The MCRA toolbox of models and data to support chemical mixture risk assessment

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.</p

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available

Erratum: The solar orbiter radio and plasma waves (RPW) instrument (Astronomy and Astrophysics (2020) 642 (A12) DOI: 10.1051/0004-6361/201936214)

The erratum concerns Fig. 9 entitled "Antenna radio-electrical properties" for which some of the parameters are not correct. The new figure with new parameters is provided in Fig. 1 of this corrigendum. Fig. 1. Corrected Antenna radio-electrical properties. (Figure Presented)

Development of a physiologically based toxicokinetic model for lead in pregnant women: The role of bone tissue in the maternal and fetal internal exposure

International audienceEpidemiological studies have shown associations between prenatal exposure to lead (Pb) and neurodevelopmental effects in young children. Prenatal exposure is generally characterized by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess internal Pb exposure during prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model that to simulates Pb levels in blood and target tissues in the fetus, especially during critical periods for brain development. An existing Pb PBPK model was adapted to pregnant women and fetuses. Using data from literature, both the additional maternal bone remodeling, that causes Pb release into the blood, and the Pb placental transfers were estimated by Bayesian inference. Additional maternal bone remodeling was estimated to start at 21.6 weeks. Placental transfers were estimated between 4.6and 283L.day-1 at delivery with high interindividual variability. Once calibrated, the p-PBPK model was used to simulate fetal exposure to Pb. Internal fetal exposure greatly varies over the pregnancy with two peaks of Pb levels in blood and brain at the end of the 1st and 3rd trimesters. Sensitivity analysis shows that the fetal blood lead levels are affected by the maternal burden of bone Pb via maternal bone remodeling and by fetal bone formation at different pregnancy stages. Coupling the p-PBPK model with an effect model such as an adverse outcome pathway could help to predict the effects on children's neurodevelopment

La modélisation intégrée de la production de sédiments après l'incendie du bassin versant du Rimbaud (Var, France)

An hydrosedimentologic model, called ETC, which deals with erosion using an hydrologic approach, was developed. Its objective is to predict erosion and sediment yield within mountainous mediterranean catchments. The erosion and sediment yield component was validated on Rimbaud basin. Before Rimbaud forest fire, only rain and liquid discharge were registered. Upon an experimental plot, whose area was 75 m2, located in the upper part of the catchment, erosion was measured. The next months before the forest fire, the hydrological and erosive processes were strongly disturbed. An automatic sampler was set up at Rimbaud gauging station and provided transited sediment concentrations. Validation results were quite promising. / Le bassin versant du Rimbaud a été dévasté à 84 % de sa surface par l'incendie d'août 1990. Dans les mois qui ont suivi, les processus hydrologiques et érosifs ont été fortement pertubés. Des observations spécifiques de l'érosion ont été conduites (MARTIN C. et al., 1993) : une parcelle de 75 m2, située dans le haut du bassin, a fait l'objet de mesures ; un préleveur d'échantillons est venu compléter le dispositif préexistant à la station de jaugeage afin de connaître le débit solide en suspension ; les dépôts dans le lit et à l'amont immédiat de la station ont été estimés sommairement par topographie. Cette situation offrait l'opportunité de valider le modèle ETC au travers de la reconstitution des premières crues de l'automne 1990

Filtration of nanoparticles: Presentation of FANA test bench

A test bench for the analysis of air filter penetration has been developed at IRSN. The paper introduces this nano-aerosol filtration test bench (FANA) and the methodology used to measure filter penetration as accurately as possible for nanoparticles. Two configurations are compared by measuring the penetration through a metallic grid. The results obtained are identical. In addition, penetration results using two filtration velocities and a particle size range of 2.5 to 400 nm are presented for different types of filtration media (F6, F9, HEPA)

Simeprevir for the treatment of hepatitis C virus infection

Laure Izquierdo,1 Fran&ccedil;ois Helle,1 Catherine Fran&ccedil;ois,1,2 Sandrine Castelain,1,2 Gilles Duverlie,1,2 Etienne Brochot1,2 1Virology Research Unit, Jules Verne University of Picardie, 2Department of Virology, Amiens University Hospital, Amiens, France Abstract: Simeprevir (TMC435, Olysio&trade;), a second-generation hepatitis C virus (HCV) protease inhibitor, has been recently approved for the treatment of genotype 1 chronic hepatitis C in combination with pegylated interferon and ribavirin. This molecule has very different characteristics from first-generation protease inhibitors. Results from trials show that simeprevir is highly effective and safe, with few adverse events. We discuss the specific features of this new treatment option for HCV infection, in terms of in vitro data, pharmacological data, and clinical trials. We also discuss the impact of Q80K polymorphism at baseline. Studies evaluating interferon-free regimens with simeprevir are ongoing. Future combinations of two or more direct-acting antiviral agents, targeting different viral enzymes and with synergistic antiviral effects, will be approved, allowing treatment of pan-genotypic HCV with optimized sustained virologic responses. Simeprevir will undoubtedly be part of future treatment strategies. Keywords: simeprevir, protease inhibitor, direct-acting antiviral agent, hepatitis C viru