Investigation of Mode-of-action and Human Relevance of Cumene-Induced Mouse Liver Tumors.

Chronic inhalation exposure of mice to high concentrations of cumene resulted in liver tumors. The aim of this review was to investigate the mode of action (MOA) for these tumors and their relevance to humans. A pilot study demonstrated the activation of constitutive-androstane receptor (CAR) and induction of hepatocyte proliferation following 7-day oral gavage of 1000 mg/kg/day cumene to female C57BL/6 mice. The induction of hepatic enzyme activities in the pilot study was consistent with CAR activation. In a 5-day inhalation study, activation of the CAR nuclear receptor, as indicated by induction of hepatic Cyp2b10 transcripts, was observed in C57BL/6 and B6C3F1, but not in CAR/Pregnane-X-Receptor knock-out (CAR/PXR-KO) female mice. Hepatocyte proliferation was identified only in cumene-exposed wild-type, but not in CAR/PXR-KO, mice. The MOA data were integrated with other existing findings for alignment with CAR-mediated MOA to determine whether alternative mechanisms may be excluded. The weight-of-evidence was evaluated using the evolved Bradford Hill criteria for causality. In addition, a human relevance framework analysis of cumene-induced liver tumors was conducted. This evaluation concluded that the CAR-mediated MOA is responsible for cumene-induced mouse liver tumors, and these tumors are not relevant to humans based upon qualitative and quantitative differences between species.