Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: A case study of lindane-induced XXXX .

@entity1 @entity410 @entity137 @entity35 @entity2359
UNASSIGNED: Approaches for extrapolating in vitro @entity137 testing results for prediction of @entity1 in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane @entity2359 . Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced @entity2359 in rodents and @entity1 . Time- and concentration-dependent lindane dosimetry was determined in primary cultures of @entity35 cortical neurons in vitro using "faux" (without electrodes) microelectrode arrays (MEAs). In vivo data were derived from literature values, and physiologically based pharmacokinetic (PBPK) modeling was used to extrapolate from @entity35 to @entity1 . The previously determined EC50 for increased firing rates in primary cultures of cortical neurons was 0.6 g/ml. Media and cell lindane concentrations at the EC50 were 0.4 g/ml and 7.1 g/ml, respectively, and cellular lindane accumulation was time- and concentration-dependent. @entity35 blood and brain lindane levels during @entity410 were 1.7-1.9 g/ml and 5-11 g/ml, respectively. Brain lindane levels associated with @entity410 in @entity35 and those predicted for @entity1 (average=7 g/ml) by PBPK modeling were very similar to in vitro concentrations detected in cortical cells at the EC50 dose. PBPK model predictions matched literature data and timing. These findings indicate that in vitro MEA results are predictive of in vivo responses to lindane and demonstrate a successful modeling approach for IVIVE of @entity35 and @entity1 @entity2359 .
