Hypothesis for mammary tumorigenesis in Sprague‐Dawley rats exposed to certain triazine herbicides

Abstract

The symmetrical triazine herbicides have been used for the preemergence control of broadleaf weeds for nearly three decades. Recently, certain members of this class, primarily the chlorotriazines (substituted in the 2 position), have been shown to evoke an increased incidence of mammary tumors in female Sprague-Dawley rats. This response was noted when these chemicals were administered in the diet for 2 yr, and most often at dietary feeding levels at or above the maximum tolerated dose (MTD). At levels exceeding the MTD the health of these animals was compromised, as manifested by toxicity-related reduced survival that was not associated with the occurrence of mammary tumors. Mammary tumors in rats frequently occur as a result of the influence of endogenous estradiol and prolactin. Those hormones, as well as progesterone, growth-stimulating, luteinizing, and follicle-stimulating hormones, were measured after 24 mo of dietary administration of the chlorotriazine, simazine. The plasma hormone pattern seen in aged female Sprague-Dawley rats administered 1000 ppm simazine in the diet for 24 mo resembled that noted for aged female controls, except that the difference was more pronounced in the simazine-treated group. These results suggest that prolonged exposure of Sprague-Dawley females to excessive levels of triazines affects the neuroendocrine system, which in turn alters the pathology of the mammary gland. These changes are comparable to those that occur naturally as the rat ages. Changes in neuroendocrine control could result in the expression of an earlier onset and/or an increased incidence of mammary tumors, which already occur at a high spontaneous rate in aging Sprague-Dawley female rats.

Possible enhancing effects of atrazine and nonylphenol on 7,12‐dimethylbenz[a]anthracene‐induced mammary tumor development in human c‐Ha‐ras proto‐oncogene transgenic rats

“…48) However, in other investigations, mammary tumor development was only noted in SD and not F344 rats, and only at or above a threshold dose (the MTD) that interferes with normal estrous cycling, causing prolonged exposure to endogenous estrogen. 16,17) SD rats exhibiting persistent estrus also have a prolonged elevation of estrogen secretion, so 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. 10) Chloro-S-triazine herbicides, such as cyanazine (CZ), atrazine (AZ), simazine (SZ), increased mammary tumors in Crl:CD BR rats, but not in F344 rats or in mice, but this is mediated through a prolactin mechanism not relevant to humans.…”

“…A number of studies have suggested that atrazine is an endocrine disruptor [8][9][10][11][12][13][14][15] and in female Sprague-Dawley, but not other strains of rats, high doses (50-1000 ppm) in the diet have been found to be associated with an increased incidence and/or an earlier onset of mammary gland tumors. [16][17][18][19][20] Alkylphenol polyethoxylates are the second largest group of nonionic surfactants in commercial production. They find practical application, not only in detergents, but also in paints, herbicides, pesticides, and many other formulated products.…”

New aspects on atrazine biodegradation

“…Comparing the acute toxicity of 40 herbicides exerting nine different modes of action on the green alga Raphidocelis subcapitata, Ma et al (2006) found that photosynthesis was the most sensitive process, and atrazine was among the most toxic herbicides tested. Triazinic compounds such as atrazine, simazine, propazine, as well their metabolites, mainly 2-hydroxyatrazine, diaminochlorotriazine, deethylatrazine and deisopropylatrazine, were shown to induce mammary gland tumors in Sprague-Dawley (SD) female rats (Stevens et al, 1994). Atrazine has also been suggested to be a potential disruptor of normal sexual development in male frogs (Hayes et al, 2002;Murphy et al, 2006) as well as to alter some aspects of the immune response (Christin et al, 2004).…”

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.…”

“…These data may suggest the species difference between the rat and mouse. With regard to the mammary tumorigenesis, several previous studies showed that female SD rats administered ATR at doses close to the MTD had an increased incidence of mammary tumors or revealed their early induction 34,35 . On the contrary, other studies with a similar experimental protocol of male SD rats, female or male Fischer 344 rats, or female or male CD-1 mice have failed to demonstrate an ATR treatment-related alteration in the mammary tumor incidence 21,23,24 .…”