Atrazine and breast cancer: a framework assessment of the toxicological and epidemiological evidence.

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."

Atrazine interaction with estrogen expression systems.

More than 40 publications have described results of atrazine responses in 17 estrogen-dependent systems and in more than a dozen different reporter and estrogen receptor-binding studies in vitro. Results from these studies have consistently failed to demonstrate that atrazine acts as an estrogen agonist. Moreover, a variety of indices of estrogen-dependent activity, in models that encompass cell incubations to whole animals, have failed to respond to atrazine. Researchers in more than a dozen laboratories have examined rats, rat tissues, human and prokaryotic cells, in addition to tissues from reptile, fish, amphibian, avian, molluscan, and insect sources, without eliciting estrogenic-like responses from atrazine. In contrast, studies of atrazine ability to antagonize estrogen-mediated responses have yielded equivocal results. Results of several studies show inhibition of estrogen-like activities by atrazine, yet many other tests have yielded negative results. Generally, in vivo models have more consistently shown that atrazine inhibits estrogen-mediated responses, whereas in more specific in vitro systems, inhibition is seldom observed. The implication is that in vivo effects of atrazine may result from inhibition of factors that are indirectly connected to the genomic interaction of estrogen (e.g., at the receptor). Potential targets of atrazine may be downstream of the ligand-receptor binding event. Atrazine may also interact with other, less specific, factors that are necessary for the completion of the estrogen-mediated response. Moreover, the apparent inhibition of cytosolic-ER binding by atrazine may, similarly, be relatively nonspecific. Observed inhibitory responses occur only at extreme doses or concentrations, i.e., several orders of magnitude greater than the level of estradiol presence in each test system. It is probable that the inhibitory effects result from very low affinity and/or low specificity interactions, which are unlikely to occur in nature. We conclude that atrazine is not an estrogen receptor agonist, but it may be a weak antagonist, when present at a high concentration under conditions of disequilibrium with estrogen. These conditions are not expected to occur as a result of normal environmental exposure.

Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment.

The Food Quality Protection Act (FQPA) of 1996 requires the United States Environmental Protection Agency to consider the cumulative effects of exposure to pesticides having a 'common mechanism of toxicity.' This paper reviews the information available on the acute neurotoxicity and mechanisms of toxic action of pyrethroid insecticides in mammals from the perspective of the 'common mechanism' statute of the FQPA. The principal effects of pyrethroids as a class are various signs of excitatory neurotoxicity. Historically, pyrethroids were grouped into two subclasses (Types I and II) based on chemical structure and the production of either the T (tremor) or CS (choreoathetosis with salivation) intoxication syndrome following intravenous or intracerebral administration to rodents. Although this classification system is widely employed, it has several shortcomings for the identification of common toxic effects. In particular, it does not reflect the diversity of intoxication signs found following oral administration of various pyrethroids. Pyrethroids act in vitro on a variety of putative biochemical and physiological target sites, four of which merit consideration as sites of toxic action. Voltage-sensitive sodium channels, the sites of insecticidal action, are also important target sites in mammals. Unlike insects, mammals have multiple sodium channel isoforms that vary in their biophysical and pharmacological properties, including their differential sensitivity to pyrethroids. Pyrethroids also act on some isoforms of voltage-sensitive calcium and chloride channels, and these effects may contribute to the toxicity of some compounds. Effects on peripheral-type benzodiazepine receptors are unlikely to be a principal cause of pyrethroid intoxication but may contribute to or enhance convulsions caused by actions at other target sites. In contrast, other putative target sites that have been identified in vitro do not appear to play a major role in pyrethroid intoxication. The diverse toxic actions and pharmacological effects of pyrethroids suggest that simple additivity models based on combined actions at a single target are not appropriate to assess the risks of cumulative exposure to multiple pyrethroids.