Thiamethoxam (
CGA293343; 3-(2-chloro-thiazol-5-ylmethyl)-5-methyl-[1,3,5]oxadiazinan-4-ylidene-N-nitroamine) was shown to increase the incidence of mouse liver
tumors in an 18-month study; however,
thiamethoxam was not hepatocarcinogenic in rats.
Thiamethoxam is not genotoxic, and, given the late life generation of mouse liver
tumors, suggests a time-related progression of key hepatic events that leads to the
tumors. These key events were identified in a series of studies of up to 50 weeks that showed the time-dependent evolution of relatively mild
liver dysfunction within 10 weeks of dosing, followed by frank signs of hepatotoxicity after 20 weeks, leading to cellular attrition and regenerative
hyperplasia. A metabolite, CGA330050, was identified as generating the mild hepatic toxicity, and another metabolite, CGA265307, exacerbated the initial toxicity by inhibiting
inducible nitric oxide synthase. This combination of metabolite-generated hepatotoxicity and increase in cell replication rates is postulated as the mode of action for
thiamethoxam-related mouse liver
tumors. The relevance of these mouse-specific
tumors to human health was assessed by using the framework and decision logic developed by ILSI-RSI. The postulated mode of action was tested against the Hill criteria and found to fulfill the comprehensive requirements of strength, consistency, specificity, temporality, dose-response, and the collective criteria of being a plausible mode of action that fits with known and similar modes of action. Whereas the postulated mode of action could theoretically operate in human liver, quantitation of the key metabolites in vivo and in vitro showed that mice, but not rats or humans, generate sufficient amounts of these metabolites to initiate the hepatic toxicity and consequent
tumors. Indeed, rats fed 3000 ppm
thiamethoxam for a lifetime did not develop hepatotoxicity or
tumors. In conclusion, the coherence and extent of the database clearly demonstrates the mode of action for mouse liver
tumorigenesis and also allows for the conclusion that
thiamethoxam does not pose a carcinogenic risk to humans.