The mammary tumor response in triazine-treated female rats: a threshold-mediated interaction with strain and species-specific reproductive senescence.

Triazine herbicides are among the most heavily used agricultural pesticides. Although they possess a very low acute toxicity in animals, a mammary tumor response has been consistently observed in Sprague-Dawley (SD) female rats following chronic oral dosing of atrazine and simazine at and above maximum tolerated doses. However, a substantial collection of detailed research has clearly shown that triazines are not genotoxic or mutagenic, nor do they possess estrogenic agonist activity that might promote mammary tumor growth. Examination of estrous cycling records of atrazine-treated SD rats revealed a premature appearance of persistent estrous episodes, beyond the prevalent occurrence normally seen in untreated, aging SD rats. A significant correlation has been found between early or severe estrous cycle disruption of atrazine-treated rats and the early appearance of mammary tumors. In studies using SD female rats fed atrazine for 6 months, then ovariectomized and administered an estrogen-containing silastic s.c. implant, a deficient luteinizing hormone surge was observed at a 400 parts per million (ppm) dose, but not at 25 or 50 ppm. Because SD rats exhibiting persistent estrus also have a prolonged elevation of estrogen secretion, it is proposed that the triazine-associated mammary tumor response is promoted by the test animal's own estrogen from ovarian follicles that fail to ovulate because gonadotropin surge sufficiency is blocked by the high dose of herbicide. It is further proposed that, because reproductive senescence in SD rats is fundamentally different from menopause in women, the animal response to dosing, as well as the enormous requisite dosing level, establishes a safety margin of very low risk to human health from this mode of action.