Should Atrazine and Related Chlorotriazines Be Considered Carcinogenic for Human Health Risk Assessment?

Chloro-s-triazines have been a mainstay of preemergent pesticides for a number of decades and have generally been regarded as having low human toxicity. Atrazine, the major pesticide in this class, has been extensively studied. In a number of experimental studies, exposure to high doses of atrazine resulted in increased weight loss not attributable to decreased food intake. Chronic studies of atrazine and simazine and their common metabolites show an elevated incidence of mammary tumors only in female Sprague Dawley (SD) rats. On the basis of the clear tumor increase in female SD rats, atrazine was proposed to be classified as a likely human carcinogen by US Environmental Protection Agency (EPA) in 1999. With Fischer rats, all strains of mice, and dogs, there was no evidence of increased incidence of atrazine-associated tumors of any type. Evidence related to the pivotal role of hormonal control of the estrus cycle in SD rats appears to indicate that the mechanism for mammary tumor induction is specific to this strain of rats and thus is not relevant to humans. In humans the menstrual cycle is controlled by estrogen released by the ovary rather than depending on the LH surge, as estrus is in SD rats. However, the relevance of the tumors to humans continues to be debated based on endocrine effects of triazines. No strong evidence exists for atrazine mutagenicity, while there is evidence of clastogenicity at elevated concentrations. Atrazine does not appear to interact strongly with estrogen receptors α or β but may interact with putative estrogen receptor GPR30 (G-protein-coupled receptor). A large number of epidemiologic studies conducted on manufacturing workers, pesticide applicators, and farming families do not indicate that triazines are carcinogenic in these populations. A rat-specific hormonal mechanism for mammary tumors has now been accepted by US EPA, International Agency for Research on Cancer, and the European Union. Chlorotriazines do influence endocrine responses, but their potential impact on humans appears to be primarily on reproduction and development and is not related to carcinogenesis.