Toxicokinetic-toxicodynamic Models Research Articles

A dynamic energy budget (DEB) model to assess the sublethal effects of imidacloprid toward Gammarus pulex at different temperatures

Environmental ambient temperature significantly impacts the metabolic activities of aquatic ectotherm organisms and influences the fate of various chemicals. Although numerous studies have shown that the acute lethal toxicity of most chemicals increases with increasing temperature, the impact of temperature on chronic effects — encompassing both lethal and sublethal endpoints — has received limited attention. Furthermore, the mechanisms linking temperature and toxicity, potentially unveiled by toxicokinetic-toxicodynamic models (TKTD), remains inadequately explored. This study investigated the effects of environmentally relevant concentrations of the insecticide imidacloprid (IMI) on the growth and survival of the freshwater amphipod Gammarus pulex at two different temperatures. Our experimental design was tailored to fit a TKTD model, specifically the Dynamic Energy Budget (DEB) model. We conducted experiments spanning three and six months, utilizing small G. pulex juveniles. We observed effects endpoints at least five times, employing both destructive and non-destructive methods, crucial for accurate model fittings. Our findings reveal that IMI at environmental concentrations (up to 0.3 μg/L) affects the growth and survival of G. pulex, albeit with limited effects, showing a 10% inhibition compared to the control group. These limited effects, observed in both lethal and sublethal aspects, suggest a different mode of action at low, environmentally-relevant concentrations in long-term exposure (3 months), in contrast to previous studies which applied higher concentrations and found that sublethal effects occurred at significantly lower levels than lethal effects in an acute test setting (4 days). Moreover, after parameterizing the DEB model for various temperatures, we identified a lower threshold for both lethal and sublethal effects at higher temperatures, indicating increased intrinsic sensitivity. Overall, this study contributes to future risk assessments considering temperature as a crucial factor and exemplifies the integration of the DEB model into experimental design for comprehensive toxicity evaluations.

The Importance of Including Variable Exposure Concentrations When Assessing Toxicity of Sediment-Associated Pharmaceuticals to an Amphipod.

Pharmaceuticals have been classified as an environmental concern due to their increasing consumption globally and potential environmental impact. We examined the toxicity of sediment-associated diclofenac and citalopram administered as both single compounds and in a mixture to the sediment-living amphipod Corophium volutator. This laboratory-based study addressed the following research questions: (1) What is the toxicity of sediment-associated diclofenac and citalopram to C. volutator? (2) Can the mixture effect be described with either of the two mixture models: concentration addition (CA) or independent action (IA)? (3) What is the importance of the choice of (i) exposure measure (start concentration, time-weighted average [TWA], full exposure profile) and (ii) effect model (concentration-response vs. the toxicokinetic-toxicodynamic model general unified threshold model for survival in its reduced form [GUTS-RED]) for the derived effect concentration values? Diclofenac was more toxic than citalopram to C. volutator as a single compound (10-day exposure). Diclofenac exposure to C. volutator provided median lethal concentrations (LC50s) within the same range (11 µg g-1 dry wt sediment) using concentration-response based on TWA and both GUTS-RED models. However, concentration-response based on measured start concentrations provided an approximately 90% higher LC50 (21.6 ± 2.0 µg g-1 dry wt sediment). For citalopram, concentration-response parameters were similar regardless of model or concentration used (LC50 85-97 µg g-1 dry wt sediment), however, GUTS-RED with the assumption of individual tolerance resulted in a lower LC50 (64.9 [55.3-74.8] µg g-1 dry wt sediment). The mixture of diclofenac and citalopram followed the CA quite closely, whereas the result was synergistic when using the IA prediction. In summary, concentration-response based on TWA and GUTS-RED provided similar and reasonably good fits compared to the data set. The implications are that GUTS-RED will provide a more flexible model, which, in principle, can extend beyond the experimental period and make predictions based on variable exposure profiles (toxicity at different time frames and at different variable exposure scenarios) compared to concentration-response, which provides contaminant toxicity at one point in time. Environ Toxicol Chem 2024;00:1-11. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Comparing Sensitivity of Different Bee Species to Pesticides: A TKTD modeling approach.

Risk assessment for bees is mainly based on data for honey bees; however, risk assessment is intended to protect all bee species. This raises the question of whether data for honey bees are a good proxy for other bee species. This issue is not new and has resulted in several publications in which the sensitivity of bee species is compared based on the values of the 48-h median lethal dose (LD50) from acute test results. When this approach is used, observed differences in sensitivity may result both from differences in kinetics and from inherent differences in species sensitivity. In addition, the physiology of the bee, like its overall size, the size of the honey stomach (for acute oral tests), and the physical appearance (for acute contact tests) also influences the sensitivity of the bee. The recently introduced Toxicokinetic-Toxicodynamic (TKTD) model that was developed for the interpretation of honey bee tests (Bee General Uniform Threshold Model for Survival [BeeGUTS]) could integrate the results of acute oral tests, acute contact tests, and chronic tests within one consistent framework. We show that the BeeGUTS model can be calibrated and validated for other bee species and also that the honey bee is among the more sensitive bee species. In addition, we found that differences in sensitivity between species are smaller than previously published comparisons based on 48-h LD50 values. The time-dependency of the LD50 and the specifics of the bee physiology are the main causes of the wider variation found in the published literature. Environ Toxicol Chem 2024;43:1431-1441. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Application of General Unified Threshold Models to Predict Time-Varying Survival of Mayfly Nymphs Exposed to Three Neonicotinoids

Pesticide exposure patterns tested in laboratory bioassays often do not match real-world pesticide exposure profiles in edge-of-field waterbodies. Toxicokinetic–toxicodynamic (TKTD) models are therefore increasingly used, as they allow for predictions of the toxic effects under actual time-variable field exposures. The TKTD models from the General Unified Threshold models of Survival (GUTS), for example, are considered ready for use by regulators for calculating the survival rates for any time-variable exposure profile. However, questions remain regarding their predictive power for compounds showing increased toxicity over time, such as neonicotinoid insecticides. The aim of the present study was therefore to compare the GUTS-predicted 28 d toxicity values of three neonicotinoids (imidacloprid, clothianidin, and thiamethoxam) for the common New Zealand mayfly genus Deleatidium spp. with those observed in a previously published study. Overall, the GUTS modeling results underestimated the toxicity values derived experimentally. From the three neonicotinoids, clothianidin showed the best fit between the estimated and observed 28 d LC50 (median-lethal-concentration) values. Shortcomings of the modeling exercise, future research needs, and implications for the application of GUTS models in regulatory risk assessment are discussed.

Identifying and Predicting Delayed Mortality with Toxicokinetic-Toxicodynamic Models.

The prevalence of standardized toxicity testing in ecotoxicology has largely obscured the notion that toxicity is a function of time as well. The necessity of considering time is vividly demonstrated by observations of delayed mortality, that is, deaths continue to occur even when animals are no longer exposed to a toxicant. In this contribution, I explore to what extent toxicokinetic-toxicodynamic (TKTD) models from the framework of the General Unified Threshold model for Survival (GUTS) can capture delayed mortality, and to what extent this phenomenon can be predicted from short-term standard tests. I use a previously published data set for fluoroquinolones in Daphnia magna that shows strongly delayed mortality (using immobilization as a proxy for death). The model analysis shows that the GUTS stochastic death models can capture delayed mortality in the complete data set with a long recovery phase, but that the delayed effects would not have been predicted from a 2-day standard test. The study underlines the limited information content of standard acute test designs. Toxicokinetic-toxicodynamic modeling offers a handle on the time aspects of toxicity but cannot always be relied on to provide accurate extrapolations based on severely limited standard tests. The phenomenon of delayed toxicity requires more structured study to clarify its prevalence and impact; I discuss several avenues for further investigation. Environ Toxicol Chem 2024;43:1030-1035. © 2024 SETAC.

Mechanistic analysis of the sub chronic toxicity of La and Gd in Daphnia magna based on TKTD modelling and synchrotron X-ray fluorescence imaging.

The release of lanthanides (Ln) into the environment has increased in recent decades due to their expanding applications in society. Studying their toxicity in aquatic ecosystems is urgent and challenging, with contradictory evidence presented in the literature. This study compared the biodistribution of La and Gd in Daphnia magna exposed to sub-chronic conditions and developed the first Toxicokinetic-Toxicodynamic (TKTD) model for these lanthanides with this model crustacean. D. magna were initially exposed for 7 days to concentrations close to the LC50 of La (2.10 mg L-1) and Gd (1.70 mg L−1). After exposure, half of the live daphnids were introduced in a clean media to allow depuration over 24 h, while the other organisms were directly prepared for synchrotron imaging measurements. Synchrotron X-ray fluorescence analysis revealed that metal distribution in the organisms was similar for both La and Gd, predominantly localized in the intestinal tract, even after the depuration process. These results indicate that ingested metal can adversely affect organisms under sub-chronic exposure conditions, highlighting the importance of using nominal concentrations as a more suitable indicator of metal bioavailability for risk assessment. The General Unified Threshold Model of Survival (GUTS) TKTD framework, in its reduced form (GUTS-RED), was developed for La and Gd using dissolved and nominal concentrations. D. magna were exposed for 7 days to concentrations from 0.5 to 5 mg L−1 of La or Gd and mortality monitored daily. The mechanistic model revealed a faster toxicokinetics for La than Gd and a higher toxicity for Gd than La in the organism. This study confirmed, despite similar chemical properties, the variation in both toxicity and toxicokinetics between these two metals.

Predicting the Metal Mixture Toxicity with a Toxicokinetic-Toxicodynamic Model Considering the Time-Dependent Adverse Outcome Pathways.

Chemicals mainly exist in ecosystems as mixtures, and understanding and predicting their effects are major challenges in ecotoxicology. While the adverse outcome pathway (AOP) and toxicokinetic-toxicodynamic (TK-TD) models show promise as mechanistic approaches in chemical risk assessment, there is still a lack of methodology to incorporate the AOP into a TK-TD model. Here, we describe a novel approach that integrates the AOP and TK-TD models to predict mixture toxicity using metal mixtures (specifically Cd-Cu) as a case study. We preliminarily constructed an AOP of the metal mixture through temporal transcriptome analysis together with confirmatory bioassays. The AOP revealed that prolonged exposure time activated more key events and adverse outcomes, indicating different modes of action over time. We selected a potential key event as a proxy for damage and used it as a measurable parameter to replace the theoretical parameter (scaled damage) in the TK-TD model. This refined model, which connects molecular responses to organism outcomes, effectively predicts Cd-Cu mixture toxicity over time and can be extended to other metal mixtures and even multicomponent mixtures. Overall, our results contribute to a better understanding of metal mixture toxicity and provide insights for integrating the AOP and TK-TD models to improve risk assessment for chemical mixtures.

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.

Investigating the Impact of Humic Acid on Copper Accumulation in Sinonovacula constricta Using a Toxicokinetic-Toxicodynamic Model.

In aquatic ecosystems, the interaction between heavy metals and dissolved organic carbon (DOC) plays a pivotal role in modifying the bioavailability of these metals. This study, employing a toxicokinetic-toxicodynamic model, delves into the interactive effects of humic acid (HA), a significant component of DOC, on the bioaccumulation and toxicity of copper (Cu) in the estuarine economic bivalve Sinonovacula constricta. Utilizing the stable isotope 65Cu as a tracer, we evaluated Cu uptake in S. constricta under varied DOC concentrations in a controlled laboratory setting. Our findings reveal that at DOC concentrations below 3.05 mg L-1, the bioavailability of Cu is reduced due to shifts in the speciation distribution of Cu, resulting in decreased bioaccumulation within S. constricta. Conversely, at DOC levels exceeding 3.05 mg L-1, the formation of colloidal Cu-HA complexes allows its entry into the bivalves' digestive system. Moreover, toxicity assays demonstrate an increase in S. constricta survival rates with higher DOC concentrations, suggesting a protective effect of DOC against Cu toxicity. The integration of accumulation and toxicity data infers that Cu-HA complexes, when ingested via the digestive tract, exhibit lower toxicity compared to Cu directly assimilated from the water phase. These findings emphasize the need to consider environmental DOC levels in assessing Cu pollution risks and provide insights for managing heavy metal toxicity in estuarine aquaculture.

A toxicokinetic–toxicodynamic model with a transgenerational damage to explain toxicity changes over generations (in Daphnia magna exposed to depleted uranium).

We used a toxicokinetic–toxicodynamic (TKTD) model to analyze chronic effects, in Daphnia magna exposed to waterborne depleted uranium (DU) for two or three successive generations (F0, F1 and F2). Our aim was to understand how DU toxicity for growth and reproduction increased across generations. For the first time in a TKTD model, we introduced a novel transgenerational damage compartment, whose level was transmitted from parents to progeny upon egg deposition. Various exposure regimes took account of differences in exposure among generations. We used a simplified dynamic energy budget applied to toxicology (DEBtox) including two independent physiological modes of action (pMoA). The first pMoA, a reduction in assimilation linked to internal concentration, was previously confirmed by complementary analyses (direct measurements of carbon assimilation, histological observations of gut epithelium alterations). The second pMoA, an increase in costs for growth and maturation linked to transgenerational damage, was the most likely among three possible pMoA affecting both growth and reproduction. Modelling results showed that internal concentration and transgenerational damage followed strongly different kinetics across generations, suggesting that the two pMoA played very contrasting roles in long-term DU toxicity for D. magna. Internal concentration only increased between generations F0 and F1, showing no further difference between generations F1 and F2. Our model was able to correctly describe and predict DU toxicity data, in all tested generations and concentrations, and provided a mechanistic explanation for the increase in DU toxicity across generations.

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.

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.

A Framework for Algae Modeling in Regulatory Risk Assessment.

The use of toxicokinetic-toxicodynamic (TKTD) modeling in regulatory risk assessment of plant protection products is increasingly popular, especially since the 2018 European Food Safety Authority (EFSA) opinion on TKTD modeling announced that several established models are ready for use in risk assessment. With careful adherence to the guidelines laid out by EFSA, we present a stepwise approach to validation and use of the Simple Algae Model Extended (SAM-X) for regulatory submission in Tier 2C. We demonstrate how the use of moving time windows across time-variable exposure profiles can generate thousands of virtual laboratory mimic simulations that seamlessly predict the effects of time-variable exposures across a full exposure profile while maintaining the laboratory conditions of the standard Organisation for Economic Co-operation and Development (OECD) growth inhibition test. Thus, every virtual laboratory test has a duration of 72 h, with OECD medium and constant light and temperature conditions. The only deviation from the standard test setup is the replacement of constant exposure conditions for time-variable concentrations. The present study demonstrates that for simulation of 72-h toxicity tests, the nutrient dynamics in the SAM-X model are not required, and we propose the alternative use of a simplified model version. For risk assessment, in accordance with the EFSA guidelines we use a median exposure profile of 10 as a threshold, meaning that if a time window within the exposure profile causes 50% growth inhibition when magnified by a factor of 10, the threshold will have been exceeded. We present a simplified example for chlorotoluron and isoproturon. The present case study brings to life our proposed framework for TKTD modeling of algae to establish whether a given exposure can be considered to be of low risk. Environ Toxicol Chem 2023;42:1823-1838. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

An impact-based environmental risk assessment model toolbox for offshore produced water discharges

We present a novel approach to environmental risk assessment of produced water discharges based on explicit impact and probability, using a combination of transport, fate and toxicokinetic-toxicodynamic models within a super-individual framework, with a probabilistic element obtained from ensemble simulations. Our approach is motivated by a need for location and species specific tools which also accounts for the dynamic nature of exposure and uptake of produced water components in the sea.Our approach is based on the well-established fate model DREAM, and accounts for time-variable exposure, considers body burden and effects for specific species and stressors, and assesses the probability of impact. Using a produced water discharge in the Barents Sea, with early life stages of spawning haddock, we demonstrate that it is possible to conduct a model-based risk assessment that highlights the effect of natural variations in environmental conditions. The benefits, limitations and potential for further improvements are discussed.

Higher Risks of Copper Toxicity in Turbid Waters: Quantifying the Bioavailability of Particle-Bound Metals to Set Site-Specific Water Quality Criteria

In coastal waters, particulate metals constitute a substantial fraction of the total metals; however, the prevalent water quality criteria are primarily based on dissolved metals, seemingly neglecting the contribution of particulate metals. Here we developed a method to quantify the toxicity risk of particulate metals, and proposed a way to calculate modifying factors (MFs) for setting site-specific criteria in turbid waters. Specifically, we used a side-by-side experimental design to study copper (Cu) bioaccumulation and toxicity in an estuarine clam, Potamocorbula laevis, under the exposure to "dissolved only" and "dissolved + particulate" 65Cu. A toxicokinetic-toxicodynamic model (TK-TD) was used to quantify the processes of Cu uptake, ingestion, assimilation, egestion, and elimination, and to relate mortality risk to tissue Cu. We find that particulate Cu contributes 40-67% of the Cu bioaccumulation when the suspended particulate matter (SPM) ranges from 12 to 229 mg L-1. The Cu-bearing SPM also increases the sensitivity of organisms to internalized Cu by decreasing the internal threshold concentration (CIT) from 141 to 76.8 μg g-1. MFs were derived based on the TK-TD model to consider the contribution of particulate Cu (in the studied SPM range) for increasing Cu bioaccumulation (MF = 1.3-2.2) and toxicity (MF = 2.3-3.9). Water quality criteria derived from dissolved metal exposure need to be lowered by dividing by an MF to provide adequate protection. Overall, the method we developed provides a scientifically sound framework to manage the risks of metals in turbid waters.

Hb or not hb - When and why accounting for background mortality in toxicological survival models matters?

Decisions in Environmental Risk Assessment (ERA) about impacts of chemical compounds on different species are based on critical effect indicators such as the 50% lethal concentration (LC50). Regulatory documents recommend concentration-response (or concentration-effect) model fitting on standard toxicity test data to get LC50 values. However, toxicokinetic-toxicodynamic (TKTD) models proved their efficiency to better exploit toxicity test data, at Tier-2 but also at Tier-1, delivering time-independent indicators. In particular, LC50 values can be obtained from the reduced General Unified Threshold model of Survival (GUTS-RED) with both variants, Stochastic Death and Individual Tolerance, that include parameter hb, the background mortality. Estimating hb during the fitting process or not depends on studies and fitting habits, while it may strongly influence the other GUTS-RED parameters, and consequently the LC50 estimate. We hypothesized that estimating hb from all data in all replicates over time should provide more precise LC50 estimates. We then explored how estimating hb impacted: (i) GUTS-RED model parameters; (ii) goodness-of-fit criteria (fitting plot, posterior predictive check, parameter correlations); (iii) LC50 accuracy and precision. We finally show that estimating hb does not impact the LC50 precision while providing more accurate and precise GUTS parameter estimates. Hence, estimating hb would lead to a more protective ERA.

Modelling the effects of the pyrethroid insecticide cypermethrin on the life cycle of the soil dwelling annelid Enchytraeus crypticus, an original experimental design to calibrate a DEB-TKTD model

The Dynamic Energy Budget theory (DEB) enables ecotoxicologists to model the effects of chemical stressors on organism life cycles through the coupling of toxicokinetic-toxicodynamic (TK-TD) models. While good progress has been made in the application of DEB-TKTD models for aquatic organisms, applications for soil fauna are scarce, due to the lack of dedicated experimental designs suitable for collecting the required time series effect data. Enchytraeids (Annelida: Clitellata) are model organisms in soil ecology and ecotoxicology. They are recognised as indicators of biological activity in soil, and chemical stress in terrestrial ecosystems. Despite this, the application of DEB-TKTD models to investigate the impact of chemicals has not yet been tested on this family. Here we assessed the impact of the pyrethroid insecticide cypermethrin on the life cycle of Enchytraeus crypticus. We developed an original experimental design to collect the data required for the calibration of a DEB-TKTD model for this species. E. crypticus presented a slow initial growth phase that has been successfully simulated with the addition of a size-dependent food limitation for juveniles in the DEB model. The DEB-TKTD model simulations successfully agreed with the data for all endpoints and treatments over time. The highlighted physiological mode of action (pMoA) for cypermethrin was an increase of the growth energy cost. The threshold for effects on survival was estimated at 73.14 mg kg− 1, and the threshold for effects on energy budget (i.e., sublethal effects) at 19.21 mg kg− 1. This study demonstrates that DEB-TKTD models can be successfully applied to E. crypticus as a representative soil species, and may improve the ecological risk assessment for terrestrial ecosystems, and our mechanistic understanding of chemical effects on non-target species.

Using the standard DEB animal model for toxicokinetic-toxicodynamic analysis

Toxicokinetic-toxicodynamic (TKTD) models are essential tools to close the gap between laboratory toxicity tests and impacts on individuals under field conditions. For sub-lethal effects on life-history traits, dynamic energy budget (DEB) theory provides a solid basis for TKTD modelling. Various DEB-based TKTD models have been presented, ranging from complex and comprehensive to simple and reduced. Here we present a complete and up-to-date model formulation at the complex end of the range. The basic part of the model, governing the life cycle of the species without toxicant stress, is formed by the standard DEB animal model. This part can directly use the species-specific model parameters from the add-my-pet (AmP) library. Additionally, we cover one extension of the standard model with metabolic acceleration for some time after birth (the abj-model). The basic DEB model is augmented by a TKTD model that explicitly considers damage as driving force for the toxic effects, and which considers various feedbacks from life-history traits to damage dynamics (e.g., dilution by growth). Several choices are needed in this linkage, which are made explicit. A Matlab-based toolbox is presented to support the model analyses, which is illustrated with a case study for the springtail Folsomia candida exposed to chlorpyrifos in food.

Modeling Time-Dependent Aquatic Toxicity of Hydrocarbons: Role of Organism Weight, Temperature, and Substance Hydrophobicity.

Oil spill exposures are highly dynamic and are not comparable to laboratory exposures used in standard toxicity tests. Toxicokinetic-toxicodynamic (TKTD) models allow translation of effects observed in the laboratory to the field. To improve TKTD model calibration, new and previously published data from 148 tests were analyzed to estimate rates characterizing the time course of toxicity for 10 fish and 42 invertebrate species across 37 hydrocarbons. A key parameter in the TKTD model is the first-order rate that incorporates passive elimination, biotransformation, and damage repair processes. The results indicated that temperature (4-26 °C), organism size (0.0001-10 g), and substance log octanol-water partition coefficient (2-6) had limited influence on this parameter, which exhibited a 5th to 95th percentile range of 0.2-2.5 day-1 (median 0.7 day-1 ). A species sensitivity distribution approach is proposed to quantify the variability of this parameter across taxa, with further studies needed for aliphatic hydrocarbons and plant species. Study findings allow existing oil spill models to be refined to improve effect predictions. Environ Toxicol Chem 2022;41:3070-3083. © 2022 ExxonMobil Biomedical Science Inc. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Explicit Consideration of Temperature Improves Predictions of Toxicokinetic-Toxicodynamic Models for Flupyradifurone and Imidacloprid in Gammarus pulex.

In the face of global climate change, where temperature fluctuations and the frequency of extreme weather events are increasing, it is needed to evaluate the impact of temperature on the ecological risk assessment of chemicals. Current state-of-the-art mechanistic effect models, such as toxicokinetic-toxicodynamic (TK-TD) models, often do not explicitly consider temperature as a modulating factor. This study implemented the effect of temperature in a widely used modeling framework, the General Unified Threshold model for Survival (GUTS). We tested the model using data from toxicokinetic and toxicity experiments with Gammarus pulex exposed to the insecticides imidacloprid and flupyradifurone. The experiments revealed increased TK rates with increasing temperature and increased toxicity under chronic exposures. Using the widely used Arrhenius equation, we could include the temperature influence into the modeling. By further testing of different model approaches, differences in the temperature scaling of TK and TD model parameters could be identified, urging further investigations of the underlying mechanisms. Finally, our results show that predictions of TK-TD models improve if we include the toxicity modulating effect of temperature explicitly.