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A risk characterization for atrazine: oncogenicity profile
J T Stevens1, C B Breckenridge, L Wetzel
1Toxicology, Novartis Crop Protection, Inc., Greensboro, North Carolina 27419, USA. james.stevens@cp.novartis.com.
Abstract:
An extensive safety database has been developed for the chlorotriazine herbicide, atrazine. The results from five oncogenicity studies conducted in the Sprague-Dawley rat, two studies in the Fischer 344 rat, and two studies in the CD-1 mouse were reviewed. No increase in the incidence of tumors of any type was observed in male or female Fischer 344 rats, male or female CD-1 mice, or male Sprague-Dawley rats fed atrazine at a maximum tolerated level in their diet for 24 mo. Female Sprague-Dawley rats fed atrazine at levels of 400, 500, and 1000 ppm developed mammary tumors earlier than did the control group. The incidence of female Sprague-Dawley rats with mammary tumors after 24 mo of treatment was statistically increased at feeding levels of > or = 70 ppm in 1 study and at 400 ppm in a second study, whereas there were no significant differences between the treated and the control group in 3 other studies. No increase in tumors of any type was observed in ovariectomized female Sprague-Dawley rats after 24 mo of atrazine treatment at the highest level tested, 400 ppm. Therefore, the mammary tumor response in female Sprague-Dawley rats following the administration of high levels of atrazine appears to be due to an acceleration of the normal reproductive aging process resulting in increased exposure to endogenous estrogen and prolactin. The Sprague-Dawley rat differs from the Fischer 344 rat, the CD-1 mouse, and humans in the endocrine control mechanisms affecting reproductive senescence and the development of the mammary tumors during aging. These data indicate that the carcinogenic effect of high doses of atrazine observed in the female Sprague-Dawley is a strain-, sex-, and tissue-specific response that does not have biological relevance to humans.
Insights
Atrazine herbicide safety was evaluated in multiple rodent studies. High doses caused mammary tumors in female Sprague-Dawley rats by accelerating aging, a response not relevant to humans.
Area of Science:
- Toxicology
- Carcinogenesis
- Endocrinology
Background:
- Atrazine is a widely used chlorotriazine herbicide.
- Extensive safety data, including oncogenicity studies, are available for atrazine.
- Rodent models are frequently used to assess herbicide safety and potential carcinogenicity.
Purpose of the Study:
- To review oncogenicity studies on atrazine in Sprague-Dawley rats, Fischer 344 rats, and CD-1 mice.
- To determine the relevance of observed tumor responses to human health.
- To investigate the mechanisms underlying potential atrazine-induced carcinogenicity.
Main Methods:
- Review of five oncogenicity studies in Sprague-Dawley rats, two in Fischer 344 rats, and two in CD-1 mice.
- Administration of atrazine at maximum tolerated levels for 24 months.
- Analysis of tumor incidence and correlation with dose levels and specific rat strains/sexes.
Main Results:
- No increased tumor incidence in Fischer 344 rats, CD-1 mice, or male Sprague-Dawley rats.
- Increased incidence and earlier onset of mammary tumors in female Sprague-Dawley rats at high atrazine doses (≥70 ppm).
- No increased tumors in ovariectomized female Sprague-Dawley rats, suggesting an endocrine-mediated mechanism.
Conclusions:
- The mammary tumor response in female Sprague-Dawley rats is linked to accelerated reproductive aging and hormonal changes (estrogen, prolactin).
- This response is specific to the Sprague-Dawley rat strain, sex, and mammary tissue.
- The observed carcinogenic effect of high-dose atrazine in this specific rat model is not considered biologically relevant to humans.