Models Used to Predict Chemical Bioaccumulation in Fish from In Vitro Biotransformation Rates Require Accurate Estimates of Blood-Water Partitioning and Chemical Volume of Distribution.

Methods for extrapolating measured in vitro intrinsic clearance to a whole-body biotransformation rate constant (k B ) have been developed to support modeled bioaccumulation assessments for fish. The inclusion of extrapolated k B values into existing bioaccumulation models improves the prediction of chemical bioconcentration factors (BCFs), but there remains a tendency for these methods to overestimate BCFs relative to measured values. Therefore, a need exists to evaluate the extrapolation procedure to assess potential sources of error in predicted k B values. Here we examine how three different approaches (empirically-based, composition-based, and poly parameter linear free energy relationships [ppLFERs]) used to predict chemical partitioning in vitro (liver S9 system; K S9W ), in blood (K BW ), and in whole fish tissues (K FW ) impact the prediction of a hepatic clearance binding term (f U ) and a chemical's apparent volume of distribution (V D ), both of which factor into the calculation of k B and the BCF. Each approach yielded different K S9W , K BW , and K FW values, but resulted in f U values that are of similar magnitude and remain relatively constant at log K OW >4. This is because K BW and K S9W values predicted by any given approach exhibit a similar dependence on log K OW (i.e., regression slope), which results in a cancelation of "errors" when f U is calculated. In contrast, differences in K BW values predicted by the three approaches translate to differences in V D , and by extension k B and the B CF, which become most apparent at log K OW >6. There is a need to collect K BW and V D data for hydrophobic chemicals in fish that can be used to evaluate and improve existing partitioning prediction approaches in extrapolation models for fish. This article is protected by copyright. All rights reserved. Environ Toxicol Chem 2022;00:0-0. © 2022 SETAC.