Reproductive toxicity in birds predicted by physiologically-based kinetics and bioenergetics modelling.

Effects on the growth and reproduction of birds are important endpoints in the environmental risk assessment (ERA) of pesticides. Toxicokinetic-toxicodynamic models based on dynamic energy budget theory (DEB) are promising tools to predict these effects mechanistically and make extrapolations relevant to ERA. However, before DEB-TKTD models are accepted as part of ERA for birds, ecotoxicological case studies are required so that stakeholders can assess their capabilities. We present such a case-study, modelling the effects of the fluopyram metabolite benzamide on the northern bobwhite quail (Colinus virginianus). We parametrised a DEB-TKTD model for the embryo stage on the basis of an egg injection study, designed to provide data for model development. We found that information on various endpoints, such as survival, growth, and yolk utilisation were needed to clearly distinguish between the performance of model variants with different TKTD assumptions. The calibration data were best explained when it was assumed that chemical uptake occurs via the yolk and that benzamide places stress on energy assimilation and mobilisation. To be able to bridge from the in vitro tests to real-life exposure, we developed a physiologically-based toxicokinetic (PBK) model for the quail and used it to predict benzamide exposure inside the eggs based on dietary exposure in a standard reproductive toxicity study. We then combined the standard DEB model with the TKTD module calibrated to the egg injection studies and used it to predict effects on hatchling and 14-day chick weight based on the exposure predicted by the PBK model. Observed weight reductions, relative to controls, were accurately predicted. Thus, we demonstrate that DEB-TKTD models, in combination with suitable experimental data and, if necessary, with an exposure model, can be used in bird ERA to predict chemical effects on reproduction.

Environmental Risk Assessment with Energy Budget Models: A Comparison Between Two Models of Different Complexity.

The extrapolation of effects from controlled standard laboratory tests to real environmental conditions is a major challenge facing ecological risk assessment (ERA) of chemicals. Toxicokinetic-toxicodynamic (TKTD) models, such as those based on dynamic energy budget (DEB) theory, can play an important role in filling this gap. Through the years, different practical TKTD models have been derived from DEB theory, ranging from the full "standard" DEB animal model to simplified "DEBtox" models. It is currently unclear what impact a different level of model complexity can have on the regulatory risk assessment. In the present study, we compare the performance of two DEB-TKTD models with different levels of complexity, focusing on model calibration on standard test data and on forward predictions for untested time-variable exposure profiles. The first model is based on the standard DEB model with primary parameters, whereas the second is a reduced version with compound parameters, based on DEBkiss. After harmonization of the modeling choices, we demonstrate that these two models can achieve very similar performances both in the calibration step and in the forward prediction step. With the data presented in the present study, selection of the most suitable TKTD model for ERA therefore cannot be based alone on goodness-of-fit or on the precision of model predictions (within current ERA procedures for pesticides) but would likely be based on the trade-off between ease of use and model flexibility. We also stress the importance of modeling choices, such as how to fill gaps in the information content of experimental toxicity data and how to accommodate differences in growth and reproduction between different data sets for the same chemical-species combination. Environ Toxicol Chem 2024;43:440-449. © 2023 ibacon GmbH. Bayer AG and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

A Toxicokinetic-Toxicodynamic Modeling Workflow Assessing the Quality of Input Mortality Data.

Toxicokinetic-toxicodynamic (TKTD) models simulate organismal uptake and elimination of a substance (TK) and its effects on the organism (TD). The Reduced General Unified Threshold model of Survival (GUTS-RED) is a TKTD modeling framework that is well established for aquatic risk assessment to simulate effects on survival. The TKTD models are applied in three steps: parameterization based on experimental data (calibration), comparing predictions with independent data (validation), and prediction of endpoints under environmental scenarios. Despite a clear understanding of the sensitivity of GUTS-RED predictions to the model parameters, the influence of the input data on the quality of GUTS-RED calibration and validation has not been systematically explored. We analyzed the performance of GUTS-RED calibration and validation based on a unique, comprehensive data set, covering different types of substances, exposure patterns, and aquatic animal species taxa that are regularly used for risk assessment of plant protection products. We developed a software code to automatically calibrate and validate GUTS-RED against survival measurements from 59 toxicity tests and to calculate selected model evaluation metrics. To assess whether specific survival data sets were better suited for calibration or validation, we applied a design in which all possible combinations of studies for the same species-substance combination are used for calibration and validation. We found that uncertainty of calibrated parameters was lower when the full range of effects (i.e., from high survival to high mortality) was covered by input data. Increasing the number of toxicity studies used for calibration further decreased parameter uncertainty. Including data from both acute and chronic studies as well as studies under pulsed and constant exposure in model calibrations improved model predictions on different types of validation data. Using our results, we derived a workflow, including recommendations for the sequence of modeling steps from the selection of input data to a final judgment on the suitability of GUTS-RED for the data set. Environ Toxicol Chem 2024;43:197-210. © 2023 Bayer AG and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Aquatic Risks at the Landscape Scale: A Case Study for Pyrethroid Use in Pome Fruit Orchards in Belgium.

Procedures for environmental risk assessment for pesticides are under continuous development and subject to debate, especially at higher tier levels. Spatiotemporal dynamics of both pesticide exposure and effects at the landscape scale are largely ignored, which is a major flaw of the current risk assessment system. Furthermore, concrete guidance on risk assessment at landscape scales in the regulatory context is lacking. In this regard, we present an integrated modular simulation model system that includes spatiotemporally explicit simulation of pesticide application, fate, and effects on aquatic organisms. As a case study, the landscape model was applied to the Rummen, a river catchment in Belgium with a high density of pome fruit orchards. The application of a pyrethroid to pome fruit and the corresponding drift deposition on surface water and fate dynamics were simulated. Risk to aquatic organisms was quantified using a toxicokinetic/toxicodynamic model for individual survival at different levels of spatial aggregation, ranging from the catchment scale to individual stream segments. Although the derivation of landscape-scale risk assessment end points from model outputs is straightforward, a dialogue within the community, building on concrete examples as provided by this case study, is urgently needed in order to decide on the appropriate end points and on the definition of representative landscape scenarios for use in risk assessment.

Joint survival modelling for multiple species exposed to toxicants.

In environmental risk assessment (ERA), the multitude of compounds and taxa demands cross-species extrapolation to cover the variability in sensitivity to toxicants. However, only the impact of a single compound to a single species is addressed by the general unified threshold model of survival (GUTS). The reduced GUTS is the recommended model to analyse lethal toxic effects in regulatory aquatic ERA. GUTS considers toxicokinetics and toxicodynamics. Two toxicodynamic approaches are considered: Stochastic death (SD) assumes that survival decreases with an increasing internalized amount of the toxicant. Individual tolerance (IT) assumes that individuals vary in their tolerance to toxic exposure. Existing theory suggests that the product of the threshold zw and killing rate bw (both SD toxicodynamic parameters) are constant across species or compounds if receptors and target sites are shared. We extend that theory and show that the shape parameter ß of the loglogistic threshold distribution in IT is also constant. To verify the predicted relationships, we conducted three tests using toxicity studies for eight arthropods exposed to the insecticide flupyradifurone. We confirmed previous verifications of the relation- between SD parameters, and the newly established relation for the IT parameter ß. We enhanced GUTS to jointly model survival for multiple species with shared receptors and pathways by incorporating the relations among toxicodynamic parameters described above. The joint GUTS exploits the shared parameter relations and therefore constrains parameter uncertainty for each of the separate species. Particularly for IT, the joint GUTS more precisely predicted risk to the separate species than the standard single species GUTS under environmentally realistic exposure. We suggest that joint GUTS modelling can improve cross-species extrapolation in regulatory ERA by increasing the reliability of risk estimates and reducing animal testing. Furthermore, the shared toxicodynamic response provides potential to reduce complexity of ecosystem models.

Physiological Dependency Explains Temperature Differences in Sensitivity Towards Chemical Exposure.

In chemical risk assessment, extrapolations from laboratory tests to more realistic conditions are essential to address the toxic effects of pesticides on individuals and populations under field conditions. To transfer toxicological laboratory tests to differing temperature conditions, or outdoor field scenarios, the consideration of temperature dependence is essential and increases realism. Special consideration is given to the impact of temperature on direct sensitivity of organisms to pesticides, for which there are only few modelling approaches available so far. We present a concept for applying physiological temperature dependencies to toxicokinetic-toxicodynamic (TKTD) parameters in the General Uniformed Threshold model of Survival (GUTS). To test this approach in an exemplary study, temperature dependencies from studies on the developmental rate of the mayfly Cloeon dipterum were applied to the parameters of a previously parameterised TKTD model of this species after exposure to imidacloprid. Using a physiologically derived temperature correction for the TKTD rate constants, model predictions for independently conducted toxicology experiments with temperature ranges between 7.8 and 26.4 °C were performed for validation. Our approach demonstrates the successful transfer of a physiological observed temperature dependency on toxicity parameters and survival patterns for Cloeon dipterum and imidacloprid as a case study.

Energetic basis for bird ontogeny and egg-laying applied to the bobwhite quail.

Birds build up their reproductive system and undergo major tissue remodeling for each reproductive season. Energetic specifics of this process are still not completely clear, despite the increasing interest. We focused on the bobwhite quail - one of the most intensely studied species due to commercial and conservation interest - to elucidate the energy fluxes associated with reproduction, including the fate of the extra assimilates ingested prior to and during reproduction. We used the standard Dynamic Energy Budget model, which is a mechanistic process-based model capable of fully specifying and predicting the life cycle of the bobwhite quail: its growth, maturation and reproduction. We expanded the standard model with an explicit egg-laying module and formulated and tested two hypotheses for energy allocation of extra assimilates associated with reproduction: Hypothesis 1, that the energy and nutrients are used directly for egg production; and Hypothesis 2, that the energy is mostly spent fueling the increased metabolic costs incurred by building up and maintaining the reproductive system and, subsequently, by egg-laying itself. Our results suggest that Hypothesis 2 is the more likely energy pathway. Model predictions capture well the whole ontogeny of a generalized northern bobwhite quail and are able to reproduce most of the data variability via variability in (i) egg size, (ii) egg-laying rate and (iii) inter-individual physiological variability modeled via the zoom factor, i.e. assimilation potential. Reliable models with a capacity to predict physiological responses of individuals are relevant not only for experimental setups studying effects of various natural and anthropogenic pressures on the quail as a bird model organism, but also for wild quail management and conservation. The model is, with minor modifications, applicable to other species of interest, making it a most valuable tool in the emerging field of conservation physiology.

Integrating earthworm movement and life history through dynamic energy budgets.

Earthworms are considered ecosystem engineers and, as such, they are an integral part of the soil ecosystem. The movement of earthworms is significantly influenced by environmental factors such as temperature and soil properties. As movement may directly be linked to food ingestion, especially of endogeic species like Aporrectodea caliginosa, changes in those environmental factors also affect life history traits such as growth and reproduction. In our laboratory studies, earthworms showed a decrease in burrowing activity with decreasing moisture levels and, to some extent, the organic matter content. The burrowing activity of earthworms was also affected by temperature, for which the casts produced per earthworm was used as a proxy in laboratory experiments. We integrated changes in earthworm movement and life histories in response to temperature, soil organic matter content and the moisture level, as observed in our experiment and reported in the literature, through dynamic energy budget (DEB) modelling. The joint parametrization of a DEB model for A. caliginosa based on movement and life history data revealed that food ingestion via movement is an integral part of the earthworms' energy budgets. Our findings highlight the importance of soil properties to be considered in the model development for earthworms. Furthermore, by understanding and incorporating the effect of environmental factors on the physiology, this mechanistic approach can help assess the impact of environmental changes such as temperature rise or drought.

A Dynamic Energy Budget Approach for the Prediction of Development Times and Variability in Spodoptera frugiperda Rearing.

A major challenge in insect rearing is the need to provide certain life cycle stages at a given time for the initiation of experimental trials. The timing of delivery, organism quality, and variability directly affect the outcome of such trials. Development times and intraspecific variability are directly linked to the availability of food and to the ambient temperature. Varying temperature regimes is an approach to adapt development times to fulfill experimental needs without impairment of larval quality. However, current practices of temperature setting may lead to increased variability in terms of development times and the frequency of particular life stages at a given point in time. In this study, we analyzed how resource availability and ambient temperature may affect the larval development of the economically important noctuid species Spodoptera frugiperda by means of dynamic energy budget modeling. More specifically, we analyzed how rearing practices such as raising of temperatures may affect the variability in larval development. Overall, the presented modeling approach provides a support system for decisions that must be made for the timely delivery of larvae and reduction of variability.

Disentangling Mechanisms Behind Chronic Lethality through Toxicokinetic-Toxicodynamic Modeling.

Ecotoxicological profiles of the 3 insecticides imidacloprid, thiacloprid, and flupyradifurone in terms of acute and chronic effects were analyzed in Chironomus riparius. Toxicokinetic-toxicodynamic modeling revealed that chironomids would die from starvation as a result of prolonged feeding inhibition under chronic exposures. The starvation effect is an indirect cause for mortality, which, for the neonicotinoids, adds to the direct/acute mortality, although the results suggests that this additional effect is not relevant for flupyradifurone. Environ Toxicol Chem 2021;40:1706-1712. © 2021 Bayer Inc. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Mechanistic Effect Modeling of Earthworms in the Context of Pesticide Risk Assessment: Synthesis of the FORESEE Workshop.

Earthworms are important ecosystem engineers, and assessment of the risk of plant protection products toward them is part of the European environmental risk assessment (ERA). In the current ERA scheme, exposure and effects are represented simplistically and are not well integrated, resulting in uncertainty when the results are applied to ecosystems. Modeling offers a powerful tool to integrate the effects observed in lower tier laboratory studies with the environmental conditions under which exposure is expected in the field. This paper provides a summary of the (In)Field Organism Risk modEling by coupling Soil Exposure and Effect (FORESEE) Workshop held 28-30 January 2020 in Düsseldorf, Germany. This workshop focused on toxicokinetic-toxicodynamic (TKTD) and population modeling of earthworms in the context of ERA. The goal was to bring together scientists from different stakeholder groups to discuss the current state of soil invertebrate modeling and to explore how earthworm modeling could be applied to risk assessments, in particular how the different model outputs can be used in the tiered ERA approach. In support of these goals, the workshop aimed at addressing the requirements and concerns of the different stakeholder groups to support further model development. The modeling approach included 4 submodules to cover the most relevant processes for earthworm risk assessment: environment, behavior (feeding, vertical movement), TKTD, and population. Four workgroups examined different aspects of the model with relevance for risk assessment, earthworm ecology, uptake routes, and cross-species extrapolation and model testing. Here, we present the perspectives of each workgroup and highlight how the collaborative effort of participants from multidisciplinary backgrounds helped to establish common ground. In addition, we provide a list of recommendations for how earthworm TKTD modeling could address some of the uncertainties in current risk assessments for plant protection products. Integr Environ Assess Manag 2021;17:352-363. © 2020 SETAC.

The Effect of Dietary Exposure to Coal Ash Contaminants within Food Ration on Growth and Reproduction in Daphnia magna.

Coal ash contains numerous contaminants and is the focus of regulatory actions and risk assessments due to environmental spills. We exposed Daphnia magna to a gradient of coal ash contamination under high and low food rations to assess the sublethal effects of dietary exposures. Whereas exposure to contaminants resulted in significant reductions in growth and reproduction in daphnids, low, environmentally relevant food rations had a much greater effect on these endpoints. Environ Toxicol Chem 2020;39:1998-2007. © 2020 SETAC.

Towards a spatiotemporally explicit toxicokinetic-toxicodynamic model for earthworm toxicity.

The aim of the environmental risk assessment of chemicals is the prevention of unacceptable adverse effects on the environment. Therefore, the risk assessment for in-soil organisms, such as earthworms, is based on two key elements: the exposure assessment and the effect assessment. In the current risk assessment scheme, these two elements are not linked. While for the exposure assessment, advanced exposure models can take the spatial and temporal scale of substances into account, the effect assessment in the lower tiers considers only a limited temporal and spatial variability. However, for soil organisms, such as earthworms, those scales play a significant role as species move through the soil in response to environmental factors. To overcome this gap, we propose a conceptual integration of pesticide exposure, ecology, and toxicological effects on earthworms using a modular modeling approach. An essential part of this modular approach is the environment module, which utilizes exposure models to provide spatially and temporally explicit information on environmental variables (e.g., temperature, moisture, organic matter content) and chemical concentrations. The behavior module uses this information and simulates the feeding and movement of different earthworm species using a trait-based approach. The resulting exposure can be processed by a toxicokinetic-toxicodynamic (TKTD) module. TKTD models are particularly suitable to make effect predictions for time-variable exposure situations as they include the processes of uptake, elimination, internal distribution, and biotransformation of chemicals and link the internal concentration to an effect at the organism level. The population module incorporates existing population models of different earthworm species. The modular approach is illustrated using a case study with an insecticide. Our results emphasize that using a modular model approach will facilitate the integration of exposure and effects and thus enhance the risk assessment of soil organisms.

Mechanistic Effect Modeling Approach for the Extrapolation of Species Sensitivity.

In the higher-tier environmental risk assessment of chemicals, species sensitivity distributions (SSDs) are used to statistically describe differences in sensitivity between species and derive community level endpoints. SSDs are usually based on the results from short-term laboratory experiments performed under constant environmental conditions. However, different species may be kept at different "optimal" temperatures, which influence their apparent sensitivity and thus the derivation of endpoints. Also, the extrapolation capacity of SSDs is largely limited to the tested species and conditions. Time-variable exposures and effects at higher levels of biological organization, including biological interactions, are not considered. The quantitative effect prediction at higher tiers would ultimately require the extrapolation of toxicokinetics and toxicodynamics to untested species and the involvement of population and community modeling. In this regard, we tested a toxicokinetic-toxicodynamic modeling approach to mechanistically consider and correct endpoints for ambient temperature and demonstrate the significance for SSDs. We explored correlations in toxicokinetic-toxicodynamic model parameters which would allow for the extrapolation of sensitivities to untested species. Finally, we illustrate the applicability of the approach for higher level effect predictions using an individual-based model. Our results suggest that mechanistic effect modeling approaches can reduce the uncertainties in higher tier effect assessments related to knowledge gaps.

REGULATION OF REPRODUCTIVE PROCESSES WITH DYNAMIC ENERGY BUDGETS.

1. The simple bioenergetic models in the family of Dynamic Energy Budget (DEB) consist of a small number of state equations quantifying universal processes, such as feeding, maintenance, development, reproduction and growth. Linking these organismal level processes to underlying suborganismal mechanisms at the molecular, cellular and organ level constitutes a major challenge for predictive ecological risk assessments. 2. Motivated by the need for process-based models to evaluate the impact of endocrine disruptors on ecologically relevant endpoints, this paper develops and evaluates two general modeling modules describing demand-driven feedback mechanisms exerted by gonads on the allocation of resources to production of reproductive matter within the DEB modeling framework. 3. These modules describe iteroparous, semelparous and batch-mode reproductive strategies. The modules have a generic form with both positive and negative feedback components; species and sex specific attributes of endocrine regulation can be added without changing the core of the modules. 4. We demonstrate that these modules successfully describe time-resolved measurements of wet weight of body, ovaries and liver, egg diameter and plasma content of vitellogenin and estradiol in rainbow trout (Oncorynchus mykiss) by fitting these models to published and new data, which require the estimation of less than two parameters per data type. 5. We illustrate the general applicability of the concept of demand-driven allocation of resources to reproduction as worked out in this paper by evaluating one of the modules with data on growth and seed production of an annual plant, the common bean (Phaseolis vulgaris).

Incorporating Suborganismal Processes into Dynamic Energy Budget Models for Ecological Risk Assessment.

A working group at the National Institute for Mathematical and Biological Synthesis (NIMBioS) explored the feasibility of integrating 2 complementary approaches relevant to ecological risk assessment. Adverse outcome pathway (AOP) models provide "bottom-up" mechanisms to predict specific toxicological effects that could affect an individual's ability to grow, reproduce, and/or survive from a molecular initiating event. Dynamic energy budget (DEB) models offer a "top-down" approach that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources. Thus, AOP models quantify linkages between measurable molecular, cellular, or organ-level events, but they do not offer an explicit route to integratively characterize stressor effects at higher levels of organization. While DEB models provide the inherent basis to link effects on individuals to those at the population and ecosystem levels, their use of abstract variables obscures mechanistic connections to suborganismal biology. To take advantage of both approaches, we developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates. We report on the type and structure of data that are generated for AOP models that may also be useful for DEB models. We also report on case studies under development that merge information collected for AOPs with DEB models and highlight some of the challenges. Finally, we discuss how the linkage of these 2 approaches can improve ecological risk assessment, with possibilities for progress in predicting population responses to toxicant exposures within realistic environments. Integr Environ Assess Manag 2018;14:615-624. © 2018 SETAC.

Modelling survival: exposure pattern, species sensitivity and uncertainty.

The General Unified Threshold model for Survival (GUTS) integrates previously published toxicokinetic-toxicodynamic models and estimates survival with explicitly defined assumptions. Importantly, GUTS accounts for time-variable exposure to the stressor. We performed three studies to test the ability of GUTS to predict survival of aquatic organisms across different pesticide exposure patterns, time scales and species. Firstly, using synthetic data, we identified experimental data requirements which allow for the estimation of all parameters of the GUTS proper model. Secondly, we assessed how well GUTS, calibrated with short-term survival data of Gammarus pulex exposed to four pesticides, can forecast effects of longer-term pulsed exposures. Thirdly, we tested the ability of GUTS to estimate 14-day median effect concentrations of malathion for a range of species and use these estimates to build species sensitivity distributions for different exposure patterns. We find that GUTS adequately predicts survival across exposure patterns that vary over time. When toxicity is assessed for time-variable concentrations species may differ in their responses depending on the exposure profile. This can result in different species sensitivity rankings and safe levels. The interplay of exposure pattern and species sensitivity deserves systematic investigation in order to better understand how organisms respond to stress, including humans.

Demographic Toxicokinetic-Toxicodynamic Modeling of Lethal Effects.

The aquatic effect assessment of chemicals is largely based on standardized measures of toxicity determined in short-term laboratory tests which are designed to reduce variability. For this purpose, uniform individuals of a species are kept under environmental and chemical exposure conditions which are as constant as possible. In nature, exposure often appears to be pulsed, effects might last longer than a few days, sensitivity might vary among different sized organisms and populations are usually size or age structured and are subject to demographic processes. To overcome this discrepancy, we tested toxicokinetic-toxicodynamic models of different complexities, including body size scaling approaches, for their ability to represent lethal effects observed for Daphnia magna exposed to triphenyltin. The consequences of the different toxicokinetic and toxicodynamic assumptions for population level responses to pulsed exposure are tested by means of an individual based model and are evaluated by confronting model predictions with population data for various pulsed exposure scenarios. We provide an example where increased model complexity reduces the uncertainty in model outputs. Furthermore, our results emphasize the importance of considering population demography in toxicokinetics and toxicodynamics for understanding and predicting potential chemical impacts at higher levels of biological organization.

Ecological Recovery Potential of Freshwater Organisms: Consequences for Environmental Risk Assessment of Chemicals.

Chemical contaminants released into the in the environment may have adverse effects on (non-target) species, populations and communities. The return of a stressed system to its pre-disturbance or other reference state, i.e. the ecological recovery, may depend on various factors related to the affected taxon, the ecosystem of concern and the type of stressor with consequences for the assessment and management of risks associated with chemical contaminants. Whereas the effects caused by short-term exposure might be acceptable to some extent, the conditions under which ecological recovery can serve as a decision criterion in the environmental risk assessment of chemical stressors remains to be evaluated. For a generic consideration of recovery in the risk assessment of chemicals, we reviewed case studies of natural and artificial aquatic systems and evaluate five aspects that might cause variability in population recovery time: (1) taxonomic differences and life-history variability, (2) factors related to ecosystem type and community processes, (3) type of disturbance, (4) comparison of field and semi-field studies, and (5) effect magnitude, i.e., the decline in population size following disturbance. We discuss our findings with regard to both retrospective assessments and prospective risk assessment.