Case Study: Weight of Evidence Evaluation of the Human Health Relevance of Thiamethoxam-Related Mouse Liver Tumors

• DOI: 10.1093/toxsci/kfi126
• Publication Date: 2005-02-17T01:34:09Z
• Authors: Timothy Pastoor; Patrick Rose; Sara Lloyd; Richard Peffer; Trevor Green
• Keywords: Mode of Action

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