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

International audienceTwo 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. We derived a model from this framework to analyse five datasets (daphnids exposed to selenium, guppies exposed to dieldrin and second, third and fourth instars chironomids exposed to copper), by extending the standard stochastic death approach. We showed the possibility to estimate properly the toxicity parameters together with inter-organisms differences of sensitivity for at least one of these parameters (here the threshold for effect). For the daphnids, there was no improvement of using the extended model, which confirms the expected low variability among genetically identical individuals. For all the other datasets, our model outperformed the standard approach without accounting for differences of sensitivity. We estimated coefficients of variations in the distribution of the logarithm of the threshold from 44 % to 4 % and showed, for chironomids, a decrease of inter-individual differences of sensitivity with the age of the larvae. All standard threshold estimates were close but above the medium value of the distribution in the new approach, which means that a concentration equal to the standard threshold would ultimately result in the death of more than half of the exposed organisms. A more relevant parameter, such as the concentration protecting 95 % of the population, would be 2-4 times inferior to the standard threshold

Analysis of toxic load calculations and fluctuation concentrations modeling for the assessment of atmospheric accidental release

Computing the effect zones around industrial facilities requires using modelling tools. For the specific case of accidental scenarios involving toxic cloud dispersion, it is necessary to make use of acute toxicity threshold values. Those thresholds can be given in terms of concentration or in terms of toxic load. The toxic load is commonly evaluated by extensions of the Haber's law that corresponds to an integration in time of concentration. The improvements achieved in the atmospheric dispersion modelling now enable to predict the intermittency of the toxic cloud. However, such new approaches raise questions about the relevance of the toxic load evaluation, knowing that many parameters which characterize biological reality and the whole process of the dose-response should be taken into account. To achieve a deterministic model, it is necessary to pool research efforts between the communities of toxicologists and the atmospheric dispersion modellers. This paper consists in confronting the level of knowledge of the fluctuation toxic cloud and biological parameters in the context of the deterministic modelling of consequences generated by an accidental toxic cloud

Pregnancy specific biochemical and physiological processes integration in p-PBPK (pregnancy-Physiologically Based PharmacoKinetics) models

International audienc

Estimations de l’exposition foetale aux pyréthrinoïdes à partir de biomarqueurs urinaires maternels grâce à la modélisation p-PBPK (toxicocinétique basée sur la physiologie de la femme enceinte)

National audienc

Bayesian analysis of a PBPK model to reconstruct the exposure of Italian women to PCB-153 via breast milk concentrations

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that induce numerous toxic effects on humans (for example, cancer, liver damage, or neurological and motor control problems for in utero exposure). Despite the banning to produce PCBs, these chemicals continue to be a human health concern through bioaccumulation. PCBs have been detected in different human media, such as blood, adipose tissues and for pregnant and lactating women in placenta, cord blood and breast milk. Breast milk samples are usually used to predict the exposure of breastfed infants, but information contained in these samples about the history of the women exposure is rarely used. In this work, we propose to perform the reverse dosimetry methodology with the breast milk concentrations. In other words, we propose to model the toxicokinetics of a PCB of interest in humans in order to simulate the internal levels and then to use the breast milk concentrations to reconstruct the exposure of women to PCBs. PCB-153 was selected for this study. PCB-153 is one of the most prevalent PCB congener detected in human tissue, and it has been suggested as a valuable indicator for PCBs in the food of animal origin (i.e. fish). Its presence in breast milk was also found to be a biomarker of total sum TEQ concentrations. Human biomonitoring of breast milk was conducted in Italy in 2008-2009 on 60 women living in 3 different areas (agricultural or industrial area). A stochastic physiologically based pharmacokinetic (PBPK) model has been recently developed to assess the tissue dosimetry of different chemicals over the human lifespan, including the pregnancy and lactation periods. This model was parameterized to simulate the PCB-153 internal levels in the Italian women. Instead of defining a constant intake through the entire life, data obtained from national food consumption studies and food contamination in Italy were used to derive the tendency of the intake of PCB-153 in the Italian population. A Bayesian analysis of the PBPK model was then performed to estimate the exposure dose of mothers during their lifetime

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

International audienceIn 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. The dose response consists in calibrating and coupling a PBPK (physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods

An Integrated and Spatialized Approach to Identify Potentially Overexposed Population : A Case Study of Chlorpyrifos Contamination

Exposure to pesticides is characterized by the multiplicity of exposure routes (food, water, soil, air) related to their presence in all environmental media. First, for a fine characterization of the environmental exposure, it is necessary to gather within the same analysis system a dataset integrating the population behavior and the local contamination of the environmental media at fine resolutions and on large territories. This integration requires a sufficient toolchain to produce or process these data in a rigorous manner, characterize the entire continuum from the source of contamination, transport, and transfer of contaminants in environmental media, and estimate external and internal exposure doses for the general population. The aim of this work is to establish an integrated methodology for the mapping of exposure indicators at fine spatial and temporal resolutions (1 km² and week) directly comparable with individual biomonitoring measurements from French cohorts. To illustrate the approach, we consider the levels of chlorpyrifos among pregnant women in the Picardy region (France). Results provide insights into the identification of areas of potential overexposure and analysis of environmental determinants, elements useful for public health decision to reduce exposure and thus health and environmental impacts. However, the exposure characterization involves uncertainties regarding modeling assumptions and data measurements. Moreover, the efficiency of exposure modeling can be limited by calculation times. To optimize numerical resolution and reduce uncertainties related to knowledge limits and data representativeness, modeling assumptions and tools need to be reconsidered to improve the methodology and allow future developments

Reconstruction of the dynamic exposure to PCBs for Italian population using physiologically based pharmacokinetic (PBPK) model and a complex approach combining human biomonitoring studies and environmental data

Polychlorinated biphenyls (PCBs) are persistent contaminants suspected to cause adverse health effects in humans. Due to their extensive use in the past and persistence in the environment significant amounts are still detectable in environmental media. The major route of human exposure is contaminated food. Since food contamination by PCBs has not been monitored frequently in the past and was rarely congener-specific, human exposure cannot be directly assessed. An alternative to this lack of data is to use exposure models developed for environmental media and to transpose the environmental model outcomes into time-variant dietary intakes. According to the hypotheses assumed, the shape and the magnitude of the modeled intakes are affected by uncertainty leading to several possible exposure scenarios. Here we propose to improve this methodology by integrating actual internal levels in humans (from biomonitoring studies) in order to reduce the uncertainty in the exposure scenario. We propose to model the exposure and the toxicokinetics of PCBs in humans and to analyze breast milk levels of Italian primiparous women in this modeling framework in order to determine the most likely scenario of exposure (i.e. the shape and magnitude). Our approach was applied to most prevalent PCB congeners detected in human milk and fluids: PCB-138 (2,2',3,4,4',5'-hexachlorobiphenyl), PCB-153 (2,2',4,4',5,5'-hexachlorobiphenyl) and PCB-180 (2,2',3,4,4',5,5' -heptachlorobiphenyl). Breast milk concentrations were measured in Italian women for PCB-138, PCB-153 and PCB-180. Forty one healthy primiparous women, not-occupationally exposed to PCBs, were included in biomonitoring study: 15 women from Giugliano in Campania, 18 from Piacenza and 8 from Milan. For each congener, three exposure scenarios were derived and a PBPK model was used to relate the lifetime exposure to the breast milk levels. For the three PCBs, we determined the most probable scenario of exposure. A Bayesian analysis was performed to estimate the magnitude of each exposure scenario for each woman using the breast milk concentrations. The intake estimates are in good agreement with previous exposure assessments based solely on food contamination demonstrating the relevance of our approach to reconstruct accurately the exposure and to fill in data gaps on exposure. The link between the exposure scenario and biomonitoring data was provided by the PBPK model in order to support the adequacy of the models according to the data (e.g., for PCB-180) or to identify possible improvements for the exposure and PBPK models (e.g., for PCB-138 and PCB-153)

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

International audiencePolycyclic Aromatic Hydrocarbons (PAHs) constitute a family of over one hundred compounds and can generally be found in complex mixtures. PAHs metabolites cause DNA damage which can lead to the development of carcinogenesis. Toxicity assessment of PAH complex mixtures is currently expressed in terms of toxic equivalents, based on Toxicity Equivalent Factors (TEFs). However, the definition of new TEFs for a large number of PAH could overcome some limitations of the current method and improve cancer risk assessment. The current investigation aimed at deriving the relative potency factors of PAHs, based on their genotoxic effect measured in vitro and analyzed with mathematical models. For this purpose, we used a new genotoxic assay (gammaH2AX) with two human cell lines (HepG2 and LS-174T) to analyze the genotoxic properties of 13 selected PAHs at low doses after 24h treatment. The dose-response for genotoxic effects was modeled with a Hill model; equivalency between PAHs at low dose was assessed by applying constraints to the model parameters. In the two cell lines tested, we observed a clear dose-response for genotoxic effects for 11 tested compounds. LS-174T was on average ten times more sensitive than HepG2 towards PAHs regarding genotoxicity. We developed new TEFs, which we named Genotoxic Equivalent Factor (GEF). Calculated GEF for the tested PAHs were generally higher than the TEF usually used. Our study proposed a new in vitro based method for the establishment of relevant TEFs for PAHs to improve cancer risk assessment

Importance of water chemistry for the toxicity of uranium on an aquatic organism

Uranium (U) is a radioactive element found at trace concentrations throughout the natural environment. Its level can increase in association with human activities associated with nuclear fuel cycle. The aim of our studies was first to investigate the influence of water chemistry on acute toxicity of uranium on Daphnia magna. Acute uranium toxicity for Daphnia magna was determined in two different exposure media, differing in pH and alkalinity. LC50 varied strongly between media, from 390+-40 g.L-1 U at pH 7 to 7.8+-3.2 mg.L-1 U at pH 8. According to the free ion activity model uranium toxicity varies as a function of free uranyl activity. This assumption was examined by calculating uranium speciation in our water conditions and in those reported in the literature. Predicted changes in free uranyl concentration could not solely explain observed differences in toxicity, which might be due to a competition or a non-competitive inhibition of H+ for uranium transport and/or the involvement of other bioavailable chemical species of uranium. Uranium toxicity was also compared to the toxicity of other alpha-emitting radionuclides and stable trace metals. Our results confirmed the general assumption that uranium chemical toxicity predominates over its radiotoxicity