Monsanto and CXR Biosciences, the investigative toxicology company, are pleased to announce the presentation of a joint poster at the upcoming Eurotox meeting. The poster describes studies performed at CXR to determine the mode of action and human relevance of rodent liver tumours induced by a fungicide.
A slightly increased incidence of liver tumours was observed at the highest dose level in a two-year rat feeding study. The mode of action and human relevance of these tumours was evaluated in a two-week rat study and in studies using cultured rat and human hepatocytes.
A substantial increase in hepatocellular proliferation (9-fold), slightly increased liver weights and minor liver histopathology were observed in the two-week study. Marked increases in CYP2B (as indicated by an ~13-fold increase in enzyme activity and ~1200-fold increase in gene expression) and lesser (~3-fold) increases in CYP3A were also observed. CYP4A was either unchanged or slightly decreased. These results strongly suggest that the mode of action for the hepatic effects, including the slightly increased incidence of liver tumours, is via activation of the CAR and possibly PXR nuclear receptors.
Strong CAR/PXR activation and increased hepatocellular proliferation following test item exposure were also observed in studies with cultured rat hepatocytes. In contrast, cultured human hepatocytes exhibited only weak CAR/PXR activation and no evidence of hepatocellular proliferation when exposed to the fungicide. The absence of a proliferative response in human hepatocytes, even at cytotoxic concentrations, indicates that the test item would be highly unlikely to cause liver tumours in humans. Therefore, the slightly increased incidence of liver tumours at the high-dose level in the two-year rat feeding study is not considered to be relevant to humans.
The poster will be presented by Monsanto at Eurotox in Edinburgh on Monday 8th September from 9.30am – 10.30am and 12.30pm to 1.30pm.
Founded in 2001, CXR Biosciences® uses its collaborative approach and toxicological expertise to help customers large and small solve issues relating to the safety of compounds or selection of research candidates. CXR Biosciences® offers tailored preclinical services in the areas of investigative & mechanistic toxicology, exploratory & discovery toxicology and PK & metabolism. Our customers include leading pharmaceutical, agrochemical, chemical, consumer product and biotechnology companies. CXR Biosciences® is located in Dundee, Scotland, United Kingdom.