Atrazine and Breast Cancer: A Framework Assessment of the Toxicological and Epidemiological Evidence

Abstract

The causal relationship between atrazine exposure and the occurrence of breast cancer in women was evaluated using the framework developed by Adami et al. (2011) wherein biological plausibility and epidemiological evidence were combined to conclude that a causal relationship between atrazine exposure and breast cancer is “unlikely”. Carcinogenicity studies in female Sprague-Dawley (SD) but not Fischer-344 rats indicate that high doses of atrazine caused a decreased latency and an increased incidence of combined adenocarcinoma and fibroadenoma mammary tumors. There were no effects of atrazine on any other tumor type in male or female SD or Fischer-344 rats or in three strains of mice. Seven key events that precede tumor expression in female SD rats were identified. Atrazine induces mammary tumors in aging female SD rats by suppressing the luteinizing hormone surge, thereby supporting a state of persistent estrus and prolonged exposure to endogenous estrogen and prolactin. This endocrine mode of action has low biological plausibility for women because women who undergo reproductive senescence have low rather than elevated levels of estrogen and prolactin. Four alternative modes of action (genotoxicity, estrogenicity, upregulation of aromatase gene expression or delayed mammary gland development) were considered and none could account for the tumor response in SD rats. Epidemiological studies provide no support for a causal relationship between atrazine exposure and breast cancer. This conclusion is consistent with International Agency for Research on Cancer’s classification of atrazine as “unclassifiable as to carcinogenicity” and the United States Environmental Protection Agency's classification of atrazine as “not likely to be carcinogenic.”

Effect of Age, Duration of Exposure, and Dose of Atrazine on Sexual Maturation and the Luteinizing Hormone Surge in the Female Sprague–Dawley Rat

“…The estrogen‐induced peak LH (7 ng/ml) in the ovariectomized 7‐week female controls was approximately twofold greater than peak LH observed in the 20‐week females (3.5–4.0 ng/ml). This level was comparable to peak LH observed in 32‐week‐old female SD controls (Simpkins et al., 2011). It has been suggested that neuroendocrine aging of the hypothalamus–pituitary–gonadal (HPG) axis in female SD rats accounts for increased estrous cycle impairment, decreased LH titer during the LH surge, and increased vulnerability to the effect of ATZ (Simpkins et al., 2011).…”

“…It has been previously shown that high doses of ATZ accelerate reproductive aging in female SD rats, as indicated by the appearance of persistent estrus, commencing after approximately 6 to 9 months of treatment (Simpkins et al., 2011). Estrous cycle data collected in this study after 3 months of treatment indicate that there were no effects of treatment on the estrous cycle at doses up to 50 mg/kg/day; 2 weeks of ATZ treatment, beginning on PND 120, also had no effect.…”

“…It is known that the reproductive aging processes in rodents are unlike those observed in nonhuman primates and in women. Reproductive senescence in women is attributed to a depletion of ovarian follicles and not to an impairment of the hypothalamic control of the LH secretion during ovulation (Simpkins et al., 2011). The control of the LH surge in women is also mediated by mechanisms that are uniquely different from rodents (Plant, 2012).…”

“…Atrazine (ATZ) inhibits electron transport in the photosynthetic pathway (photosystem II) of plants by reversibly binding to the D1 protein (Devine et al., 1993; Trebst, 2008). Oral (gavage) administration of ATZ suppressed the estrogen‐induced (Simpkins et al., 2011) or estrogen‐plus‐progesterone‐induced (McMullin et al., 2004) luteinizing hormone (LH) surge in ovariectomized adult female Sprague–Dawley (SD) (Simpkins et al., 2011), Long Evans (Cooper et al., 2000, 2007), and Wistar (McMullin et al., 2004; Foradori et al., 2009a) rats. ATZ also suppressed the endogenous LH surge that occurs on the afternoon of proestrus in intact, normally cycling female SD rats when administered as a gavage bolus dose of 50 mg/kg/day, but not when administered as a temporally distributed dose in feed (500 ppm) at equivalent daily doses (Foradori et al., 2014).…”

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“…Atrazine was acknowledged by US EPA as Group C, i.e., possible human carcinogen (Donna et al, 1989). Mcelroy study suggests that a tumor was developed in the woman due to exposure of triazines (Mcelroy et al, 2007;Simpkins et al, 2011).…”