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Recent guidance identified toxicokinetic-toxicodynamic (TK-TD) modeling 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 modeling appropriately is not explained. This case study addresses these issues through 2 examples of individual-level risk assessment for 2 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 European Food Safety Authority (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 2 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 on 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.

In natural ecosystems it is not unusual for an organism to be exposed both to chemical and physical stressful factors at the same time. Herein we present results of the study on nickel toxicity to the carabid beetle, Pterostichus oblongopunctatus, and effect of Ni and temperature on the beetles respiration rates. In the first part of the study (Experiment I) we measured the survival, respiration rates and internal Ni concentrations in animals exposed for 245 d at constant temperature (20 degrees C) to food contaminated with Ni at nominal concentrations 0; 600; 1,200; 2,400; 4,800; and 9,600 mg kg(-1) dry weigh (dw). The LC(50) was estimated at 8,351 mg Ni kg(-1), with no effect on fertility. We found a significant positive correlation between Ni concentration in food and internal body concentration of Ni, and a negative correlation between Ni exposure and the respiration rate. Based on these results, the concentration of 2,400 mg kg(-1) (LOEC for the respiration rate) was selected for the second part of the study (Experiment II) in which field-collected males of P. oblongopunctatus were exposed to Ni-contaminated food for 64 d and then to uncontaminated food for the next 64 d at three temperatures: 10, 15 and 20 degrees C. In this part of the study we found that the temperature under which the beetles were kept affected their respiration rates, and that effect of Ni on the respiration was significant only in animals originating from 20 degrees C. The results from both experiments indicate that negative effects of nickel appear only after relatively long exposure.