Perspectives for integrating human and environmental risk assessment and synergies with socio-economic analysis

International audienceFor more than a decade, the integration of human and environmental risk assessment (RA) has become an attractive vision. At the same time, existing European regulations of chemical substances such as REACH (EC Regulation No. 1907/2006), the Plant Protection Products Regulation (EC regulation 1107/2009) and Biocide Regulation (EC Regulation 528/2012) continue to ask for sector-specific RAs, each of which have their individual information requirements regarding exposure and hazard data, and also use different methodologies for the ultimate risk quantification. In response to this difference between the vision for integration and the current scientific and regulatory practice, the present paper outlines five medium-term opportunities for integrating human and environmental RA, followed by detailed discussions of the associated major components and their state of the art. Current hazard assessment approaches are analyzed in terms of data availability and quality, and covering non-test tools, the integrated testing strategy (ITS) approach, the adverse outcome pathway (AOP) concept, methods for assessing uncertainty, and the issue of explicitly treating mixture toxicity. With respect to exposure, opportunities for integrating exposure assessment are discussed, taking into account the uncertainty, standardization and validation of exposure modeling as well as the availability of exposure data. A further focus is on ways to complement RA by a socio-economic assessment (SEA) in order to better inform about risk management options. In this way, the present analysis, developed as part of the EU FP7 project HEROIC, may contribute to paving the way for integrating, where useful and possible, human and environmental RA in a manner suitable for its coupling with SEA

Évaluer l’effet d’un contaminant en mésocosmes : des outils d’analyse statistique plus pertinents à l’échelle des communautés

High medicine consumption in France and inefficient wastewater treatment mean that many pharmaceutical compounds are discharged into surface water. The effect on aquatic ecosystems is largely unknown. Ineris can reproduce river ecosystems in its outdoor facilities, called mesocosms. Ineris studied the effect of Diclofenac, an anti-inflammatory drug, on seasonal changes in the mesocosms. The data generated are traditionally analysed by multivariate statistics. We modified an existing method which is designed for mesocosm data, the Principal Response Curve (PRC) method, thus allowing for focusing on changes in community structure rather than on changes of total abundance. Better understanding of the underlying methods provides keys to knowing how to adapt the PRC method to various data characteristics. The objective is to increase relevance of the communitylevel No Observed Effect Concentration (NOEC), the final output used in risk assessment.La France est le pays qui consomme le plus de médicaments en Europe et les stations d’épuration ne permettent pas d’éliminer tous les résidus. Ainsi, une vingtaine de substances a été retrouvée au moins une fois dans des eaux potables à des concentrations variant de quelques nanogrammes par litre pour les eaux souterraines et de surface à quelques centaines de nanogrammes par litre pour les effluents de station de traitement des eaux usées. Les données écotoxicologiques permettant d’évaluer les risques liés aux substances pharmaceutiques sont cependant peu nombreuses. La maîtrise des risques liés aux résidus de médicaments était un engagement du Grenelle de l’environnement, repris par le premier plan national sur les résidus de médicaments dans l’eau. L’un des objectifs de ce plan était d’acquérir des connaissances scientifiques et techniques relatives à la présence, au devenir et aux effets des résidus de médicaments sur l’environnement et la santé humaine, afin d’évaluer le risque pour les écosystèmes et l’homme. Le projet DOREMIPHARM, financé par l’Agence nationale de sécurité du médicament (ANSM), a été à l’origine de la production de données d’écotoxicologie et de l’adaptation d’outils statistiques à des fins d’évaluation des risques pour les écosystèmes aquatiques

A kernel-based method for assessing uncertainty on individual QSAR predictions

International audienceThe assessment of uncertainty attached to individual predictions is now a priority for sound decision-making in risk assessment. QSAR predictive uncertainty is affected by a variety of factors related to the quality of the training set data, the adopted statistical models, and the distance between the query chemical and the training set. We developed a method to quantify uncertainty associated with individual linear QSAR predictions that integrates both model and experimental error uncertainty and that defines an applicability domain based on the density of training set data. Our method is based on chemical spaces defined by latent variables identified by Partial Least Squares (PLS) regressions. The method provides a kernel regression estimate of the activity of interest as well as a measure of predictive uncertainty based on a mathematical estimation of the domain of applicability and on local propagation of uncertainty associated with training set data

Modelling structure activity landscapes with cliffs : a kernel regression-based approach

International audienceQuantitative Structure-Activity Relationship (QSAR) models are increasingly used in hazard and risk assessment. Even when models with linear relationships between activity and a small number of descriptors are built and validated regarding predictivity and statistical assumptions, similar structures can exhibit large differences in activity known as similarity paradoxes or activity cliffs. In order to reduce the impact that similarity paradoxes can have on predictions we have devised a statistical method based on Nadaraya-Watson kernel regression. According to our method, activity cliffs filter out contributions of neighbouring chemicals especially along the cliff axis. Our method decreases density-based certainty in particular for chemicals with strong prediction errors and the implementation of Structure-Activity Landscape Index (SALI) curves shows that our method improves the prediction of activity cliff ranks. We also provide useful indications on the density-based applicability domain and the reliability of individual predictions

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

International audienceThe 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., Pseudokirchneriella subcapitata 72-hour EC50, Daphnia magna 48-hour EC50 and Oryzias latipes 96-hour LC50). This paper investigates the relationships between the chemical structure and both the toxicity of the chemicals and the cross-species differences in sensitivity. The physicochemical properties of the chemicals were represented by the categories they belonged to in several widely-used categorisation schemes implemented by the freely available OECD (Q)SAR Toolbox and by quantitative molecular descriptors using DRAGON software. The outputs of these software products were analysed and compared in terms of quality of prediction and biological interpretation. Amongst the categorisations implemented by the OECD Toolbox, those focussing on bioaccumulation or biotransformation appeared to be the most interesting in terms of environmental prediction on a whole set of chemicals, in particular as the predicted biotransformation half-life is strongly dependent on hydrophobicity. In predicting toxicity towards each species, simple linear regression on logP performed better than PLS regression of toxicity on a very large set of molecular descriptors. However, the predictions based on the interspecies correlations performed better than the QSAR predictions. The results in terms of cross-species comparisons encourage the use of test strategies focussing on reducing the number of tests on fish

Measurement of consumers’ wine-related knowledge

International audienceIt is stated, according to the paradigm of knowledge-based economy, that information asymmetry between consumers and producers is reduced thanks to information availability and dissemination through the Internet or other media channels. Conversely to this statement, several articles have pointed out that knowledge-based economy reinforces the information asymmetry between experts and novices among the consumers. Accordingly, we consider the heterogeneity of consumers by means of k-means clustering applied to a knowledge-oriented questionnaire. We then try to identify and qualify the differences between several groups of French respondents regarding their attitudes and behaviour towards wine

Le modèle embryonnaire de poisson zèbre transgénique cyp19a1b-GFP

Agonist ligands of estrogen receptors have been extensively studied in recent years because of their effects on reproduction and development of aquatic organisms such as fish. While there is a need to develop fish-specific mechanism-based bioassays to screen estrogenic potency of chemicals alone, it is also important to consider that organisms are often exposed to mixtures of endocrine disruptors (EDs) that are able to produce significant effects, even when each chemical is present at low doses that individually do not induce observable effects. We recently developed an in vivo mechanism-based assay called EASZY that uses transgenic zebrafish cyp19a1b-GFP embryos expressing GFP under the control of the cyp19a1b promoter. EASZY is a rapid and cost-effective assay allowing to screen estrogenic activity of chemicals and was further used to explore combined effect of ED. The tested mixtures of estrogenic compounds acted predominantly in an additive manner on the expression of GFP demonstrating that combined effects of estrogenic compounds can be predicted by using dose addition, although in some cases deviations were observed. The effects of combinations of EDs from different categories were also explored by testing a binary mixture of estradiol and testosterone. Overall, we show that the use of cyp19a1b-GFP zebrafish embryo assay combined with predictive modelling is relevant to further explore the effect of complex mixture of EDs.Les perturbateurs endocriniens et en particulier les agonistes des récepteurs des oestrogènes (ou oestrogènes mimétiques) ont été largement étudiés au cours de ces dernières années en raison de leurs effets sur la reproduction et le développement des organismes aquatiques tels que les poissons. Face aux préoccupations que posent ces composés pour les espèces et les milieux aquatiques, il est important de disposer d’outils aptes à caractériser les effets des substances seules vis-à-vis du système endocrinien des poissons dans une démarche d’évaluation du risque a priori, c’est-à-dire avant que les substances ne contaminent les milieux. Il convient aussi de considérer que, dans l’environnement, les poissons sont le plus souvent exposés simultanément à des mélanges de différents produits chimiques pouvant agir comme des oestrogènes mimétiques. Présents généralement à des concentrations faibles, ils peuvent néanmoins induire des réponses biologiques et ce, même si chacune des substances du mélange est présente à une concentration inférieure à celle conduisant à un effet. Ce constat a stimulé ces dernières années de nombreux travaux visant à évaluer les effets combinés de substances en mélange pour s’assurer in fine que les risques associés aux mélanges de composés chimiques puissent être correctement pris en compte. Cependant, les études sur la toxicité combinée des substances requièrent des plans d’expériences complexes et sont demandeuses en ressources expérimentales ce qui explique probablement qu’elles se soient majoritairement basées jusqu’à présent sur l’utilisation de modèles in vitro

Establishing validated concentration limits for ecotoxicological tests HP 14 for waste

The hazard properties of waste in Europe are defined in the Commission Regulation (EU) N° 1357/2014 of 18 December 2014 replacing Annex III to Directive 2008/98/EC of the European Parliament and of the Council on waste and repealing certain Directives, excepted for the most frequent one, HP 14 ‘Ecotoxic’ (Hennebert et al. 2014). The Directorate General Environment launched in May, 2014 a “Call for tenders ENV.A.2/ETU/2014/0023r - Study to assess the impacts of different classification approaches for hazard property “H 14” on selected waste streams”, HP 14 being calculated from the chemical composition of the waste with different methods. The results of this study are not published at the time of this abstract. An independent study on 120 wastes has ranked the four calculation methods that are proposed (Hennebert et al. 2016) and has tested a 5th variant with multiplying factors for the most ecotoxic substances (M-factors of the CLP), with 80% matching with the European List of Waste. For these calculation methods, the speciation of the elements into substances must be hypothesized. Ecotoxicological tests could provide a straightforward classification without hypothesis of speciation. It is accepted in chemical regulation that results of tests overwhelm results of calculations. The design of the toxicity tests follows a dose/response or dilution approach, meaning that the waste (eluate or solid) is mixed with different amount of a control substrate (e.g. culture medium of reconstituted water or artificial soil), and that a biological parameter is measured for each dilution. The results of these tests can be expressed as ECx values (concentration of eluate or solid in the mixture with the control substrate producing a biological effect of x %, namely 20% or 50% of growth, mobility, reproduction, etc.). An EC50 of 8% means that a dilution of the culture media with 8% of waste produces a reduction of 50% of i.e. mobility. Preparation of eluates (liquid/solid ratio = 10 l/kg dry matter, 24h) and mixtures of waste with control substrate are carried out according to EN 14735. An aquatic and terrestrial tests battery with bacteria, plant and invertebrate animal is proposed by Pandard and Römbke (2013), from a previous proposal of Ökopoll (2008). The test battery can be operated stepwise, and stopped if one test result is lower than its proposed concentration limits. In France a previous proposal of 1997 is used, sometimes in a modified version in 2006 (Pandard et al 2006). Concentration limits of 10% for acute tests and 1% for chronic tests are proposed but without validation, and unsatisfactory results. If one of the ECx values measured by the tests for a given waste is below its concentration limit, the waste is classified as hazardous. The waste is considered as non-hazardous only if the results of all ECx values are above their respective concentration limits. Hence, a validated concentration limit (classifying the waste hazardous or non hazardous) for each test should be the lowest ECx value measured with a panel of non ecotoxic waste (by the European List of Waste taken as reference). Simultaneously, it must be checked with a panel of ecotoxic waste that at least one ECx is below the proposed concentration limits. The results of this original method will be presented in the paper