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 res ponse has been consistently observed in Sprague-Dawley(SD) female rats Foll owing chronic oral dosing of atrazine and simazine at and above maximum tol erated doses. However, a substantial collection of detailed research has cl early shown that triazines are not genotoxic or mutagenic, nor do they poss ess estrogenic agonist activity that might promote mammary tamer growth. Ex amination 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 correla tion has been found between early or severe estrous cycle disruption of atr azine-treated rats and the early appearance of mammary tumors. In studies u sing SD female rats fed atrazine for 6 months, then ovariectomized and admi nistered an estrogen-containing silastic s.c. implant, a deficient luteiniz ing 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 triaz ine-associated mammary tumor response is promoted by the test animal's own estrogen from ovarian follicles that fail to ovulate because gonadotropin s urge sufficiency is blocked by the high dose of herbicide. It is further pr oposed that, because reproductive senescence in SD rats is Fundamentally di fferent from menopause in women, the animal response to dosing, as well as the enormous requisite dosing level, establishes a safety margin of very lo w risk to human health from this mode of action. (C) 1999 Elsevier Science Inc. All rights reserved.