Scientific Opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) effect models for regulatory risk assessment of pesticides for aquatic organisms
2018; Wiley; Volume: 16; Issue: 8 Linguagem: Inglês
10.2903/j.efsa.2018.5377
ISSN1831-4732
AutoresColin Ockleford, Paulien Adriaanse, Philippe Berny, T.C.M. Brock, Sabine Duquesne, Sandro Grilli, Antonio F. Hernández, Susanne Hougaard Bennekou, Michael Klein, Thomas Kühl, Ryszard Laskowski, Kyriaki Machera, Olavi Pelkonen, Silvia Pieper, Robert H. Smith, Michael Stemmer, Ingvar Sundh, A. Tiktak, Christopher John Topping, Gerrit Wolterink, Nina Cedergreen, Sandrine Charles, Andreas Focks, Melissa Reed, Maria Arena, Alessio Ippolito, Harry Byers, Ivana Teodorović,
Tópico(s)Pesticide and Herbicide Environmental Studies
ResumoEFSA JournalVolume 16, Issue 8 e05377 Scientific OpinionOpen Access Scientific Opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) effect models for regulatory risk assessment of pesticides for aquatic organisms EFSA Panel on Plant Protection Products and their Residues (PPR), EFSA Panel on Plant Protection Products and their Residues (PPR)Search for more papers by this authorColin Ockleford, Colin OcklefordSearch for more papers by this authorPaulien Adriaanse, Paulien AdriaanseSearch for more papers by this authorPhilippe Berny, Philippe BernySearch for more papers by this authorTheodorus Brock, Theodorus BrockSearch for more papers by this authorSabine Duquesne, Sabine DuquesneSearch for more papers by this authorSandro Grilli, Sandro GrilliSearch for more papers by this authorAntonio F Hernandez-Jerez, Antonio F Hernandez-JerezSearch for more papers by this authorSusanne Hougaard Bennekou, Susanne Hougaard BennekouSearch for more papers by this authorMichael Klein, Michael KleinSearch for more papers by this authorThomas Kuhl, Thomas KuhlSearch for more papers by this authorRyszard Laskowski, Ryszard LaskowskiSearch for more papers by this authorKyriaki Machera, Kyriaki MacheraSearch for more papers by this authorOlavi Pelkonen, Olavi PelkonenSearch for more papers by this authorSilvia Pieper, Silvia PieperSearch for more papers by this authorRobert H Smith, Robert H SmithSearch for more papers by this authorMichael Stemmer, Michael StemmerSearch for more papers by this authorIngvar Sundh, Ingvar SundhSearch for more papers by this authorAaldrik Tiktak, Aaldrik TiktakSearch for more papers by this authorChristopher J. Topping, Christopher J. ToppingSearch for more papers by this authorGerrit Wolterink, Gerrit WolterinkSearch for more papers by this authorNina Cedergreen, Nina CedergreenSearch for more papers by this authorSandrine Charles, Sandrine CharlesSearch for more papers by this authorAndreas Focks, Andreas FocksSearch for more papers by this authorMelissa Reed, Melissa ReedSearch for more papers by this authorMaria Arena, Maria ArenaSearch for more papers by this authorAlessio Ippolito, Alessio IppolitoSearch for more papers by this authorHarry Byers, Harry ByersSearch for more papers by this authorIvana Teodorovic, Ivana TeodorovicSearch for more papers by this author EFSA Panel on Plant Protection Products and their Residues (PPR), EFSA Panel on Plant Protection Products and their Residues (PPR)Search for more papers by this authorColin Ockleford, Colin OcklefordSearch for more papers by this authorPaulien Adriaanse, Paulien AdriaanseSearch for more papers by this authorPhilippe Berny, Philippe BernySearch for more papers by this authorTheodorus Brock, Theodorus BrockSearch for more papers by this authorSabine Duquesne, Sabine DuquesneSearch for more papers by this authorSandro Grilli, Sandro GrilliSearch for more papers by this authorAntonio F Hernandez-Jerez, Antonio F Hernandez-JerezSearch for more papers by this authorSusanne Hougaard Bennekou, Susanne Hougaard BennekouSearch for more papers by this authorMichael Klein, Michael KleinSearch for more papers by this authorThomas Kuhl, Thomas KuhlSearch for more papers by this authorRyszard Laskowski, Ryszard LaskowskiSearch for more papers by this authorKyriaki Machera, Kyriaki MacheraSearch for more papers by this authorOlavi Pelkonen, Olavi PelkonenSearch for more papers by this authorSilvia Pieper, Silvia PieperSearch for more papers by this authorRobert H Smith, Robert H SmithSearch for more papers by this authorMichael Stemmer, Michael StemmerSearch for more papers by this authorIngvar Sundh, Ingvar SundhSearch for more papers by this authorAaldrik Tiktak, Aaldrik TiktakSearch for more papers by this authorChristopher J. Topping, Christopher J. ToppingSearch for more papers by this authorGerrit Wolterink, Gerrit WolterinkSearch for more papers by this authorNina Cedergreen, Nina CedergreenSearch for more papers by this authorSandrine Charles, Sandrine CharlesSearch for more papers by this authorAndreas Focks, Andreas FocksSearch for more papers by this authorMelissa Reed, Melissa ReedSearch for more papers by this authorMaria Arena, Maria ArenaSearch for more papers by this authorAlessio Ippolito, Alessio IppolitoSearch for more papers by this authorHarry Byers, Harry ByersSearch for more papers by this authorIvana Teodorovic, Ivana TeodorovicSearch for more papers by this author First published: 23 August 2018 https://doi.org/10.2903/j.efsa.2018.5377Citations: 44 Correspondence: pesticides.ppr@efsa.europa.eu Requestor: EFSA Question number: EFSA-Q-2012-00960 Panel members: Paulien Adriaanse, Philippe Berny, Theodorus Brock, Sabine Duquesne, Sandro Grilli, Antonio F Hernandez-Jerez, Susanne Hougaard, Michael Klein, Thomas Kuhl, Ryszard Laskowski, Kyriaki Machera, Colin Ockleford, Olavi Pelkonen, Silvia Pieper, Robert Smith, Michael Stemmer, Ingvar Sundh, Ivana Teodorovic, Aaldrik Tiktak, Chris J Topping and Gerrit Wolterink Acknowledgements: The Panel on Plant Protection Products and their Residues wishes to thank for the support provided to this scientific output the member of the Working Group (WG): Theodorus Brock, Nina Cedergreen, Sandrine Charles, Sabine Duquesne, Andreas Focks, Michael Klein, Melissa Reed and Ivana Teodorovic and EFSA staff member: Maria Arena, Alessio Ippolito and Harry Byers. In addition the PPR Panel wishes to thank Roman Ashauer, Tjalling Jager and Thomas Preuss for their support to the WG as hearing experts. Adopted: 27 June 2018 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Following a request from EFSA, the Panel on Plant Protection Products and their Residues (PPR) developed an opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) models and their use in prospective environmental risk assessment (ERA) for pesticides and aquatic organisms. TKTD models are species- and compound-specific and can be used to predict (sub)lethal effects of pesticides under untested (time-variable) exposure conditions. Three different types of TKTD models are described, viz., (i) the ‘General Unified Threshold models of Survival’ (GUTS), (ii) those based on the Dynamic Energy Budget theory (DEBtox models), and (iii) models for primary producers. All these TKTD models follow the principle that the processes influencing internal exposure of an organism, (TK), are separated from the processes that lead to damage and effects/mortality (TD). GUTS models can be used to predict survival rate under untested exposure conditions. DEBtox models explore the effects on growth and reproduction of toxicants over time, even over the entire life cycle. TKTD model for primary producers and pesticides have been developed for algae, Lemna and Myriophyllum. For all TKTD model calibration, both toxicity data on standard test species and/or additional species can be used. For validation, substance and species-specific data sets from independent refined-exposure experiments are required. Based on the current state of the art (e.g. lack of documented and evaluated examples), the DEBtox modelling approach is currently limited to research applications. However, its great potential for future use in prospective ERA for pesticides is recognised. The GUTS model and the Lemna model are considered ready to be used in risk assessment. Summary In 2008, the Panel on Plant Protection Products and their Residues (PPR Panel) was tasked by the European Food Safety Authority (EFSA) with the revision of the Guidance Document on Aquatic Ecotoxicology under Council Directive 91/414/EEC (SANCO/3268/2001 rev.4 (final), 17 October 2002).1 As a third deliverable of this mandate, the PPR Panel is asked to develop a Scientific Opinion describing the state of the art of Toxicokinetic/Toxicodynamic (TKTD) models for aquatic organisms and prospective environmental risk assessment (ERA) for pesticides with the main focus on: (i) regulatory questions that can be addressed by TKTD modelling, (ii) available TKTD models for aquatic organisms, (iii) model parameters that need to be included and checked in evaluating the acceptability of regulatory relevant TKTD models, and (iv) selection of the species to be modelled. Chapter 2 presents the underlying concepts, terminology, application domains and complexity levels of three different classes of TKTD models intended to be used in risk assessment, viz., (i) the ‘General Unified Threshold models of Survival’ (GUTS), (ii) toxicity models derived from the Dynamic Energy Budget theory (DEBtox models), and (iii) models for primary producers. All TKTD models follow the principle that the processes influencing internal exposure of an organism, summarised under Toxicokinetics (TK), are separated from the processes that lead to damage and effects/mortality, summarised by the term Toxicodynamics (TD). The ultimate aim of GUTS is to predict survival of individuals (as influenced by mortality and/or immobility) under untested time-variable or constant exposure conditions. The GUTS modelling framework connects the external concentration with a so-called damage dynamic, which is in turn connected to a hazard resulting in simulated mortality/immobility when an internal damage threshold is exceeded. Within this framework, two reduced versions of GUTS are available: GUTS-RED-SD based on the assumption of Stochastic Death (SD) and GUTS-RED-IT based on the assumption of Individual Tolerance (IT). DEBtox modelling is the application of the Dynamic Energy Budget (DEB) theory to deal with effects of toxic chemicals on life-history traits (sublethal endpoints). DEBtox models incorporate a dynamic energy budget part for growth and reproduction endpoints at the individual level. Therefore, DEBtox models consist of two parts, (i) the DEB or ‘physiological’ part that describes the physiological energy flows and (ii) the part that accounts for uptake and effects of chemicals, named ‘TKTD part’. The third class of TKTD models presented are developed for primary producers. With respect to the analysis of toxic effects for primary producers, the main endpoint measured is not survival but growth. For that reason, the assessment of toxic effects on algae and vascular plants needs a submodel addressing growth as a baseline, and a connected TKTD part. Chapter 3 deals with the problem formulation step that sets the scene for the use of the TKTD models within the risk assessment. TKTD models are species and substance specific. TKTD models may either focus on standard test species (Tier-2C1) or also incorporate relevant additional species (Tier-2C2). If risks are triggered in Tier-1 (standard test species approach) and exposure is likely to be shorter than in standard tests, the development of TKTD models for standard test species is the most straightforward option. If Tier-2A (geometric mean/weight-of-evidence approach) or Tier-2B (species sensitivity distribution approach) information is also available, the development of TKTD models for a wider array of species may be the way forward to refine the risk assessment. Validated TKTD models for these species may be an option to evaluate specific risks, using available field-exposure profiles, by calculating exposure profile-specific LPx/EPx values (= multiplication factor to an entire specific exposure profile that causes x% Lethality or Effect), informed by an appropriate aquatic exposure assessment. Exposure profile-specific LPx/EPx can be used in the Tier-2C risk assessment by using the same rules and extrapolation techniques (statistical analysis and assessment factors) as used in experimental Tier-1 (standard test species approach), Tier-2A (geometric mean/weight-of-evidence approach) and Tier-2B (species sensitivity distribution approach). The GUTS model framework is considered to be an appropriate approach to use in the acute risk assessment scheme for aquatic invertebrates, fish and aquatic stages of amphibians. In the chronic risk assessment, it is only appropriate to use a validated GUTS model if the critical endpoint is mortality/immobility, which is not often the case. If a sublethal endpoint is the most critical in the chronic lower-tier assessment for aquatic animals, the dynamic energy budget modelling framework combined with a TKTD part (DEBtox) is the appropriate approach to select in the refined risk assessment. TKTD models developed for primary producers may be used in the chronic risk assessment scheme with a focus on inhibition of growth rate and/or yield. Note that experimental tests and TKTD model assessments for algae and fast-growing macrophytes like Lemna to some extent assess population-level effects, since in the course of the test reproduction occurs. Chapter 4 deals with the GUTS framework. This framework is considered ready for use in aquatic ERA, since a sufficient number of application examples and validation exercises for aquatic species and pesticides are published in the scientific literature, and user-friendly modelling tools are available. Consequently, in this chapter, detailed information is provided on testing, calibration, validation and application of the GUTS modelling framework. Documentation of the formal GUTS model, and of the verification of two example implementations of the GUTS model equations in different programming languages (R and Mathematica) are presented. In addition, sensitivity analyses of both implementations are described, and an introduction is presented for GUTS parameter estimation both in the Bayesian and frequentist approach. The uncertainty, related to the stochasticity of the survival process in small groups of individuals, is discussed, and the numerical approximation of parameter confidence/credible limits is described. A checklist for the evaluation of parameter estimation in GUTS model applications is given. Descriptions of relevant GUTS modelling output are also given. Approaches to propagate the stochasticity of survival in combination with parameter uncertainty to predictions of survival over time and to LPx/EPx values are presented, allowing the calculation of corresponding confidence/credible limits. The validation of GUTS models is discussed, including requirements for the validation data sets. Qualitative and quantitative model performance criteria are suggested that appear as most suitable for GUTS, and TKTD modelling in general, including the posterior prediction check (PPC), the Normalised Root Mean Square Error (NRMSE) and the survival-probability prediction error (SPPE). Finally, chapter 4 gives an example of the calibration, validation and application of the GUTS framework for risk assessment. In Appendix A, A, A–D, GUTS model implementations in Mathematica and R, the results of the application example with the GUT-RED models and supporting information on the GUTS-RED exercise are provided, respectively. Source codes of the GUTS implementations in Mathematica and R are available in Appendix E. Chapter 5 deals with the documentation, implementation, parameter estimation and output of DEBtox modelling as illustrated with a case study on lethal and sublethal effects of time-variable exposure to cadmium for Daphnia magna. This case study was selected since sufficiently calibrated and validated DEBtox models for pesticide and aquatic organisms were not yet available in the open literature, including raw data and programming source code to allow for re-running all calculations. This lack of published examples of DEBtox models for pesticides and aquatic organisms, as well as the fact that no user-friendly DEBtox modelling tools are currently available, results in the conclusion that these models are not yet ready for use in aquatic risk assessment for pesticides. Nevertheless, the DEBtox modelling approach is recognised as an important research tool with great potential for future use in prospective ERA for pesticides. The DEBtox model described in chapter 5 for cadmium and Daphnia magna illustrates the potential of the DEBtox modelling framework to deal with several kinds of data, namely survival, growth and reproduction data together with bioaccumulation data. It also proves the feasibility of estimating all DEBtox parameters from simple toxicity test data under a Bayesian framework. In Appendix A.2.2, a short overview of the DEBtox model implementation in R is given. The respective R code is available in an archive in Appendix E. Chapter 6 evaluates the models currently available for primary producers, which all rely on a submodel for growth, driven by a range of external inputs such as temperature, irradiance, nutrient and carbon availabilities. The effect of the pesticide (TKTD part) on the net growth rate is described by a dose–response relationship, linking either external (the algae part) or scaled or measured internal concentrations to the inhibition of the growth rate. All experiments and tests of the models until now have been done under fixed growth conditions, as is the case for standard algae, Lemna and Myriophyllum tests. This was done because the focus has been on evaluating the model ability to predict effects under time-variable exposure scenarios using predicted exposure profiles (e.g. FOCUS step 3 or 4) and Tier-1 toxicity data as a starting point. The growth part of the models, however, all have the potential to incorporate changes in temperature, irradiance, nutrient and carbon availabilities in future applications. TKTD models to describe effects of time-variable exposures have been developed for two algal species and one PSII inhibiting herbicide. The largest drawback for implementing the algae models in pesticide risk assessment is that the flow-through experimental setup used for model calibration/validation to simulate long-term variable exposures of pesticides to fast growing populations of algae has not yet been standardised, nor has the robustness of the setup been ring-tested. The current experimental setup of refined exposure tests for algae and the algae models is considered an important research tools but probably not yet mature enough to use for risk-assessment purposes. Lemna is the most thoroughly tested macrophyte species for which a calibrated and validated model has been documented for a sulfonyl-urea compound. A Lemna TKTD model can be calibrated with data from the already standardised OECD Lemna test, as long as pesticide concentrations and growth are monitored several times during the exposure phase and the test is prolonged with a one week recovery period. Growth can be most easily and non-destructively monitored by measuring surface area or frond number on a daily basis. If properly documented, the published Lemna model can be the basis for a compound-specific Lemna model to evaluate the effects of field-exposure profiles in Tier-2C, particularly if in the Tier-1 assessment Lemna is the only standard test species that triggers a potential risk. The published Myriophyllum modelling approach is not yet as well developed, calibrated, validated and documented as that for Lemna. Developing a model for Myriophyllum is complicated, as this macrophyte also has a root compartment (in the sediment) where the growth conditions (redox potential, pH, nutrient and gas availabilities, sorptive surfaces, etc.), and therefore, bioavailability of pesticides, are very different from the conditions in the shoot compartment (water column). In addition, Myriophyllum grows submerged making inorganic carbon availability in the water column a complicated affair compared to Lemna, for which access to CO2 through the atmosphere is constant and unlimited. Due to the complexity of the Myriophyllum system and the relative novelty of the published modelling approach, the available Myriophyllum model has not yet been very extensively tested and publicly assessable model codes are not yet available. OECD guidelines for conducting tests with Myriophyllum are available. In order to optimise the use of experimental data from such standardised Myriophyllum tests for model calibration, however, it is necessary that the tests are prolonged with a recovery phase in clean water and that growth is monitored over time (non-destructively as shoot numbers and length). Although the published Myriophyllum modelling approach may be a good basis to further develop TKTD models for rooted submerged macrophytes, it currently is considered not yet fit-for-purpose in prospective ERA for pesticides. The currently available Myriophyllum model needs further documentation, calibration and validation. Chapter 7 describes how TKTD models submitted in dossiers can be evaluated by regulatory authorities. Annex A, A–C provide checklists for the evaluation of GUTS models, DEBtox models and models for primary producers. It expands on the information provided by the EFSA Opinion on Good Modelling Practice in the context of mechanistic effect models for risk assessment (EFSA PPR Panel, 2014). The chapter mainly focuses on GUTS models but also provides considerations required for DEBtox and primary producer models. The chapter covers all stages of the modelling cycle and the documentation of the model use. For GUTS models the basic model structure is always fixed and consequently several stages of the modelling cycle have been covered in this Opinion, so they do not need to be evaluated again for each use. This includes the conceptual model and the formal model. For parameter estimation of each application, all experimental data used to calibrate and validate the model should be evaluated to ensure they are of sufficient quality. The computer model can be evaluated using a combination of the ring-test data set, a set of default scenarios and testing against an independent implementation. The regulatory model also needs to be evaluated. The environmental scenario may be covered by using standard exposure models (FOCUS), leaving the parameter estimation as the key area to evaluate. The evaluation of model analysis (sensitivity and uncertainty analysis and validation) is also described. The final stage is the evaluation of the model use that includes information about tools available to the evaluators to check the modelling. For DEBtox models, the evaluation of the DEB (physiological) part of the model is separated from the evaluation of the TKTD part of the model. Chapter 7 focusses on the TKTD part and starts with the assumption that the DEB part has been evaluated and accepted before it is used for a regulatory risk assessment. For primary producer models, as with DEBtox models, the evaluation of the physiological part of the model is separated from the evaluation of the TKTD part of the model. For Lemna, this has been covered in this Opinion. For other primary producers, the evaluation of the physiological part of the model needs to be completed before use in regulatory risk assessment. Documentation of any TKTD model application should be done following Annex D. Chapter 8 illustrates the possible use of validated TKTD models as tools in the Tier-2C risk assessment for plant protection products. The important steps that need to be considered when conducting an ERA by means of validated TKTD models are described. The description of the approach is followed by an example data set for an organophosphorus insecticide. This case study aims to explore how GUTS modelling can be used as a Tier-2C approach in acute ERA in combination with step 3 or step 4 FOCUSsw exposure profiles. In addition, this case study aims to compare the outcome of the experimental effect assessment tiers (standard test species approach, geometric mean approach, species sensitivity distribution approach, model ecosystem approach) with results of GUTS modelling to put the Tier-2C approach into perspective. Chapter 9 concludes that, based on the current state of the art (e.g. lack of documented and evaluated examples), the DEBtox modelling approach is currently limited to research applications. However, its great potential for future use in prospective ERA for pesticides is recognised. The GUTS model and the Lemna model are considered ready to be used in risk assessment. Two examples on the evaluation of existing TKTD models (one for GUTS and one for DEBtox) used in the context of PPP authorisation are reported in Appendices F and G. Comments received by the Pesticide Steering Network and related replies are reported in Appendix H. Guide to the reader: the main topic concerns the implementation of modelling techniques for prospective ERA; hence its stays at the interface of different expertise areas. Taking this into account, the document was structured to allow focussing on sections linked to specific expertise. Chapters 1, 2 and 3 provide a general context: after presenting the scope of the Scientific Opinion, general principles behind TKTD models are described and the scene for the use of the TKTD models within the risk assessment for aquatic organisms is set. Therefore, these chapters are recommended for getting a complete picture of this document. Chapters 4, 5 and 6 focus on the description of specific TKTD models. As such the content of these chapters contain rather technical concepts and explanations, particularly addressing modellers. These chapters may be difficult for readers without modelling experience. Understanding of the technical details included in this part, however, is not critical for the reading and understanding of the following chapters. Chapters 7 and 8 illustrate in details how TKTD models can be used in the PPP ERA context, particularly addressing risk assessors. Evaluation criteria for modelling applications are also given in chapter 7. Hence, it is recommended that this part is also carefully considered by modellers providing elaborations for the risk assessment. Checklists for the evaluation of TKTD models are given in Annex A, A –C. Model summary for the model documentation is included in Annex D. 1 Introduction 1.1 Background and Terms of Reference as provided by the requestor In 2008 the Panel on Plant Protection Products and their Residues (PPR) was tasked by EFSA with the revision of the Guidance Document on Aquatic Ecotoxicology under Council Directive 91/414/EEC (SANCO/3268/2001 rev.4 (final), 17 October 2002) (European Commission, 2002). As a third deliverable of this mandate, the PPR Panel is asked to develop a Scientific Opinion describing the state of the art of Toxicokinetic-Toxicodynamic (TKTD) effect models for aquatic organisms with a focus on the following aspects: Regulatory questions that can be addressed by TKTD modelling Available TKTD models for aquatic organisms Model parameters that need to be included in relevant TKTD models and that need to be checked in evaluating the acceptability of effect models Selection of the species to be modelled. In 2013, EFSA Panel on Plant Protection Products and their residues published the document “Guidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-field surface waters” as a first deliverable within the EFSA mandate of the revision of the former Guidance Document on Aquatic Ecotoxicology. This document (EFSA PPR Panel, 2013) focuses on experimental approaches within the tiered effect assessment scheme for typical (pelagic) water organisms, indicating already how mechanistic effect models could be used within the tiered approach. As a second deliverable the document “Scientific Opinion on the effect assessment for pesticides on sediment organisms in edge-of-field surface water” was published in 2015 (EFSA PPR Panel, 2015). This document focuses on experimental effect assessment procedures for typical sediment-dwelling organisms and exposure to pesticides via the sediment compartment. Initially, it was emphasized that the third deliverable would focus on mechanistic effect models as tools for the prospective effect assessment procedures for aquatic organisms. Although different types of mechanistic effect models with a focus on different levels of biological organisation are described in the scientific literature (e.g. individual-level models, population-level models, community-level models, landscape/watershed-level models), this Scientific Opinion (SO) predominantly deals with TKTD models as Tier-2 tools in the aquatic risk assessment for pesticides. These relatively simple, mechanistic effect models are considered to be in a stage of development that might soon enable their appropriate use in the prospective environmental risk assessment for pesticides, particularly to predict potential risks of time-variable exposures on aquatic organisms. This is of relevance since in most edge-of-field surface waters time-variable exposures are more often the rule than the exception. A consultation with Member States of the Pesticides Steering Network was held in March 2018. Comments and related replies are reported in Appendix H. 1.2 Scope of the opinion and restrictions This SO describes the state-of-the-art of TKTD models developed for aquatic organisms and exposure to pesticides in aquatic ecosystems with a focus on prospective environmental risk assessment (ERA) within the context of the regulatory framework underlying the authorisation of plant protection products in the EU. Within this context, TKTD models developed for specific pesticides and specific species of water organisms – such as fi
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