Comparison of different in vitro hepatocyte models for in vitro to in vivo extrapolation of liver-mediated thyroid hormone clearance in rats

Beas Bhattacharya¹, Helen Tinwell², Claudia Lopez Zazueta², Ahtasham Raza³, Rashin Ghaffari³, Josiah McKenna¹, Zachary Sutake¹, Enrica Bianchi¹, Jessica LaRocca¹ 

¹Corteva Agriscience, Indianapolis, IN, United States. ²Bayer SAS, Lyon, France ³Corteva Agriscience, Haskell R&D Center, Newark, DE

Background and Purpose: 

Traditionally, rodent repeat dose studies have been used to describe liver-mediated thyroid effects and the key events for this mode of action (MoA) to support the human non-relevance of the adverse thyroid outcomes. The rodent liver-mediated thyroid hormone clearance has been recognized as not relevant to human health due to quantitative differences between species. Here we have utilized in vitro new approach methodologies (NAMs) to characterize rodent thyroid toxicity and establish human relevance without significant animal use. Given the quantitative differences between rat and human liver functions, it is crucial to illustrate the key event relationships underlying thyroid disruption and the liver-thyroid adverse outcomes in rodents. These alternative approaches can also help reduce animal testing by substituting some in vivo assays for thyroid endpoints. We have investigated two in vitro hepatocyte models for liver-induced thyroid toxicity and applied quantitative in vitro to in vivo extrapolation (QIVIVE) for the biological and mechanistic characterization of hepatic UGT induction and T4 clearance and metabolism in rats.