MicroRNA-155 promotes neointimal hyperplasia through smooth muscle-like cell-derived RANTES in arteriovenous fistulas

Objective

Arteriovenous fistula (AVF) suffers from a high number of failures caused by insufficient outward remodeling and venous neointimal hyperplasia formation. The aim was to investigate the exact mechanism by which microRNA-155 (miR-155) in the outflow vein of AVF is regulated.

Biomonitoring equivalents for di-isononyl phthalate (DINP)

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for di-isononyl phthalate (DINP) from Health Canada, the United States Consumer Product Safety Commission (US CPSC), and the European Food Safety Authority (EFSA). Controlled dosing data reporting the urinary excretion fractions of major DINP metabolites following administration of labeled DINP are reviewed, and BE values corresponding to the available exposure guidance values are derived assuming chronic, steady-state intake and excretion at those exposure values. The BE values range from 1500 to 3600μg/L (1900-4600μg/g creatinine) based on the sum of three oxidative metabolites. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data, including the transience of the biomarkers relative to exposure frequency, are discussed. The BE values derived here can be used as screening tools for evaluation of population biomonitoring data for DINP in the context of existing risk assessments and can assist in prioritization of the potential need for additional risk assessment efforts for DINP relative to other chemicals.     

The Short Time Exposure (STE) test for predicting eye irritation potential: Intra-laboratory reproducibility and correspondence to globally harmonized system (GHS) and EU eye irritation classification for 109 chemicals

Short Time Exposure (STE) test is an easy in vitro eye irritation test that assesses cytotoxicity in SIRC cells (rabbit corneal cell line) following a 5 min dose treatment. To assess intra-laboratory reproducibility, medium control, three vehicles (saline, saline containing 5% (w/w) dimethyl sulfoxide, and mineral oil) and three standard chemicals (sodium lauryl sulfate, calcium thioglycolate, and Tween 80) were evaluated. Assessments were repeated 30 times for vehicles and 18 times for standard chemicals; resulting in almost the same cell viability and a low coefficient of variation value. In addition, the STE eye irritation rankings of three standard chemicals, as calculated on the cell viabilities in 5% and 0.05% solutions were in agreement in all tests. Based on these results, high intra-laboratory reproducibility was confirmed.In addition, the irritation category (irritant and non-irritant) was evaluated for 109 chemicals with STE test, globally harmonized system (GHS) classification, and European Union (EU) classification. The results of the evaluation found the STE classification to have an accuracy with GHS classification of 87% and with EU classification of 83%, which confirmed the excellent correspondence.The correspondence of STE rankings (1, 2, and 3) based on the prediction model by STE test with the eye irritation rankings by GHS (non-irritant, categories 2 and 1) and EU (non-irritant, R36, and R41) was 76% and 71%, respectively.Based on the above results, STE test was considered to be a promising alternative method for assessing eye irritation that has high intra-laboratory reproducibility as well as an excellent predictability of eye irritation.     

Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

There are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data.     

中药复方在欧盟注册的对策探析

在前人研究的基础上,明晰了中药复方在欧盟注册的障碍,并从奠定认同基础、实现文化融合、渗透法律理念、优化注册方案等角度全方位地对中药复方在欧盟顺利注册提出对策,以期为我国中药复方在欧盟成功注册提供参考。     

Application of scientific criteria to food allergens of public health importance

Scientific criteria for identifying allergenic foods of public health importance (Björkstén, B., Crevel, R., Hischenhuber, C., Løvik, M., Samuels, F., Strobel, S., Taylor, S.L., Wal, J.-M., Ward, R., 2008. Criteria for identifying allergenic foods of public health importance. Regulatory Toxicology and Pharmacology 51(1), 42–52) have been further refined to incorporate an assessment of the strength of available scientific evidence (van Bilsen, J.H., Ronsmans, S., Crevel, R.W., Rona, R.J., Przyrembel, H., Penninks, A.H., Contor, L., Houben, G.F., 2011. Evaluation of scientific criteria for identifying allergenic food of public health importance. Regulatory Toxicology and Pharmacology 60, 281–289). A multi-disciplinary group was invited to critically test the refined approach. They independently evaluated selected publications on coconut, soy and/or peanut allergy, scored them using the newly developed level of evidence criteria, and debated proposed approaches for combining and utilising the scores to measure the overall impact of an allergen in public health impact assessments. The evaluation of selected publications using the modified criteria produced a relatively consistent result across the experts. These refined criteria were judged to be a way forward for the identification of allergenic foods of public health importance, and for prioritisation of allergen risk management and future data gathering. The debate to combine available evidence when assessing whether an allergenic food is of sufficient public health importance to warrant active management led to proposals on how to weight and combine evidence on allergen severity, potency and prevalence. The refined criteria facilitate a debate to find a meaningful sequence of steps to summarise the available information in relation to a food allergen.     

Acute oral toxicity of 3-MCPD mono- and di-palmitic esters in Swiss mice and their cytotoxicity in NRK-52E rat kidney cells

The acute oral toxicity of 1-palmitoyl-3-chloropropanediol (3-MCPD 1-monopalmitate) and 1,2-bis-palmitoyl-3-chloropropanediol (3-MCPD dipalmitate) in Swiss mice were examined, along with their cytotoxicity in NRK-52E rat kidney cells. LD₅₀ (median lethal dose) value of 3-MCPD 1-monopalmitate was determined 2676.81 mg/kg body weight (BW). The results showed that 3-MCPD 1-monopalmitate dose-dependently decreased the mean body weight, and caused significant increase of serum urea nitrogen and creatinine in dead mice compared to the control and survived mice. Major histopathological changes in mice fed 3-MCPD 1-monopalmitate were renal tubular necrosis, protein casts and spermatids decrease in the seminiferous tubules. According to the limit test for 3-MCPD dipalmitate, LD₅₀ value of 3-MCPD dipalmitate was presumed to be greater than 5000 mg/kg BW. Obvious changes were not observed on mean body weight, absolute and relative organ weight or serum urea nitrogen and creatinine levels in mice fed 3-MCPD dipalmitate. However, renal tubular necrosis, protein casts and spermatids decrease were also observed in the dead mice. In addition, MTT and LDH assay results only showed the cytotoxicity of 3-MCPD 1-monopalmitate in NRK-52E rat kidney cells in a dose-dependent manner. Together, the results indicated a greater toxicity of 3-MCPD 1-monopalmitate compared to 3-MCPD dipalmitate.