Mode Of Action Of Atrazine For Mammary Tumor Formation In The Female Sprague-Dawley Rat

Atrazine is a widely used agricultural herbicide. It inhibits plant photosynthesis but has very low toxicity in animals and humans. However, long-term high-dose studies using Sprague-Dawley (SD) female rats revealed an increased incidence or earlier appearance of mammary tumors. The mammary tumor response was unique to the SD female rat and was not seen in the male SD rat, three strains of mice, or the Fischer 344 (F-344) rat, which more closely models the human female than the SD rat. A high spontaneous incidence of mammary tumors occur naturally in aged SD female rats, and it was of interest to determine if the response noted with atrazine could be related to the mechanism underlying their normal occurrence.Because mammary tumors in rats are usually promoted by estrogens and/or prolactin, the possibility that atrazine impacts hormonal activity has been investigated in a large number of published studies; however, no evidence of estrogenicity or prolactin-stimulating activity has been reported. It has been observed, however, that estrous cycles can be disrupted by very high doses of atrazine in the SD rat, which can lead to an increased percentage of lifetime days with elevated estrogen levels. The estrogen is present as a secretion from ovaries, which appear not to ovulate.Additional research has found that high doses of atrazine administered to female SD rats - acutely or chronically - reduce the output of luteinizing hormone (LH), a pituitary hormone that is necessary for timely ovulation and normal estrous cycling. This specific inhibitory mechanism of atrazine action is a key step in the mode of action responsible for mammary tumors in the SD rat.Reduced LH secretion, disrupted estrous cycling, and an internal environment supportive of mammary tumor growth are all normal occurrences in aging SD rats, and it appears that administering atrazine enhances these normal, age-related events. The F-344 rat that is not as disposed to these age-related events was also unresponsive to atrazine for the disruption of estrous cycles, in addition to being unresponsive to atrazine for the development of mammary tumors. Because the reproductive decline as women age toward menopause does not progress in the same manner as in SD female rats, it is highly unlikely that atrazine could have a similar effect in women. Furthermore, the no-effect levels for this set of responses in the SD rat are thousands of times greater than potential human exposure. Data support the conclusion that current exposure levels to atrazine would not pose a threat to human reproductive health from the mechanisms observed in test rodents. These data also support the conclusion that atrazine is not likely to cause cancers in humans.