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Intérêt des réponses immunitaires dans le cadre des études de biosurveillance
No full textInternational audienceImmune parameters are interesting in biomonitoring studies as they reflect environmental contamination and fish health status. Nevertheless, fish immunomarkers could be influenced by many environmental and interindividual parameters. All these confounding factors limit the interpretation of variation between sites and may disturb the routine environmental risk assessment. Characterizing the remaining natural sources of biomarker variability could allow discriminating responses induced by pollutant exposure and background noise. In this way, establishment of reference values, that consider the major sources of variation, may be of great interest for environmental monitoring studies. Moreover, connection has been established between the destabilization of the fish immune system caused by sublethal doses of contaminants and a defect in fish pathogen resistance. In this way, we proposed to develop a stress on stress responses by using some bacterial endotoxin, which mimic pathogen effect, and chemical exposure. This method can be a promising approach for the assessment of pollutant effects in aquatic ecosystems by determining biological threshold values. This biological threshold values could indicate the real capacity of fish to respond during pathogenic conditionLes écosystèmes sont dépendants des conditions de vie qui leur sont fournies : toute pollution y engendre des effets néfastes. De ce fait, il est primordial de pouvoir statuer sur l’état chimique et écologique des masses d’eau afin de caractériser le risque environnemental induit et de prendre des décisions en conséquence sur sa gestion. Néanmoins, la réglementation actuelle, ne s’appuyant que sur le caractère a posteriori d’une dégradation, s’avère insuffisamment prédictive de l’effet à long terme des modifications d’un écosystème. En complément des méthodes conventionnelles de détermination de la qualité des masses d’eau (état chimique et écologique), d’autres approches basées sur les mécanismes d’action des polluants permettent une évaluation plus précoce et plus explicative de l’impact de la contamination sur les organismes. En effet, les contaminants sont susceptibles de causer, directement ou indirectement, des effets nuisibles sur les principaux systèmes physiologiques comprenant les systèmes endocriniens, reproducteurs, nerveux et immunitaires. De tels effets peuvent remettre en cause la croissance, la reproduction, voire la survie des organismes sur lesquels ils s’appliquent. Ainsi, une approche biologique basée sur l’étude des biomarqueurs, permet de rendre compte des effets potentiels sur les individus. Même si les biomarqueurs ne permettent pas une identification formelle des substances responsables, de par leur prédictivité, ils présentent une place importante en complément des approches « substances » et « écologiques
Towards reproducible measurement of nanoparticle size using dynamic light scattering: Important controls and considerations
No full textInternational audienceIt is prerequisite to characterize nanoparticles in dispersions in particular with respect to their size and size distribution before they can be used in toxicological testing. This requires robust methods with high reproducibility. The aim of this study was to apply interlaboratory comparisons using Dynamic Light Scattering (DLS), in order to evaluate the reproducibility of nanoparticle size determinations. DLS is well established in most nanotoxicological laboratories. Due to the fact that this technique appears easy to use it has become a standard technique nowadays. Still, reproducibility and in particular differences between different commercial instruments have not been addressed systematically before. Our aim was to develop a robust standard operating procedure (SOP). Therefore, at the beginning, experiments were performed with dispersions of rather monodisperse and spherical particles in water. Significant differences were observed between the results obtained with different commercial instruments for DLS, especially when fitting the data using mathematical inversion methods. As a consequence of the different settings applied when fitting the data, significant errors could be made especially when working with dilute dispersions of very small particles. Here we have identified options how to overcome possible issues. However, It should be noted, that in practice, nanoparticles may have significant polydispersities and/or be non-spherical. The potential of the DLS technique in this situation should be noted that in nanoparticles may have significant polydispersities and/or be non-spherical. The potential of the DLS technique in this situation is evaluated. A combination of two different techniques (DLS and electron microscopy for instance) is recommended to fully interpret the results
Maternal cumulative exposure to extremely low frequency electromagnetic fields and pregnancy outcomes in the Elfe cohort
No full textInternational audienceObjectives : To study the relations between maternal cumulative exposure to extremely low frequency electromagnetic fields (ELF EMF) and the risk of moderate prematurity and small for gestational age within the Elfe cohort. Methods : The Elfe study included 18,329 infants born at 33 weeks of gestation or more in France in 2011 and was designed to follow the children until 20 years of age. Gestational age and anthropometric data at birth were collected in medical records and small for gestational age was defined according to a French customized growth standard. During interviews, mothers were asked to report their job status during pregnancy. If employed, their occupation was coded according to the International Standard Classification of Occupations 1988 and the date on which they stopped their work was recorded. Cumulative exposure to ELF EMF during pregnancy was assessed, for both mothers who worked and those who did not during pregnancy, using a recently-updated job-exposure matrix (JEM). Cumulative exposure was considered as a categorical variable (< 17.5, 17.5–23.8, 23.8–36.2, 36.2–61.6 or ≥ 61.6 μT-days), a binary variable (< 44.1 and ≥ 44.1 μT-days) and a continuous variable. Associations were analyzed by logistic regression, adjusting for the mother's lifestyle factors, sociodemographic characteristics and some mother's medical history during and before pregnancy. Analyses were restricted to single births and to complete values for the pregnancy outcomes (n = 16,733). Results : Cumulative exposure was obtained for 96.0% of the mothers. Among them, 37.5% were classified in the 23.8–36.2 μT-days category, but high exposures were rare: 1.3% in the ≥ 61.6 μT-days category and 5.5% in the ≥ 44.1 μT-days category. No significant association was observed between maternal cumulative exposure and moderate prematurity and small for gestational age in this exposure range. Conclusion : This large population-based study does not suggest that maternal exposure to ELF EMF during pregnancy is highly associated with risks of moderate prematurity or small for gestational age
Modelling the effect of season, sex and body size on the three-spined stickleback, Gasterosteus aculeatus, cellular innate immunomarkers: a proposition of laboratory reference ranges
No full textInternational audienceDue to their sensitivity to environmental contamination and their link with fish health status, innate immunomarkers are of great interest for environmental risk assessment studies. Nevertheless, the lack of knowledge about the effect of confounding factors can lead to data misinterpretation and false diagnoses. The aim of this study was to evaluate the impact of three confounding factors (season, sex and body size) on laboratory three-spined stickleback innate immunomarkers. Stickleback immunomarkers present a strong seasonality with higher immune capacities in late winter-early spring and a disturbance during the spawning period in late spring-summer. Sex and body size have seasonally-dependant effect on almost all tested immunomarkers. Laboratory reference ranges were designed using modelling tools and compared with data obtained from in vivo chemical expositions. The predictive power of the model was varying between immunomarkers, but the control data of the in vivo experiments were globally well-adjusted in the laboratory reference ranges. Moreover, some statistical effects of the in vivo exposures were correlated with an augmentation of data outside the reference ranges, indicating a possible harmful effect for the organisms. The reference ranges designed here for laboratory conditions seem to be attractive in biomonitoring studies and should be tested in field condition
Developing TK databases and tools to support food safety assessment
No full textInternational audiencerequirements for pre-market authorisation of pesticides (regulation 283-284/2013) for which comparative in vitro metabolism (rat) human and in vivo rat TK data are required. As a consequence, EFSA has been involved in collaborative research to develop TK tools and databases for food safety in the human health, animal health and ecological area. After problem formulation, risk assessors may start at low tier (e.g. basic information and default values) under time and resource constraints, or use all data available for a particular chemical. In this situation, ADME and toxicity information may allow sound dose response modelling and a full quantitative assessment. In a broad context, developing generic tools and databases allow replacing default values with quantitative metrics for physiological, TK and toxicity parameters in any data situation. First, physiological parameters for species of interest are collected and integrated, within a set of differential equations, into generic models. These range from allometric scaling, one compartment model to full physiologically-based TK models (PB-TK). Third, databases reporting physico-chemical and ADME properties, TK parameters and bioaccumulation provide input data to run the models for predicting blood concentrations or elimination patterns. Applications are illustrated including modelling interspecies differences in renal elimination using allometric scaling, integrating variability in human metabolism into generic PB-TK models and development of a modelling platform: TKplate (Wiecek et al., 2018, Darney et al., 2018). Future perspectives include the development of guidance and case studies to use TK tools in routine risk assessment and training programmes
Possible effects of radiofrequency electromagnetic fields on in vivo C6 brain tumors in Wistar rats
No full textInternational audiencePurpose : Glioblastoma is a malignant brain tumor which has one of the poorest prognosis. It is not clear if toxic environmental factors can influence its aggressiveness. Recently, it was suggested that brain cancer patients with heavy cell phone use showed reduced survival. Here we aimed to assess the effect of controlled brain averaged specific absorption rate (BASAR) from heavy use of cell phone radiofrequency electromagnetic fields (RF–EMF) on in vivo C6 brain tumors in Wistar rats. Methods : C6 cells grafted male rats were exposed to GSM 900 MHz signal at environmental BASAR, 0 (sham), 0.25 or 0.5 W/kg (5 days a week, 45 min a day in restraint), or were cage controls (no restraint). At death, tumor volume and immunohistochemistry for CD31, cleaved caspase (CC) 3 and Ki67 were assessed to examine vascularization, apoptosis and cellular divisions, respectively. Moreover, immune cell invasion, necrosis and mitotic index were determined. Results : Results showed no BASAR effect on survival (31 days post-graft median), tumor volume, mitotic index, vascularization, infiltration, necrosis or cell division. However, results suggested a BASAR-dependent reduction of immune cell invasion and apoptosis. Conclusions : Our data suggested an action of RF–EMF by reducing immune cell invasion and glioblastoma cell apoptosis, at probably too low amplitude to impact survival. Further replication studies are needed to confirm these observations
PBPK modeling of zebrafish embryo for reprotoxicity assessment of valproic acid and some of its analogs
No full textInternational audienceIntroduction: Understanding and predicting chemical effects on development and reproduction is a complex challenge. The zebrafish embryo is an in vitro test system increasingly used for its transparency, short development time, easy husbandry and gene homologies with humans. Objectives: To better explain and predict developmental toxic effects observed in zebrafish embryo, we are developing a generic physiologically-based pharmacokinetic (PBPK) model to predict target organ concentrations of neutral or ionizable chemicals. We present an application of the model in the assessment of the teratogenicity of valproic acid (VPA) and nine analogs. Material and Methods: Quasi steady-state distribution of chemicals is modeled in ten embryo organs, and in two sub-cellular organelles: lysosomes and mitochondria. The partition coefficients between the organs or organelles and the culture medium depend on physico-chemical properties of the substances. Organ volumes grow over the first 5 days of life. Liver metabolism can be linear or saturable. For VPA and analogs, metabolic parameters were estimated by Bayesian fitting of the model to data on culture medium and embryo concentrations during repeated dosing. Results: The kinetic data were reasonably well fitted by the model (Figure 1), even though residual uncertainty was substantial. Linear clearance estimates for VPA and analogs were around 10-10 to 10-11L/min, which for an embryo volume of 3×10-7L, correspond to half-lives of about 11.5h. Embryo organ concentrations were used to calculate dose-response for general lethality and heart defectcaused deaths. Naïve dose-responses were also calculated using nominal dose. Using target organ concentrations shifts substantially the magnitude of dose-response parameters and the relative toxicity ranking of the VPA analogs studied (Figure 2). Conclusion: The model can be used to relate zebrafish effects observed in vitro to cellular exposures. It should improve the translation of in vitro zebrafish data to humans for safety assessment
Public Engagement in Science & Technology : The case of stakeholder committees in research organizations in France
No full textInternational audienceThis paper draws on the analysis of an institutional innovation: the creation of stakeholder committees in public research organisations. In France, this innovation dates back from the 2000’s. The official objective is to open up the governance to members of the ‘civic society’ in order to increase research pluralism and to improve the alignment between ‘societal needs’ and production of scientific and technical knowledge. So far, such opening up has not been studied. As these stakeholder committees have now ten years experiences, successes and failures, the time is ripe to thoroughly analyse this institutional innovation. Can such committees influence knowledge production and orientations? Does it change the sociology of people involved in scientific decisions? What practices does it promote in scientific institutions? To explore those general questions, this paper pays attention “to rules and rule making” of stakeholder committees (Epstein 1998, Fischer 2000, Weisman 1998, Frickel & Moore 2005). Here we focus on specific rules: accreditation as a representative (people and organizations) – hearing (roles and knowledges) – file process – agendas setting – relationships to other institutional governance parts. Our comparative study draws on the analysis of 4 stakeholder committees settled as part of scientific governance in French expertise and research institutions in sanitary and environmental fields. Qualitative and quantitative data were collected by participant observatory, interviews and archival work. The results shows that public engagement is highly shaped by rules processes