Application of a generic fish PBTK model for binary mixtures of chemicals

Abstract : The integration of mechanistic approaches in Environmental risk assessment requires the integration of processes to move towards estimating internal dose from exposure or environmental concentrations (external dose) to predict toxicity in each taxa or the whole ecosystem. In this context, the overall objective of this work is to develop models to integrate TK data for environmental risk assessment of single and multiple chemicals. Three steps were defined to fulfil this objective: (i) Data collection of biological, physiological, and toxicological variables to calibrate and develop PBTK models, (ii) Development of PBTK models for environmental risk assessment of single chemicals, (iii) Development of PBTK models for environmental risk assessment of multiple chemicals. Generic PBTK models for single compounds in rainbow trout (Oncorrynchus mykiss), fathead minnow (Pimephales promelas), stickleback (Gastrosteus aculeatus) and zebrafish (Danio rerio) have been developed. Physiological description and parameters proposed by Nichols et al. [1] were updated by an extensive litterature search. New mathematical functions were proposed to integrate the main factors influencing the toxicokinetics (water temperature, growth dilution, reproduction cycle,…). Default values for compound-specific parameters were estimated by QSAR models based on hydrobycity [2, 3]. An optional interaction terms was added to the mixture PBTK models for metabolic interactions such as competitive inhibition. Two case studies were selected based on availability of toxicokinetic (TK) and toxicdynamic (TD) data for single compounds and for mixtures. In the first case study, the interaction between melamine and cyanuric acid was studied and in a second case study, the interaction between chlorpyrifos and permethrin was modelled. The models developped enable to model interactions that are observed between exposure concentrations and final effects. The QSAR estimations of certain compound-specific parameters can compensate for the lack of data in fish. Extrapolation from one species to another with the various models developed can also help bridge gaps. [1] Nichols et al. 1990. Toxicol Appl Pharmacol 106:433-447. [2] Bertelsen et al. 1998.. Environ Toxicol Chem 17:1447-1455. [3] Nichols et al. 2006. Aquat Toxicol 78:74-90.
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Cléo Tebby, Rémy Beaudouin, Audrey Grech, Céline Brochot. Application of a generic fish PBTK model for binary mixtures of chemicals. 28. SETAC Europe annual meeting, May 2018, Rome, Italy. ⟨ineris-01853358⟩

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