Citation:

Saunders, L., J. Nichols, J. Arnot, J. Armitage, AND F. Wania. An amended in vitro–in vivo extrapolation model that accounts for first pass clearance effects on chemical bioaccumulation in fish. Environmental Science: Processes & Impacts. Royal Society of Chemistry, Cambridge, Uk, 25(4):741-754, (2023). https://doi.org/10.1039/D2EM00522K

Impact/Purpose:

Biotransformation has been shown to substantially reduce the extent to which organic chemicals accumulate in fish. Absent some means to estimate this activity, however, it is not possible to predict these impacts for untested chemicals and species. To address this challenge, researchers have developed methods to extrapolate measured rates of in vitro intrinsic (hepatic) clearance in fish to the whole animal (in vitro-in vivo extrapolation, or IVIVE) to predict a whole-body biotransformation rate constant. This biotransformation rate constant may then used as an input to established bioconcentration models that predict chemical accumulation occurring during a water-only exposure. Standardized methods for measuring in vitro intrinsic clearance in fish and predicting chemical bioconcentration have been provided as OECD Test Guidelines (nos. 319A and B). The purpose of the described work was to amend existing models to provide a means for using in vitro biotransformation data to predict chemical accumulation that occurs in a diet-only, or combined diet and waterborne exposure. Existing models predict the effect of biotransformation on chemical accumulation following a dietary exposure, but all such models fail to account for first-pass clearance effects on chemical uptake; that is, clearance that occurs in the liver and tissues of the gastrointestinal tract before the chemical enters the general circulation. Instead, these models assume that biotransformation only operates against chemicals once they have entered the general circulation. The results of the present model-based effort indicate that failure to properly account for first-pass clearance effects on chemical uptake can result in substantial underestimation of true biotransformation impacts on chemical bioaccumulation, particularly at higher rates of hepatic and/or intestinal (tissue) activity. Moreover, an evaluation of existing dietary uptake data for several test chemicals suggests that microbial biotransformation within the lumen of the gastrointestinal tract (gut contents) may also limit chemical uptake. The described work substantially advances current understanding of the impact of biotransformation on chemical bioaccumulation in fish and provides a mechanistically valid modeling framework that may be used by scientists to investigate such impacts. As such, this paper will be of interest to scientists and risk assessors within EPA Program Offices that deal with the regulation of bioaccumulative organic chemicals, including the Office of Pesticide Programs (OPP) and the Office of Pollution Prevention and Toxics (OPPT).

Description:

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 (kB; d−1). This estimate of kB 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 kDEP ≥ 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.

URLs/Downloads:

Record Details: