Prediction of human response to chemical exposures is the primary challenge of pharmaceutical and environmental toxicology research. The complexity of human responses to xenobiotic exposures presents significant challenges to modeling and multi-faceted characterization of toxicological and pharmacological dynamics. At the National Toxicology Program, we are developing novel approaches to estimate human hepatic response to xenobiotic exposures through development and application of physiologically-relevant in vitro liver models. In particular, we have focused on modeling functionally-relevant drug metabolism competence and metabolic activation of xenobiotics associated with liver injury including environmental compounds (benzo(a)pyrene & aflatoxin) and pharmaceuticals (e.g., cyclophosphamide, troglitazone, & trovafloxacin). Pairing these differentiated cell culture models with high dimensional assay platforms (e.g., high throughput transcriptomics, cell health) has enabled development and qualification of new approach methods that leverage the biological relevance of 3D culture models with the resolving power of concentration-response modeling. This includes quantitative estimation of liver injury potential with unknown chemical exposures. The results have revealed the power of resolution achieve through concentration-response modeling to characterize and de-convolute the complexities of biological response to xenobiotic exposures towards translational application and toxicological interpretation.
1. Understand the impact of 3D cell culture on liver metabolism modeling in vitro
2. Become familiar with data-driven estimations of liver injury potential in response to xenobiotic exposures using high throughput transcriptomics