Models Used to Predict Chemical Bioaccumulation in Fish from in Vitro Biotransformation Rates Require Accurate...

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. 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; K_S9W ), in blood (K_BW ), and in whole fish tissues (K_FW ) impact the prediction of a chemical's hepatic clearance binding term (f_U ) and 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 were of similar magnitude and remained relatively constant at log octanol-water partition ratios (K_OW ) greater than 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 BCF, which become most apparent at log K_OW greater than 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. Environ Toxicol Chem 2023;42:33-45. © 2022 SETAC.