The overall objective of our research is to reduce the uncertainty related to the estimation of bioaccumulation of organic chemicals in fish in ecological risk assessment (ERA). Based on a combination of different in vitro approaches to estimate chemical uptake and biotransformation with toxicokinetic (TK) and quantitative structure activity relationship (QSAR) models, we aim to develop a tiered approach, integrating modelling with testing strategies to aid in the rapid assessment of bioaccumulation potential (Figure 1). The tiered testing strategy can provide information and guidance for (1) bioaccumulation (hazard) assessment; (2) refining exposure estimation to support risk assessment; (3) TK models to aid in the interpretation of toxicity testing data and to guide experimental testing; and (4) knowledge as input into adverse outcome pathways (AOPs) to strengthen quantitative links between molecular or cellular events and apical effects. Our in vitro approaches will consider major sites of uptake of chemicals (gill, intestine) as well of biotransformation (liver, and potentially gill and intestine). TK models will include simpler one-compartment (1-CoTK) and more sophisticated multi-compartment physiologically-based TK (PBTK) models. The results from 1-CoTK and PBTK model simulations covering a range of chemical hydrophobicity and biotransformation for various bioaccumulation assessment metrics will be compared to hypothesize when more data intensive (higher tiered) PBTK-in vitro models are required to refine bioaccumulation assessment and TK data. Screening-level, whole body primary biotransformation rate constant (kM) QSARs and 1-CoTK models will be applied to aid the selection of chemicals to test the model hypotheses.
The specific objectives of our research are as follows:
1. Integrate current knowledge on TK models and biotransformation / bioaccumulation data to develop hypotheses regarding discrepancies in bioaccumulation predictions between screening-level models and PBTK models and use this information to select candidate chemicals to test the different model hypotheses (predictions);
2. Develop an hypothesis-driven in vitro testing strategy for chemicals selected in 1, such that in vitro models focus on those that represent the most likely route of uptake/biotransformation;
3. Quantify uptake (gill/intestine) and/or biotransformation (liver/gill/intestine) rates according to the developed in vitro testing strategy;
4. Implement experimental data into models and test model performance (i.e., hypotheses in objectives 1 and 2 above); if deemed necessary, design in vivo experiments for clarification and improve models;
5. Synthesize the information gained into a tiered framework that can be used in hazard and risk assessment and provide quantitative links between molecular or cellular effects and apical endpoints for AOPs.