In Vitro-In Vivo Extrapolation of Hepatic Biotransformation Data for Fish. III. An In-depth Case Study with Pyrene.

Computational models that predict chemical bioaccumulation in fish generally account for biotransformation using an apparent first-order whole-body rate constant (k ; d ). The use of such models requires, therefore, that methods exist for estimating k , ideally without the need to expose live animals. One promising approach for estimating k involves the extrapolation of measured in vitro intrinsic clearance (CL ) to the whole animal (in vitro-in vivo extrapolation, [IVIVE]). To date, however, the accuracy of such predictions has been difficult to assess due to uncertainties associated with one or more extrapolation factors and/or a mismatch between fish used to generate in vitro data and those used to conduct in vivo exposures. In the present study we employed a combined in vitro and in vivo experimental approach to evaluate the IVIVE procedure using pyrene (PYR) as a model chemical. To the extent possible, measured rates of CL were extrapolated to estimates of k using extrapolation factors based on measured values. In vitro material (liver S9 fraction) was obtained from fish exposed to PYR in a controlled bioconcentration study protocol. Fish from the same study were then used to estimate in vivo k values from an analysis of chemical depuration data. Averaged across four study groups, k values estimated by IVIVE underestimated those determined from in vivo data by 2.6-fold. This difference corresponds to a 4.1-fold underestimation of true in vivo intrinsic clearance, assuming the liver is the only site of biotransformation. These findings are consistent with previous work performed using mammals and have important implications for use of measured CL values in bioaccumulation assessments with fish. Environ Toxicol Chem 2023;42:1501-1515. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.