Using toxicokinetic‐toxicodynamic modeling as an acute risk assessment refinement approach in vertebrate ecological risk assessment

Abstract

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.

How to use mechanistic effect models in environmental risk assessment of pesticides: Case studies and recommendations from the SETAC workshop MODELINK

“…Case study 1 (Ducrot et al this issue) focused on acute risk assessment in vertebrates. The task was to evaluate the risk from application of a single hypothetical pesticide, via seed treatment in winter cereals, for small granivorous birds (skylarks) and small omnivorous mammals (wood mouse); moreover, to evaluate the risk from another hypothetical pesticide, applied in a pulsed treatment, for fish (fathead minnow).…”

“…A standard test species might be relevant for modeling if the main question is to extrapolate the effects measured in standard toxicity tests to other exposure conditions or to longer exposure durations. An example is given in Ducrot et al (this issue) for extrapolating lethal effects on fish from standardized tests to prolonged or time‐variable exposure conditions by TK‐TD modeling. Such a use of models is comparable to the experimental tier of modified exposure studies (EFSA ), where other uncertainties, such as regarding species‐to‐species extrapolation or population‐level effects, remain.…”

“…There was consensus during the workshop that MEMs can be used for both vertebrates and invertebrates to answer specific questions that have arisen after standard and higher‐tier studies. For example, they can be used to better describe exposure and effects of organisms (see case study 1, Ducrot et al this issue) or they can be used to extrapolate effects and recovery of vulnerable populations from a community‐level study (e.g., a mesocosm study) to other habitat types or landscapes (e.g., case studies 4 and 5, Dohmen et al this issue).…”

Coupling toxicokinetic–toxicodynamic and population models for assessing aquatic ecological risks to time‐varying pesticide exposures

“…A toxicokinetic–toxicodynamic model is one of the most suitable methods of incorporating realistic exposure patterns into effects (Ducrot et al ). Coupling toxicokinetic–toxicodynamic and population models also integrates several organismal effects (e.g., survival and reproduction) into a unified risk evaluation (population growth, recovery rate, etc.).…”

“…Linking toxicokinetic-toxicodynamic to population models is a useful way to incorporate variations in life history strategies into the risk evaluation of time-varying exposure concentrations. This has often been accomplished through either individual-based models or matrix models (Billoir et al 2007;Gabsi et al 2014;Galic et al 2014;Liu et al 2014;Dohmen et al 2016;Ducrot et al 2016). However, despite the usefulness of toxicokinetictoxicodynamic for this purpose, and despite the routine use of population models in ecology, conservation biology, and natural resource management, the application of such models in environmental risk assessment is extremely limited (Schmolke et al 2010;Galic et al 2014;Hommen et al 2016).…”