Acute Quetiapine Intoxication: Relationship Between Ingested Dose, Serum Concentration and Clinical Presentation-Structured Literature Review and Analysis.

Over the past decade, quetiapine has become one of the most commonly used psychotropic drugs in acute intoxication events worldwide. A structured literature review and analysis were conducted to assess the relationship between the kinetic and dynamic profiles in acute quetiapine intoxication. The correlation between dose and peak serum concentration (cmax) was determined using Pearson's correlation coefficient. Binary logistic regression was used to evaluate dose and cmax as predictors of the most common clinical events, signs and symptoms. One hundred and thirty-four cases of acute quetiapine ingestion were included in the analysis, with a median ingested dose of 10 g and a median cmax of 4 mg/L. The typical half-life was estimated to be 16.5 h, significantly longer than at therapeutic doses. For the immediate-release formulation, a biphasic disposition could not be excluded. Dose and cmax demonstrated a weak but significant correlation (r = 0.256; N = 63; p = 0.043). Central nervous system depression and tachycardia were the most common clinical signs. Higher doses and concentrations increased the risk of severe intoxication and were good predictors of intubation, tachycardia, hypotension, QTc prolongation and seizures, but not QRS prolongation, arrhythmia, heart block, hypokalaemia or acidosis. The thresholds for dose and cmax that increased the risk for individual signs and symptoms varied widely. However, doses > 3 g or cmax > 2 mg/L can be considered as alert levels that represent a high risk for severe clinical course of acute quetiapine intoxication.

Visible Combined Near-Infrared in Situ Imaging Revealed Dynamic Effects of Microplastic Fibers and Beads in Zebrafish.

Microplastics (MPs) as emerging contaminants are widely present in the environment and are ubiquitously ingested and accumulated by aquatic organisms. MPs may be quickly eliminated after a brief retention in aquatic animals (such as the digestive tract); thus, understanding the damage caused by MPs during this process and whether the damage can be recovered is important. Here, we proposed the use of visible light imaging to track MPs combined with near-infrared (NIR) imaging to reveal the in situ impacts of MPs. The combination of these two techniques allows for the simultaneous investigation of the localization and functionality of MPs in vivo. We investigated the effects of two types of MPs on zebrafish, microplastic fibers (MFs) and microplastic beads (MBs). The results showed that MPs larger than 10 µm primarily accumulated in the intestines of zebrafish. Both MFs and MBs disrupted the redox balance of the intestine, and the location of the damage was consistent with the heterogeneous accumulation of MPs. MFs caused greater and more difficult-to-recover damage compared to MBs, which was closely related to the slower elimination rate of MFs. Our study highlights the importance of capturing the dynamic toxicological effects of MPs on organisms. Fibrous MPs and spherical MPs clearly had distinct effects on their toxicokinetics and toxicodynamics in fish.

Application of toxicokinetic-toxicodynamic models in the aquatic ecological risk assessment of metals: A review.

The issue of toxic metal pollution is a considerable environmental concern owing to its complex nature, spatial and temporal variability, and susceptibility to environmental factors. Current water quality criteria and ecological risk assessments of metals are based on single-metal toxicity data from short-term, simplified indoor exposure conditions, ignoring the complexity of actual environmental conditions. This results in increased uncertainty in predicting toxic metal toxicity and risk assessment. Using appropriate bioavailability and effect modeling of metals is critical for establishing environmental quality standards and performing risk assessments for metals. Traditional dose-effect models are based on a static statistical relationship and fall short of revealing the bioavailability and effect processes of metals and do not effectively assess ecological impacts under complex exposure conditions. This paper summarizes the toxicokinetic-toxicodynamic (TK-TD) model, which is gaining interest in environmental and ecotoxicological research. The key concepts, and theories of its construction theories, are discussed and the application of the TK-TD model in toxicity prediction and risk assessment of different metals in the aquatic environment, and trends in the development of the TK-TD model are highlighted. The findings of our review prove that the TK-TD model can effectively predict toxic metal toxicity in real time and under complex exposure conditions in the future.

Role of albumin in the metabolism and excretion of ochratoxin A.

Ochratoxin A (OTA) is known to be strongly bound to serum albumin, but it remains unknown how albumin affects its metabolism and kinetics. To close this gap, we used a mouse model, where heterozygous albumin deletion reduces serum albumin to concentrations similar to hypoalbuminemic patients and completely eliminates albumin by a homozygous knockout. OTA and its potential metabolites (OTα, 4-OH-OTA, 7'-OH-OTA, OTHQ, OP-OTA, OTB-GSH, OTB-NAC, OTB) were time-dependently analyzed in plasma, bile, and urine by LC-MS/MS and were compared to previously published hepatotoxicity and nephrotoxicity data. Homozygous albumin deletion strongly accelerated plasma clearance as well as biliary and urinary excretion of the parent compound and its hydroxylation products. Decreasing albumin in mice by the heterozygous and even more by the homozygous knockout leads to an increase in the parent compound in urine which corresponded to increased nephrotoxicity. The role of albumin in OTA-induced hepatotoxicity is more complex, since heterozygous but not homozygous nor wild-type mice showed a strong biliary increase in the toxic open lactone OP-OTA. Correspondingly, OTA-induced hepatotoxicity was higher in heterozygous than in wild-type and homozygous animals. We present evidence that albumin-mediated retention of OTA in hepatocytes is required for formation of the toxic OP-OTA, while complete albumin elimination leads to rapid biliary clearance of OTA from hepatocytes with less formation of OP-OTA. In conclusion, albumin has a strong influence on metabolism and toxicity of OTA. In hypoalbuminemia, the parent OTA is associated with increased nephrotoxicity and the open lactone with increased hepatotoxicity.

Emerging organic contaminants in drinking water systems: Human intake, emerging health risks, and future research directions.

Few earlier reviews on emerging organic contaminants (EOCs) in drinking water systems (DWS) focused on their detection, behaviour, removal and fate. Reviews on multiple exposure pathways, human intake estimates, and health risks including toxicokinetics, and toxicodynamics of EOCs in DWS are scarce. This review presents recent advances in human intake and health risks of EOCs in DWS. First, an overview of the evidence showing that DWS harbours a wide range of EOCs is presented. Multiple human exposure to EOCs occurs via ingestion of drinking water and beverages, inhalation and dermal pathways are discussed. A potential novel exposure may occur via the intravenous route in dialysis fluids. Analysis of global data on pharmaceutical pollution in rivers showed that the cumulative concentrations (µg L-1) of pharmaceuticals (mean ± standard error of the mean) were statistically more than two times significantly higher (p = 0.011) in South America (11.68 ± 5.29), Asia (9.97 ± 3.33), Africa (9.48 ± 2.81) and East Europe (8.09 ± 4.35) than in high-income regions (2.58 ± 0.48). Maximum cumulative concentrations of pharmaceuticals (µg L-1) decreased in the order; Asia (70.7) had the highest value followed by South America (68.8), Africa (51.3), East Europe (32.0) and high-income regions (17.1) had the least concentration. The corresponding human intake via ingestion of untreated river water was also significantly higher in low- and middle-income regions than in their high-income counterparts. For each region, the daily intake of pharmaceuticals was highest in infants, followed by children and then adults. A critique of the human health hazards, including toxicokinetics and toxicodynamics of EOCs is presented. Emerging health hazards of EOCs in DWS include; (1) long-term latent and intergenerational effects, (2) the interactive health effects of EOC mixtures, (3) the challenges of multifinality and equifinality, and (4) the Developmental Origins of Health and Disease hypothesis. Finally, research needs on human health hazards of EOCs in DWS are presented.

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.

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.

Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals-The State of the Art and Future Priorities.

The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological "read-across" approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher-throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real-world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2024;43:513-525. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Diuron and its metabolites induce mitochondrial dysfunction-mediated cytotoxicity in urothelial cells.

In the environment, or during mammalian metabolism, the diuron herbicide (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is transformed mainly into 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous research suggests that such substances are toxic to the urothelium of Wistar rats where, under specific exposure conditions, they may induce urothelial cell degeneration, necrosis, hyperplasia, and eventually tumors. However, the intimate mechanisms of action associated with such chemical toxicity are not fully understood. In this context, the purpose of the current in vitro study was to analyze the underlying mechanisms involved in the urothelial toxicity of those chemicals, addressing cell death and the possible role of mitochondrial dysfunction. Thus, human 1T1 urothelial cells were exposed to six different concentrations of diuron, DCA, and DCPMU, ranging from 0.5 to 500 µM. The results showed that tested chemicals induced oxidative stress and mitochondrial damage, cell cycle instability, and cell death, which were more expressive at the higher concentrations of the metabolites. These data corroborate previous studies from this laboratory and, collectively, suggest mitochondrial dysfunction as an initiating event triggering urothelial cell degeneration and death.

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.

Advancing probabilistic risk assessment by integrating human biomonitoring, new approach methods, and Bayesian modeling: A case study with the mycotoxin deoxynivalenol.

Deoxynivalenol (DON) is a mycotoxin frequently observed in cereals and cereal-based foods, with reported toxicological effects including reduced body weight, immunotoxicity and reproductive defects. The European Food Safety Authority used traditional risk assessment approaches to derive a deterministic Tolerable Daily Intake (TDI) of 1 µg/kg-day, however data from human biomarkers studies indicate widespread and variable exposure worldwide, necessitating more sophisticated and advanced methods to quantify population risk. The World Health Organization/International Programme on Chemical Safety (WHO/IPCS) has previously used DON as a case example in replacing the TDI with a probabilistic toxicity value, using default uncertainty and variability distributions to derive the Human Dose corresponding to an effect size M in the Ith percentile of the population (HDMI) for M = 5 % decrease in body weight and I = 1 %. In this study, we extend this case study by incorporating (1) Bayesian modeling approaches, (2) using both in vivo data and in vitro population new approach methods to replace default distributions for interspecies toxicokinetic (TK) differences and intraspecies TK and toxicodynamic (TD) variability, and (3) integrating biomonitoring data and probabilistic dose-response functions to characterize population risk distributions. We first derive an HDMI of 5.5 [1.4-24] µg/kg-day, also using TK modeling to converted the HDMI to Biomonitoring Equivalents, BEMI for comparison with biomonitoring data, with a blood BEMI of 0.53 [0.17-1.6] µg/L and a urinary excretion BEMI of 3.9 [1.0-16] µg/kg-day. We then illustrate how this integrative approach can advance quantitative risk characterization using two human biomonitoring datasets, estimating both the fraction of population with an effect size M ≥ 5 % as well as the distribution of effect sizes. Overall, we demonstrate that integration of Bayesian modeling, human biomonitoring data, and in vitro population-based TD data within the WHO/IPCS probabilistic framework yields more accurate, precise, and comprehensive risk characterization.

An in silico insight on the mechanistic aspects of gelsenicine toxicity: A reverse screening study pointing to the possible involvement of acetylcholine binding receptor.

Gelsedine-type alkaloids are highly toxic plant secondary metabolites produced by shrubs belonging to the Gelsemium genus. Gelsenicine is one of the most concerning gelsedine-type alkaloids with a lethal dose lower than 1 mg/Kg in mice. Several reported episodes of poisoning in livestock and fatality cases in humans due to the usage of Gelsemium plants extracts were reported. Also, gelsedine-type alkaloids were found in honey constituting a potential food safety issue. However, their toxicological understanding is scarce and the molecular mechanism underpinning their toxicity needs further investigations. In this context, an in silico approach based on reverse screening, docking and molecular dynamics successfully identified a possible gelsenicine biological target shedding light on its toxicodynamics. In line with the available crystallographic data, it emerged gelsenicine could target the acetylcholine binding protein possibly acting as a partial agonist against α7 nicotinic acetylcholine receptor (AChR). Overall, these results agreed with evidence previously reported and prioritized AChR for further dedicated analysis.

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science.

The use of Drosophila melanogaster for studies of toxicology has grown considerably in the last decade. The Drosophila model has long been appreciated as a versatile and powerful model for developmental biology and genetics because of its ease of handling, short life cycle, low cost of maintenance, molecular genetic accessibility, and availability of a wide range of publicly available strains and data resources. These features, together with recent unique developments in genomics and metabolomics, make the fly model especially relevant and timely for the development of new approach methodologies and movements toward precision toxicology. Here, we offer a perspective on how flies can be leveraged to identify risk factors relevant to environmental exposures and human health. First, we review and discuss fundamental toxicologic principles for experimental design with Drosophila. Next, we describe quantitative and systems genetics approaches to resolve the genetic architecture and candidate pathways controlling susceptibility to toxicants. Finally, we summarize the current state and future promise of the emerging field of Drosophila metabolomics for elaborating toxic mechanisms. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.

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.

Interaction between γ-Hydroxybutyric Acid and Ethanol: A Review from Toxicokinetic and Toxicodynamic Perspectives.

Gamma-hydroxybutyric acid (GHB) is a potent, short-acting central nervous system depressant as well as an inhibitory neurotransmitter or neuromodulator derived from gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter. The sodium salt of GHB, sodium oxybate, has been used for the treatment of narcolepsy and cataplexy, whereas GHB was termed as a date rape drug or a club drug in the 1990s. Ethanol is the most co-ingested drug in acute GHB intoxication. In this review, the latest findings on the combined effects of GHB and ethanol are summarized from toxicokinetic and toxicodynamic perspectives. For this purpose, we mainly discussed the pharmacology and toxicology of GHB, GHB intoxication under alcohol consumption, clinical cases of the combined intoxication of GHB and ethanol, and previous studies on the toxicokinetic and toxicodynamic interactions between GHB and ethanol in humans, animals, and an in vitro model. The combined administration of GHB and ethanol enhanced sedation and cardiovascular dysfunction, probably by the additive action of GABA receptors, while toxicokinetic changes of GHB were not significant. The findings of this review will contribute to clinical and forensic interpretation related to GHB intoxication. Furthermore, this review highlights the significance of studies aiming to further understand the enhanced inhibitory effects of GHB induced by the co-ingestion of ethanol.

A Novel Lepidoptera bioassay analysed using a reduced GUTS model.

Lepidopteran species can be both pests and also beneficial pollinators for agricultural crops. However, despite these important roles, the effects of pesticides on this diverse taxa are relatively understudied. To facilitate the assessment of pesticides and other chemical hazards on this taxa, we present a novel bioassay capable of testing chemical sensitivity to lepidopteran larvae through dietary exposure. We used Mamestra brassicae caterpillars as a model lepidopteran and tested their sensitivity for the organophosphate insecticide chlorpyrifos. We exposed larvae to an artificial diet spiked with chlorpyrifos and monitored survival over time, as well as weight change over a 96-hour exposure period. To test the repeatability and reliability of the developed bioassay, the experiment was repeated three times. The survival in time data collected enabled analysis with the General Unified Threshold of Survival (GUTS) model, recently recognized by EFSA as a ready-to-use tool for regulatory purposes. The GUTS modelling was used to derive a set of relevant toxicokinetic and toxicodynamic parameters relating to the larval response to exposure over time. We found that across the three repeats studies there was no more than a threefold difference in LC50 values (13.1, 18.7 and 8.1 mg/Kg) at 48 h and fourfold difference at 96 h, highlighting the repeatability of the bioassay. We also highlighted the potential of the method to observe sub-lethal effects such as changes in weight. Finally, we discuss the applications of this new bioassay method to chemical risk assessments and its potential for use in other scenarios, such as mixture or pulsed exposure testing.

Cumulative Risk Meets Inter-Individual Variability: Probabilistic Concentration Addition of Complex Mixture Exposures in a Population-Based Human In Vitro Model.

Although humans are continuously exposed to complex chemical mixtures in the environment, it has been extremely challenging to investigate the resulting cumulative risks and impacts. Recent studies proposed the use of "new approach methods," in particular in vitro assays, for hazard and dose−response evaluation of mixtures. We previously found, using five human cell-based assays, that concentration addition (CA), the usual default approach to calculate cumulative risk, is mostly accurate to within an order of magnitude. Here, we extend these findings to further investigate how cell-based data can be used to quantify inter-individual variability in CA. Utilizing data from testing 42 Superfund priority chemicals separately and in 8 defined mixtures in a human cell-based population-wide in vitro model, we applied CA to predict effective concentrations for cytotoxicity for each individual, for "typical" (median) and "sensitive" (first percentile) members of the population, and for the median-to-sensitive individual ratio (defined as the toxicodynamic variability factor, TDVF). We quantified the accuracy of CA with the Loewe Additivity Index (LAI). We found that LAI varies more between different mixtures than between different individuals, and that predictions of the population median are generally more accurate than predictions for the "sensitive" individual or the TDVF. Moreover, LAI values were generally <1, indicating that the mixtures were more potent than predicted by CA. Together with our previous studies, we posit that new approach methods data from human cell-based in vitro assays, including multiple phenotypes in diverse cell types and studies in a population-wide model, can fill critical data gaps in cumulative risk assessment, but more sophisticated models of in vitro mixture additivity and bioavailability may be needed. In the meantime, because simple CA models may underestimate potency by an order of magnitude or more, either whole-mixture testing in vitro or, alternatively, more stringent benchmarks of cumulative risk indices (e.g., lower hazard index) may be needed to ensure public health protection.

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.

The effects of different temperatures in mercury toxicity to the terrestrial isopod Porcellionides pruinosus.

Climate changes and metal contamination are pervasive stressors for soil ecosystems. Mercury (Hg), one of the most toxic metals, has been reported to interact with temperature. However, compared to aquatic biota, little is known about how temperature affects Hg toxicity and bioaccumulation to soil organisms. Here, toxicity and bioaccumulation experiments were replicated at 15 °C, 20 °C, and 25 °C to understand how sub-optimal temperatures affect the toxicokinetics and toxicodynamics of Hg via soil. Genotoxicity and energy reserves were also assessed to disclose potential trade-offs in life-history traits. Results underpin the complexity of temperature-Hg interactions. Survival was determined mainly by toxicokinetics, but toxicodynamics also played a significant role in defining survival probability during early stages. The processes determining survival probability were faster at 25 °C: General Unified Threshold of Survival (GUTS) model identified an earlier/steeper decline in survival, compared to 20 °C or 15 °C, but it also approached the threshold faster. Despite potentiation of Hg genotoxicity, temperature promoted faster detoxification, either increasing toxicokinetics rates or damage repair mechanisms. This metabolism-driven increase in detoxification led to higher depletion of energy reserves and likely triggered stress response pathways. This work emphasized the need for comprehensive experimental approaches that can integrate the multiple processes involved in temperature-metal interactions.

In Vitro-In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned.

Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however, to a smaller extent, although an internationally agreed document was published already in 2010 (IPCS/WHO), but at that time, PBK modeling was based mostly on in vivo data as the example in the IPCS/WHO document indicates. Recently, the OECD has published a guidance document which set standards on how to characterize, validate, and report PBK models for regulatory purposes. In the past few years, we gained experience on using in vitro data for performing quantitative in vitro-in vivo extrapolation (QIVIVE), in which biokinetic data play a crucial role to obtain a realistic estimation of human exposure. In addition, pharmaco-/toxicodynamic aspects have been introduced into the approach. Here, three examples with different drugs/chemicals are described, in which different approaches have been applied. The lessons we learned from the exercise are as follows: 1) in vitro conditions should be considered and compared to the in vivo situation, particularly for protein binding; 2) in vitro inhibition of metabolizing enzymes by the formed metabolites should be taken into consideration; and 3) it is important to extrapolate from the in vitro measured intracellular concentration and not from the nominal concentration to the tissue/organ concentration to come up with an appropriate QIVIVE for the relevant adverse effects.