Evaluation of the human relevance of chemically induced liver carcinogenesis by using chimeric mice with human hepatocytes

<p>Human carcinogenicity of chemicals is assessed mainly from the results of carcinogenicity studies using rodents. However, it has been known that there are many cases that the positive results of rat carcinogenicity studies are not relevant to human. Thus, in human risk assessments of chemicals, it is extremely important that human relevancy is evaluated by clarifying mode of action (MOA) of carcinogenicity and its species differences. </p><p>We evaluated human relevancy of rat hepatocellular tumors caused by synthetic pyrethroids (metofluthrin, momfluorothrin) in in vitro hepatocyte culture system, the nuclear receptor constitutive androstane receptor (CAR) knockout rats, and chimeric mice with human hepatocytes (PXB mouse). Using phenobarbital (PB) as a positive control, gene expressions, hepatocellular enzyme activities, and histopathological changes including hepatocellular proliferation were investigated. Consequently, it was revealed that both synthetic pyrethroids induced hepatocellular proliferation and tumor formation in rats by CAR activation in the same manner as PB, while no cell proliferation was induced in human hepatocytes in PXB mouse. Based on these results, we concluded that carcinogenic MOA of both pesticides is not relevant to human, and the European authority accepted our conclusion. Especially, PXB mouse is a useful model to evaluate effects on human hepatocytes. </p>