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Use of isolated hepatocytes to predict measured hepatic clearance of five polyaromatic hydrocarbons by perfused trout livers
Citation:
Fay, K., P. Fitzsimmons, A. Hoffman, AND J. Nichols. Use of isolated hepatocytes to predict measured hepatic clearance of five polyaromatic hydrocarbons by perfused trout livers. Presented at Society of Toxicology, March 10 - 14, 2013.
Impact/Purpose:
not applicable
Description:
Measured rates of in vitro hepatic clearance by fish have been used by several authors as inputs to predictive models for chemical accumulation. The resulting predictions are consistent with observed trends in bioaccumulation and provide a proof of principal for the approach. Questions remain, however, concerning the utility of different in vitro metabolizing systems, the accuracy of several in vitro-to-in vivo extrapolation factors, and the role of protein binding as a determinant of free chemical concentration. In this study, fresh and cryopreserved hepatocytes isolated from sexually immature male and female rainbow trout (Oncorhynchus mykiss) were used to measure the in vitro intrinsic clearance (CLin vitro,int) of five polyaromatic hydrocarbons. These CLin vitro,int values were then extrapolated to the intact organ and compared to measured levels of clearance (CLH) by isolated perfused trout livers. To facilitate these comparisons, hepatocellularity scaling factors were determined for male and female trout. In addition, solid phase microextraction (SPME) methods were employed to determine unbound chemical concentrations in vitro and in the isolated liver preparation. Generally, the hepatocytes performed well in predicting CLH rates exhibited by perfused livers. Hepatocellularity and binding values were not different between the sexually immature male and female trout. Furthermore, predicted CLH values for the five compounds did not differ between the sexes. Finally, CLH values determined using both hepatocytes and isolated perfused livers were extrapolated to the whole animal and incorporated into a one-compartment bioconcentration model. Model-predicted bioconcentration factors (BCF) were consistent with measured values for fish.