John Wiley & Sons, Ltd.

Using toxicokinetic‐toxicodynamic modelling as an acute risk assessment refinement approach in vertebrates ecological risk assessment

Recent guidance identified toxicokinetic‐toxicodynamic (TK‐TD) modelling as a relevant approach for risk assessment refinement. Yet, its added‐value compared to other refinement options is not detailed, and how to conduct the modelling appropriately is not explained. This case‐study addresses these issues through two examples of individual level risk assessment for two hypothetical plant protection products: (1) evaluating the risk for small granivorous birds and small omnivorous mammals of a single application as a seed treatment in winter cereals and (2) evaluating the risk for fish after a pulsed treatment in the edge‐of‐field zone. Using acute test data, we conducted the first tier risk assessment as defined in the EFSA guidance. When first tier risk assessment highlighted a concern, refinement options were discussed. Cases where the use of models should be preferred over other existing refinement approaches were highlighted. We then practically conducted the risk assessment refinement by using two different models as examples. In example 1, a TK model accounting for toxicokinetics and relevant feeding patterns in the skylark and in the wood mouse was used to predict internal doses of the hypothetical active ingredient in individuals based upon relevant feeding patterns in an in‐crop situation and identify the residue levels leading to mortality. In example 2, a TK‐TD model accounting for toxicokinetics, toxicodynamics and relevant exposure patterns in the fathead minnow was used to predict the time course of fish survival for relevant FOCUS SW exposure scenarios and identify which scenarios might lead to mortality. Models were calibrated using available standard data and implemented to simulate the time‐course of internal dose of active ingredient or survival for different exposure scenarios. Simulation results were discussed and used to derive the risk assessment refinement endpoints used for decision. Finally, we compared the ‘classical’ risk assessment approach with the model‐based approach. These comparisons showed that TK and TK‐TD models can bring more realism to the risk assessment through the possibility to study realistic exposure scenarios and to simulate relevant mechanisms of effects (including delayed toxicity and recovery). Noticeably, using TK‐TD models is currently the most relevant way to directly connect realistic exposure patterns to effects. We conclude with recommendations on how to properly use TK and TK‐TD model in acute risk assessment for vertebrates. This article is protected by copyright. All rights reserved

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