Toxicokinetic-Toxicodynamic Model to Assess Thermal Stress.

Temperature is a crucial environmental factor affecting the distribution and performance of ectothermic organisms. This study introduces a new temperature damage model to interpret their thermal stress. Inspired by the ecotoxicological damage model in the General Unified Threshold model for Survival (GUTS) framework, the temperature damage model assumes that damage depends on the balance between temperature-dependent accumulation and constant repair. Mortality due to temperature stress is driven by the damage level exceeding a threshold. Model calibration showed a good agreement with the measured survival of Gammarus pulex exposed to different constant temperatures. Further, model simulations, including constant temperatures, daily temperature fluctuations, and heatwaves, demonstrated the model's ability to predict temperature effects for various environmental scenarios. With this, the present study contributes to the mechanistic understanding of temperature as a single stressor while facilitating the incorporation of temperature as an additional stressor alongside chemicals in mechanistic multistressor effect models.

Elimination Resistance: Characterizing Multi-compartment Toxicokinetics of the Neonicotinoid Thiacloprid in the Amphipod Gammarus pulex Using Bioconcentration and Receptor-Binding Assays.

Delayed toxicity is a phenomenon observed for aquatic invertebrates exposed to nicotinic acetylcholine receptor (nAChR) agonists, such as neonicotinoids. Furthermore, recent studies have described an incomplete elimination of neonicotinoids by exposed amphipods. However, a mechanistic link between receptor binding and toxicokinetic modeling has not been demonstrated yet. The elimination of the neonicotinoid thiacloprid in the freshwater amphipod Gammarus pulex was studied in several toxicokinetic exposure experiments, complemented with in vitro and in vivo receptor-binding assays. Based on the results, a two-compartment model was developed to predict the uptake and elimination kinetics of thiacloprid in G. pulex. An incomplete elimination of thiacloprid, independent of elimination phase duration, exposure concentrations, and pulses, was observed. Additionally, the receptor-binding assays indicated irreversible binding of thiacloprid to the nAChRs. Accordingly, a toxicokinetic-receptor model consisting of a structural and a membrane protein (including nAChRs) compartment was developed. The model successfully predicted internal thiacloprid concentrations across various experiments. Our results help in understanding the delayed toxic and receptor-mediated effects toward arthropods caused by neonicotinoids. Furthermore, the results suggest that more awareness toward long-term toxic effects of irreversible receptor binding is needed in a regulatory context. The developed model supports the future toxicokinetic assessment of receptor-binding contaminants.

The effect of temperature on toxicokinetics and the chronic toxicity of insecticides towards Gammarus pulex.

A comprehensive understanding of chemical toxicity and temperature interaction is essential to improve ecological risk assessment under climate change. However, there is only limited knowledge about the effect of temperature on the toxicity of chemicals. To fill this knowledge gap and to improve our mechanistic understanding of the influence of temperature, the current study explored toxicokinetics and the chronic toxicity effects of two insecticides, imidacloprid (IMI) and flupyradifurone (FPF), on Gammarus pulex at different temperatures (7-24 °C). In the toxicokinetics tests, organisms were exposed to IMI or FPF for 2 days and then transferred to clean water for 3 days of elimination at 7, 18, or 24 °C. In the chronic tests, organisms were exposed to the individual insecticides for 28 days at 7, 11, or 15 °C. Our research found that temperature impacted the toxicokinetics and the chronic toxicity of both IMI and FPF, while the extent of such impact differed for each insecticide. For IMI, the uptake rate and biotransformation rate increased with temperature, and mortality and food consumption inhibition was enhanced by temperature. While for FPF, the elimination rate increased with temperature at a higher rate than the increasing uptake rate, resulting in a smaller pronounced effect of temperature on mortality compared to IMI. In addition, the adverse effects of the insecticides on sublethal endpoints (food consumption and dry weight) were exacerbated by elevated temperatures. Our results highlight the importance of including temperature in the ecological risk assessment of insecticides in light of global climate change.

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.

Comparing the acute and chronic toxicity of flupyradifurone and imidacloprid to non-target aquatic arthropod species.

Flupyradifurone (FPF) is a new type of butenolide insecticide. It was launched on the market in 2015 and is considered an alternative to the widely used neonicotinoids, like imidacloprid (IMI), some of which are banned from outdoor use in the European Union. FPF is claimed to be safe for bees, but its safety for aquatic organisms is unknown. Its high water solubility, persistence in the environment, and potential large-scale use make it urgent to evaluate possible impacts on aquatic systems. The current study assessed the acute and chronic toxicity of FPF for aquatic arthropod species and compared these results with those of imidacloprid. Besides, toxicokinetics and toxicokinetic-toxicodynamic models were used to understand the mechanisms of the toxicity of FPF. The present study results showed that organisms take up FPF slower than IMI and eliminate it faster. In addition, the hazardous concentration 5th percentiles (HC05) value of FPF derived from a species sensitivity distribution (SSD) based on acute toxicity was found to be 0.052 µmol/L (corresponding to 15 µg/L), which was 37 times higher than IMI (0.0014 µmol/L, corresponding to 0.36 µg/L). The chronic 28 days EC10 of FPF for Cloeon dipterum and Gammarus pulex were 7.5 µg/L and 2.9 µg/L, respectively. For G. pulex, after 28 days of exposure, the no observed effect concentration (NOEC) of FPF for food consumption was 0.3 µg/L. A toxicokinetic-toxicodynamic (TKTD) model parameterised on the acute toxicity data well predicted the observed chronic effects of FPF on G. pulex, indicating that toxicity mechanisms of FPF did not change with prolonged exposure time, which is not the case for IMI.

Combined effects of heatwaves and micropollutants on freshwater ecosystems: Towards an integrated assessment of extreme events in multiple stressors research.

Freshwater ecosystems are strongly influenced by weather extremes such as heatwaves (HWs), which are predicted to increase in frequency and magnitude in the future. In addition to these climate extremes, the freshwater realm is impacted by the exposure to various classes of chemicals emitted by anthropogenic activities. Currently, there is limited knowledge on how the combined exposure to HWs and chemicals affects the structure and functioning of freshwater ecosystems. Here, we review the available literature describing the single and combined effects of HWs and chemicals on different levels of biological organization, to obtain a holistic view of their potential interactive effects. We only found a few studies (13 out of the 61 studies included in this review) that investigated the biological effects of HWs in combination with chemical pollution. The reported interactive effects of HWs and chemicals varied largely not only within the different trophic levels but also depending on the studied endpoints for populations or individuals. Hence, owing also to the little number of studies available, no consistent interactive effects could be highlighted at any level of biological organization. Moreover, we found an imbalance towards single species and population experiments, with only five studies using a multitrophic approach. This results in a knowledge gap for relevant community and ecosystem level endpoints, which prevents the exploration of important indirect effects that can compromise food web stability. Moreover, this knowledge gap impairs the validity of chemical risk assessments and our ability to protect ecosystems. Finally, we highlight the urgency of integrating extreme events into multiple stressors studies and provide specific recommendations to guide further experimental research in this regard.

Toxicokinetic Models for Bioconcentration of Organic Contaminants in Two Life Stages of White Sturgeon (Acipenser transmontanus).

The white sturgeon (Acipenser transmontanus) is an endangered ancient fish species that is known to be particularly sensitive to certain environmental contaminants, partly because of the uptake and subsequent toxicity of lipophilic pollutants prone to bioconcentration as a result of their high lipid content. To better understand the bioconcentration of organic contaminants in this species, toxicokinetic (TK) models were developed for the embryo-larval and subadult life stages. The embryo-larval model was designed as a one-compartment model and validated using whole-body measurements of benzo[a]pyrene (B[a]P) metabolites from a waterborne exposure to B[a]P. A physiologically based TK (PBTK) model was used for the subadult model. The predictive power of the subadult model was validated with an experimental data set of four chemicals. Results showed that the TK models could accurately predict the bioconcentration of organic contaminants for both life stages of white sturgeon within 1 order of magnitude of measured values. These models provide a tool to better understand the impact of environmental contaminants on the health and the survival of endangered white sturgeon populations.

A Novel Multispecies Toxicokinetic Modeling Approach in Support of Chemical Risk Assessment.

Standardized laboratory tests with a limited number of model species are a key component of chemical risk assessments. These surrogate species cannot represent the entire diversity of native species, but there are practical and ethical objections against testing chemicals in a large variety of species. In previous research, we have developed a multispecies toxicokinetic model to extrapolate chemical bioconcentration across species by combining single-species physiologically based toxicokinetic (PBTK) models. This "top-down" approach was limited, however, by the availability of fully parameterized single-species models. Here, we present a "bottom-up" multispecies PBTK model based on available data from 69 freshwater fishes found in Canada. Monte Carlo-like simulations were performed using statistical distributions of model parameters derived from these data to predict steady-state bioconcentration factors (BCFs) for a set of well-studied chemicals. The distributions of predicted BCFs for 1,4-dichlorobenzene and dichlorodiphenyltrichloroethane largely overlapped those of empirical data, although a tendency existed toward overestimation of measured values. When expressed as means, predicted BCFs for 26 of 34 chemicals (82%) deviated by less than 10-fold from measured data, indicating an accuracy similar to that of previously published single-species models. This new model potentially enables more environmentally relevant predictions of bioconcentration in support of chemical risk assessments.

ECORISK2050: An Innovative Training Network for predicting the effects of global change on the emission, fate, effects, and risks of chemicals in aquatic ecosystems.

By 2050, the global population is predicted to reach nine billion, with almost three quarters living in cities. The road to 2050 will be marked by changes in land use, climate, and the management of water and food across the world. These global changes (GCs) will likely affect the emissions, transport, and fate of chemicals, and thus the exposure of the natural environment to chemicals. ECORISK2050 is a Marie Sklodowska-Curie Innovative Training Network that brings together an interdisciplinary consortium of academic, industry and governmental partners to deliver a new generation of scientists, with the skills required to study and manage the effects of GCs on chemical risks to the aquatic environment. The research and training goals are to: (1) assess how inputs and behaviour of chemicals from agriculture and urban environments are affected by different environmental conditions, and how different GC scenarios will drive changes in chemical risks to human and ecosystem health; (2) identify short-to-medium term adaptation and mitigation strategies, to abate unacceptable increases to risks, and (3) develop tools for use by industry and policymakers for the assessment and management of the impacts of GC-related drivers on chemical risks. This project will deliver the next generation of scientists, consultants, and industry and governmental decision-makers who have the knowledge and skillsets required to address the changing pressures associated with chemicals emitted by agricultural and urban activities, on aquatic systems on the path to 2050 and beyond.

In vitro-in vivo and cross-life stage extrapolation of uptake and biotransformation of benzo[a]pyrene in the fathead minnow (Pimephales promelas).

Understanding internal dose metrics is integral to adequately assess effects environmental contaminants might have on aquatic wildlife, including fish. In silico toxicokinetic (TK) models are a leading approach for quantifying internal exposure metrics for fishes; however, they often do not adequately consider chemicals that are actively biotransformed and have not been validated against early-life stages (ELS) that are often considered the most sensitive to the exposure to contaminants. To address these uncertainties, TK models were parameterized for the rapidly biotransformed chemical benzo[a]pyrene (B[a]P) in embryo-larval and adult life stages of fathead minnows. Biotransformation of B[a]P was determined through measurements of in vitro clearance. Using in vitro-in vivo extrapolation, in vitro clearance was integrated into a multi-compartment TK model for adult fish and a one-compartment model for ELS. Model predictions were validated using measurements of B[a]P metabolites from in vivo flow-through exposures to graded concentrations of water-borne B[a]P. Significantly greater amounts of B[a]P metabolites were observed with exposure to greater concentrations of parent compound in both life stages. However, when assessing biotransformation capacity, no differences in phase I or phase II biotransformation were observed with greater exposures to B[a]P. Results of modelling suggested that biotransformation of B[a]P can be successfully implemented into in silico models to accurately predict life stage-specific abundances of B[a]P metabolites in either whole-body larvae or the bile of adult fish. Models developed increase the scope of applications in which TK models can be used to support environmental risk assessments.