 parts ppb, respectively (39).…”

Promoting Effects of Ethinylestradiol but not Atrazine on <i>N</i>-ethyl-<i>N</i>-nitrosourea-induced Uterine Carcinogenesis in ICR Mice

“…With regard to the carcinogenicity, ATR at a dose of 750 ppm induced mammary carcinomas and uterine endometrial adenocarcinomas in F344 rats over 24 months 12 . In addition, chronic feeding of high dietary levels of ATR increased the number of days in estrus and fastened the onset of mammary tumors in female Sprague-Dawley rats 22,34 . However, in the present study, there was no modifying effect of ATR on uterine carcinogenesis.…”

“…It has been reported that SD rats given 400 ppm ATR in food to rats for 12 months had an increased number of days of vaginal estrous, increased levels of plasma estradiol, and decreased levels of plasma progesterone by the treatment for 9 to 12 months 22 . In addition, the incidence of uterine adenocarcinomas has been shown to increase in F344 rats by the treatment of ATR over 24 months 22 . Based on these reports, it is likely that uterine tumors are induced by ATR treatment over 26 weeks by prolonged-hormonal influence in the mice model.…”

“…The maximum tolerated oral dose (MTD) in chronic toxicity studies has been estimated to be 300 ppm in the diet (50 mg/kg body weight) in rats 21 . Eldridge et al reported that estrogenic effects such as prolonged diestrus and persistent estrus of estrus cycle were seen in SD rats by the administration of 400 ppm ATR in the diet by 26 weeks 22 . In our previous study in which female p53(+/-) mice received an intraperitoneal injection of 120 mg/kg body weight of ENU followed by a diet containing 400 ppm ATR, no significant differences on the development of uterine proliferative lesions were observed in the ENU + ATR group as compared to the ENU alone group (unpublished data).…”