Thiamethoxam is a
neonicotinoid insecticide that is not a
mutagen, but it did cause a significant increase in
liver cancer in mice, but not rats, in chronic dietary feeding studies. Previous studies in mice have characterized a carcinogenicity mode of action that involved depletion of plasma
cholesterol, cell death, both as single cell
necrosis and as apoptosis, and sustained increases in cell replication rates. In a study reported in this article, female rats have been exposed to
thiamethoxam in their diet at concentrations of 0, 1000, and 3000 ppm for 50 weeks, a study design directly comparable to the mouse study in which the mode of action changes were characterized. In rats,
thiamethoxam had no adverse effects on either the biochemistry or histopathology of the liver at any time point during the study. Cell replication rates were not increased, in fact they were significantly decreased at several time points. The lack of effect on the rat liver is entirely consistent with the lack of liver
tumor formation in the two-year
cancer bioassay. Comparisons of the metabolism of
thiamethoxam in rats and mice have shown that concentrations of the parent chemical were either similar or higher in rat blood than in mouse blood in both single dose and the dietary studies strongly indicating that
thiamethoxam itself is unlikely to play a role in the development of liver
tumors. In contrast, the concentrations of the two metabolites, CGA265307 and CGA330050, shown to play a role in the development of liver damage in the mouse, were 140- (CGA265307) and 15- (CGA330050) fold lower in rats than in mice following either a single oral dose, or dietary administration of
thiamethoxam for up to 50 weeks. Comparisons of the major metabolic pathways of
thiamethoxam in vitro using mouse, rat, and human liver fractions have shown that metabolic rates in humans are lower than those in the rat suggesting that
thiamethoxam is unlikely to pose a hazard to humans exposed to this chemical at the low concentrations found in the environment or during its use as an
insecticide.