Differences in sensitivity between earthworms and enchytraeids exposed to two commercial fungicides.

The use of pesticides in crop fields may have negative effects on soil Oligochaeta Annelida, i.e., earthworms and enchytraeids, and thus affect soil quality.

An individual-based model of zebrafish population dynamics accounting for energy dynamics.

Developing population dynamics models for zebrafish is crucial in order to extrapolate from toxicity data measured at the organism level to biological levels relevant to support and enhance ecological risk assessment. To achieve this, a dynamic energy budget for individual zebrafish (DEB model) was coupled to an individual based model of zebrafish population dynamics (IBM model). Next, we fitted the DEB model to new experimental data on zebrafish growth and reproduction thus improving existing models.

Energy-based modelling to assess effects of chemicals on Caenorhabditis elegans: a case study on uranium.

The ubiquitous free-living nematode Caenorhabditis elegans is a powerful animal model for measuring the evolutionary effects of pollutants which is increasingly used in (eco) toxicological studies. Indeed, toxicity tests with this nematode can provide in a few days data on the whole life cycle. These data can be analysed with mathematical tools such as toxicokinetic-toxicodynamic modelling approaches.

A physiologically based toxicokinetic model for the zebrafish Danio rerio.

Zebrafish (Danio rerio) is a widely used model for toxicological studies, in particular those related to investigations on endocrine disruption. The development and regulatory use of in vivo and in vitro tests based on this species can be enhanced by toxicokinetic modeling. For this reason, we propose a physiologically based toxicokinetic (PBTK) model for zebrafish describing the uptake and disposition of organic chemicals.

Effects of bisphenol A on different trophic levels in a lotic experimental ecosystem.

Bisphenol A (BPA) is commonly used by manufacturers and can be found in many aquatic ecosystems. Data relative to BPA ecotoxicity are only available for studies in laboratory conditions on macro-invertebrates and fish. There is thus a lack of information for other trophic levels such as macrophytes.

A non-invasive method based on head morphology to sex mature three-spined stickleback (Gasterosteus aculeatus L.) in rearing conditions.

A mathematical model to distinguish mature female and male three-spined sticklebacks Gasterosteus aculeatus L. 1758 is proposed. This method is based on sexual dimorphism in the head morphology.

Consequences of a multi-generation exposure to uranium on Caenorhabditis elegans life parameters and sensitivity.

The assessment of toxic effects at biologically and ecologically relevant scales is an important challenge in ecosystem protection. Indeed, stressors may impact populations at much longer term than the usual timescale of toxicity tests. It is therefore important to study the evolutionary response of a population under chronic stress.

Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: a case study with acetaminophen.

In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only 'as a last resort' or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on in vitro tests and QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose-response model predicting hepatotoxicity.

Comparison of species sensitivity distributions based on population or individual endpoints.

Species sensitivity distributions (SSDs) developed from individual and population endpoints were compared based on simulations and a case study. The simulations were performed with five invertebrate species accounting for the diversity of benthic macroinvertebrate communities in large European lowland rivers and for five benthic invertebrates used as laboratory species. Population growth rate 10% effective concentration (EC10) values were, in most of the simulations, higher than the lowest of the EC10 values at the individual level.

A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk.

In this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter-individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient.

Individual sensitivity distribution evaluation from survival data using a mechanistic model: implications for ecotoxicological risk assessment.

Two main alternatives are typically used to model mechanistically dose-survival relationship in ecotoxicity tests. Effects are related to a concentration of concern, for instance body concentration, and, to account for their differences relative to time-to-death, individuals have either different concentration thresholds for death ("individual tolerance approach"), or equal probability to die, with death occurring randomly ("stochastic death approach"). A general framework to unify both approaches has recently been proposed.

Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs.

The world faces complex challenges for chemical hazard assessment. Microfluidic bioartificial organs enable the spatial and temporal control of cell growth and biochemistry, critical for organ-specific metabolic functions and particularly relevant to testing the metabolic dose-response signatures associated with both pharmaceutical and environmental toxicity. Here we present an approach combining a microfluidic system with (1)H NMR-based metabolomic footprinting, as a high-throughput small-molecule screening approach.

A linear model to predict chronic effects of chemicals on Daphnia magna.

Chronic toxicity data for Daphnia magna are information requirements in the context of regulations on chemical safety. This paper proposes a linear model for the prediction of chemically-induced effects on the reproductive output of D. magna.

Kinetic modelling of in vitro cell-based assays to characterize non-specific bindings and ADME processes in a static and a perfused fluidic system.

Recently, physiologically based perfusion in vitro systems have been developed to provide cell culture environment close to in vivo cell environment (e.g., fluidic conditions, organ interactions).

Exploring an ecotoxicity database with the OECD (Q)SAR Toolbox and DRAGON descriptors in order to prioritise testing on algae, daphnids, and fish.

The European regulation on chemicals (REACh) places emphasis on reduction of systematic toxicity testing, thus fostering development of alternative methods. Consequently, we analysed acute toxicity data gathered by the Japanese Ministry of Environment for three species belonging to three different trophic levels (i.e.

Biology-based modeling to analyze uranium toxicity data on Daphnia magna in a multigeneration study.

Recent studies have investigated chronic toxicity of waterborne depleted uranium on the life cycle and physiology of Daphnia magna. In particular, a reduction in food assimilation was observed. Our aims here were to examine whether this reduction could fully account for observed effects on both growth and reproduction, for three successive generations, and to investigate through microscope analyses whether this reduction resulted from direct damage to the intestinal epithelium.

Predicting in vivo gene expression in macrophages after exposure to benzo(a)pyrene based on in vitro assays and toxicokinetic/toxicodynamic models.

Predictive toxicology aims at developing methodologies to relate the results obtained from in vitro experiments to in vivo exposure. In the case of polycyclic aromatic hydrocarbons (PAHs), a substantial amount of knowledge on effects and modes of action has been recently obtained from in vitro studies of gene expression. In the current study, we built a physiologically based toxicokinetic (PBTK) model to relate in vivo and in vitro gene expression in case of exposure to benzo(a)pyrene (BaP), a referent PAH.

What can be learnt from an ecotoxicity database in the framework of the REACh regulation?

Since REACh applies in all of EU, special emphasis has been put on the reduction of systematic ecotoxicity testing. In this context, it is important to extract a maximum of information from existing ecotoxicity databases in order to propose alternative methods aimed at replacing and reducing experimental testing. Consequently, we analyzed a database of new chemicals registered in France and Europe during the last twenty years reporting aquatic ecotoxicity data with respect to three trophic levels (i.

Environmental risk assessment for the serotonin re-uptake inhibitor fluoxetine: Case study using the European risk assessment framework.

The serotonin re-uptake inhibitor fluoxetine was selected for an environmental risk assessment, using the most recent European guideline (EMEA 2006) within the European Union (EU)-funded Environmental Risk Assessment of Pharmaceuticals (ERAPharm) project due to its environmental persistence, acute toxicity to nontarget organisms, and unique pharmacokinetics associated with a readily ionizable compound. As a widely prescribed psychotropic drug, fluoxetine is frequently detected in surface waters adjacent to urban areas because municipal wastewater effluents are the primary route of entry to aquatic environments. In Phase I of the assessment, the initial predicted environmental concentration of fluoxetine in surface water (initial PEC(SW)) reached or exceeded the action limit of 10 ng/L, when using both a default market penetration factor and prescription data for Sweden, Germany, and the United Kingdom.

From individual to population level effects of toxicants in the tubicifid Branchiura sowerbyi using threshold effect models in a Bayesian framework.

Effects of zinc were studied in the freshwater worm Branchiura sowerbyi using partial and full life-cycle tests. Only newborn and juveniles were sensitive to zinc, displaying effects on survival, growth, and age at first brood at environmentally relevant concentrations. Threshold effect models were proposed to assess toxic effects on individuals.

Comparison of models to analyze mortality data and derive concentration-time response relationship of inhaled chemicals.

The derivation of thresholds for lethal effects for inhaled chemicals is a key issue in accidental risk management because they largely determine the outcome of land use planning, among which localization of habitations in the vicinity of a factory. This derivation is generally performed on the basis of rodent lethality data analyzed by statistical models able to extrapolate effects for different times and concentrations of exposure. A model commonly used in France is the standard probit model.

Development of a physiologically based kinetic model for 99m-technetium-labelled carbon nanoparticles inhaled by humans.

Particulate air pollution is associated with respiratory and cardiovascular morbidity and mortality. Recent studies investigated whether and to which extent inhaled ultrafine particles are able to translocate into the bloodstream in humans. However, their conclusions were conflicting.

Substance-tailored testing strategies in toxicology: an in silico methodology based on QSAR modeling of toxicological thresholds and Monte Carlo simulations of toxicological testing.

The design of toxicological testing strategies aimed at identifying the toxic effects of chemicals without (or with a minimal) recourse to animal experimentation is an important issue for toxicological regulations and for industrial decision-making. This article describes an original approach which enables the design of substance-tailored testing strategies with a specified performance in terms of false-positive and false-negative rates. The outcome of toxicological testing is simulated in a different way than previously published articles on the topic.