CONSIDERATIONS FOR USING REPRODUCTION DATA IN TOXICOKINETIC-TOXICODYNAMIC MODELLING.

Toxicokinetic-toxicodynamic (TKTD) modelling is essential to make sense of the time dependence of toxic effects, and to interpret and predict consequences of time-varying exposure. These advantages have been recognised in the regulatory arena, especially for environmental risk assessment (ERA) of pesticides, where time-varying exposure is the norm. We critically evaluate the link between the modelled variables in TKTD models and the observations from laboratory ecotoxicity tests. For the endpoint reproduction, this link is far from trivial. The relevant TKTD models for sub-lethal effects are based on Dynamic-Energy Budget (DEB) theory, which specifies a continuous investment flux into reproduction. In contrast, experimental tests score egg or offspring release by the mother. The link between model and data is particularly troublesome when a species reproduces in discrete clutches, and even more so when eggs are incubated in the mother's brood pouch (and release of neonates is scored in the test). This situation is quite common among aquatic invertebrates (e.g., cladocerans, amphipods, mysids), including many popular test species. In this discussion paper, we treat these and other issues with reproduction data, reflect on their potential impact on DEB-TKTD analysis, and provide preliminary recommendations to correct them. Both modellers and users of model results need to be aware of these complications, as ignoring them could easily lead to unnecessary failure of DEB-TKTD models during calibration, or when validating them against independent data for other exposure scenarios. This article is protected by copyright. All rights reserved.

[1]  Pierre Petitgas,et al.  Modeling fish growth and reproduction in the context of the Dynamic Energy Budget theory to predict environmental impact on anchovy spawning duration , 2009 .

[2]  D. S. Glazier,et al.  How do interactive maternal traits and environmental factors determine offspring size in Daphnia magna , 2014 .

[3]  S. Kooijman,et al.  Quantitative aspects of metabolic organization: a discussion of concepts. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[4]  Monika Hammers-Wirtz,et al.  Offspring fitness in Daphnia: Is the Daphnia reproduction test appropriate for extrapolating effects on the population level? , 2000 .

[5]  Sebastiaan A.L.M. Kooijman,et al.  Analysis of toxicity tests on Daphnia survival and reproduction , 1996 .

[6]  Tjalling Jager,et al.  Revisiting simplified DEBtox models for analysing ecotoxicity data , 2020 .

[7]  Sebastiaan A.L.M. Kooijman,et al.  Models in stress research , 2017 .

[8]  T. Jager,et al.  Modeling responses of Daphnia magna to pesticide pulse exposure under varying food conditions: intrinsic versus apparent sensitivity , 2006, Ecotoxicology.

[9]  A. J. Tessier,et al.  Estimating food limitation in cladoceran populations1 , 1982 .

[10]  Roman Ashauer,et al.  A METHOD TO PREDICT AND UNDERSTAND FISH SURVIVAL UNDER DYNAMIC CHEMICAL STRESS USING STANDARD ECOTOXICITY DATA , 2013, Environmental toxicology and chemistry.

[11]  S. H. Bennekou,et al.  Scientific Opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) effect models for regulatory risk assessment of pesticides for aquatic organisms , 2018, EFSA journal. European Food Safety Authority.

[12]  Sebastiaan A L M Kooijman,et al.  Making Sense of Ecotoxicological Test Results: Towards Application of Process-based Models , 2006, Ecotoxicology.

[13]  S. Charles,et al.  Bayesian modelling of daphnid responses to time-varying cadmium exposure in laboratory aquatic microcosms. , 2011, Ecotoxicology and environmental safety.

[14]  Elke I. Zimmer,et al.  Dynamic energy budgets in population ecotoxicology: Applications and outlook , 2014 .

[15]  P. Veber,et al.  Statistical handling of reproduction data for exposure-response modeling. , 2013, Environmental science & technology.

[16]  Tjalling Jager,et al.  Some good reasons to ban ECx and related concepts in ecotoxicology. , 2011, Environmental science & technology.

[17]  Roman Ashauer,et al.  Advantages of toxicokinetic and toxicodynamic modelling in aquatic ecotoxicology and risk assessment. , 2010, Journal of environmental monitoring : JEM.

[18]  Roman Ashauer,et al.  Sublethal effect modelling for environmental risk assessment of chemicals: Problem definition, model variants, application and challenges. , 2020, The Science of the total environment.

[19]  Roman Ashauer,et al.  How to Evaluate the Quality of Toxicokinetic—Toxicodynamic Models in the Context of Environmental Risk Assessment , 2018, Integrated environmental assessment and management.