An amended in vitro–in vivo extrapolation model that accounts for first pass clearance effects on chemical bioaccumulation in fish. Issue 4 (6th March 2023) - Saunders, Leslie J.
Abstract : An amended in vitro – in vivo extrapolation model that accounts for first pass clearance effects on chemical bioaccumulation in fish. Pre-systemic biotransformation can significantly reduce chemical oral bioavailability, which can reduce dietary chemical bioaccumulation potential. Abstract : Measured rates of in vitro intrinsic clearance for fish may be extrapolated to the whole animal as a means of estimating a whole-body biotransformation rate constant ( k B ; d −1 ). This estimate of k B can then be used as an input to existing bioaccumulation prediction models. Most in vitro – in vivo extrapolation / bioaccumulation (IVIVE/B) modeling efforts to date have focused on predicting the chemical bioconcentration in fish (aqueous only exposure), with less attention paid to dietary exposures. Following dietary uptake, biotransformation in the gut lumen, intestinal epithelia, and liver can reduce chemical accumulation; however, current IVIVE/B models do not consider these first pass clearance effects on dietary uptake. Here we present an amended IVIVE/B model that accounts for first pass clearance. The model is then used to examine how biotransformation in the liver and intestinal epithelia (alone or combined) may impact chemical accumulation that occurs during dietary exposure. First pass clearance by the liver can greatly reduce dietary uptake of contaminants, but these effects are only apparent at rapid rates of in vitro biotransformation (first order depletion rate constant k DEP ≥ 10 h −1 ). The impact of first pass clearance becomes more pronounced when biotransformation in the intestinal epithelia is included in the model. Modelled results suggest that biotransformation in the liver and intestinal epithelia cannot entirely explain reduced dietary uptake reported in several in vivo bioaccumulation tests. This unexplained reduction in dietary uptake is attributed to chemical degradation in the gut lumen. These findings underscore the need for research to directly investigate luminal biotransformation in fish.