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 (kB) have been developed to support modeled bioaccumulation assessments for fish. The inclusion of extrapolated kB 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 kB values. We examined how three different approaches (empirically based, composition based, and polyparameter linear free energy relationships [ppLFERs]) used to predict chemical partitioning in vitro (liver S9 system; KS9W), in blood (KBW), and in whole fish tissues (KFW) impact the prediction of a chemical's hepatic clearance binding term (fU) and apparent volume of distribution (VD), both of which factor into the calculation of kB and the BCF. Each approach yielded different KS9W, KBW, and KFW values, but resulted in fU values that were of similar magnitude and remained relatively constant at log octanol–water partition ratios (KOW) greater than 4. This is because KBW and KS9W values predicted by any given approach exhibit a similar dependence on log KOW (i.e., regression slope), which results in a cancelation of "errors" when fU is calculated. In contrast, differences in KBW values predicted by the three approaches translate to differences in VD, and by extension kB and the BCF, which become most apparent at log KOW greater than 6. There is a need to collect KBW and VD data for hydrophobic chemicals in fish that can be used to evaluate and improve existing partitioning prediction approaches in extrapolation models for fish. Environ Toxicol Chem 2023;42:33–45. © 2022 SETAC [ABSTRACT FROM AUTHOR]