Overview of in vitro-in vivo extrapolation approaches for the risk assessment of nanomaterial toxicity.

Nanomaterials are increasingly used in many applications due to their enhanced properties. To ensure their safety for humans and the environment, nanomaterials need to be evaluated for their potential risk. The risk assessment analysis on the nanomaterials based on animal or in vivo studies is accompanied by several concerns, including animal welfare, time and cost needed for the studies.

Plasma cells are not restricted to the CD27+ phenotype: characterization of CD27-CD43+ antibody-secreting cells.

Unlabelled: Circulating antibody-secreting cells are present in the peripheral blood of healthy individuals reflecting the continued activity of the humoral immune system. Antibody-secreting cells typically express CD27. Here we describe and characterize a small population of antibody-secreting class switched CD19+CD43+ B cells that lack expression of CD27 in the peripheral blood of healthy subjects.

Impact of Particle Size on Toxicity, Tissue Distribution and Excretion Kinetics of Subchronic Intratracheal Instilled Silver Nanoparticles in Mice.

The unique physicochemical properties of silver nanoparticles (AgNPs) make them useful in a wide range of sectors, increasing their propensity for human exposure, as well as the need for thorough toxicological assessment. The biodistribution of silver, hematological parameters and GSH/GSSG levels in the lung and liver were studied in mice that were intratracheally instilled with AgNP (5 and 50 nm) and AgNO once a week for 5 weeks, followed by a recovery period of up to 28 days (dpi). Data was gathered to build a PBPK model after the entry of AgNPs into the lungs.

Insects as Diet and Therapy: Perspectives on Their Use for Combating Diabetes Mellitus in Tanzania.

More than 450 million people worldwide are suffering from diabetes and this number is expected to increase. In developing countries, such as Tanzania, the number of patients suffering from diabetes and associated diseases is increasing as well. Up to 80% of the Tanzanian people rely on traditional medicines for their health care services.

Valorisation Potential of Using Organic Side Streams as Feed for , and .

Due to increasing welfare and population, the demand for alternative protein sources, obtained with minimal use of natural resources, is rising in today's society. Insects have the potential to be used as an alternative protein source since they are considered to be able to convert low-value biomass into high-value components, resulting in opportunities for valorisation of organic side streams. Moreover, insects are suggested to be a sustainable protein source, referring to the efficient "feed to body" mass conversion potential.

Development of a classification model for the antigenotoxic activity of flavonoids.

Genotoxic agents are capable of causing damage to genetic material and the cumulative DNA damage causes mutations, involved in the development of various pathological conditions, including cancer. Antigenotoxic agents possess the potential to counteract these detrimental cellular modifications and may aid in preventing, delaying, or decreasing the severity of these pathological conditions. An important class of natural products for which promising antigenotoxic activities have already been shown, are the flavonoids.

Insects as an Alternative Source for the Production of Fats for Cosmetics.

Insects may provide an environmentally friendly way of producing high-quality bio-based materials that can be implemented for cosmetic applications. Insects can be bred on organic waste, in high numbers, and on small surfaces, therefore, making large scale industrial breeding possible. Fats from three insect species: the black soldier fly (BSF) (), the locust (), and the house cricket () were evaluated for potential use in skin care.

Evaluation of existing (Q)SAR models for skin and eye irritation and corrosion to use for REACH registration.

The performance of the (Q)SAR models Derek Nexus, Toxtree and Case Ultra for the prediction of skin and eye irritation/corrosion is investigated. For irritation and corrosion of the skin, 117 compounds and for the eye, 125 compounds were listed. The balance between the groups positive and negative for irritation and corrosion was maintained.

Integrating High-Dimensional Transcriptomics and Image Analysis Tools into Early Safety Screening: Proof of Concept for a New Early Drug Development Strategy.

During drug discovery and development, the early identification of adverse effects is expected to reduce costly late-stage failures of candidate drugs. As risk/safety assessment takes place rather late during the development process and due to the limited ability of animal models to predict the human situation, modern unbiased high-dimensional biology readouts are sought, such as molecular signatures predictive for in vivo response using high-throughput cell-based assays. In this theoretical proof of concept, we provide findings of an in-depth exploration of a single chemical core structure.

Identification of in vitro and in vivo disconnects using transcriptomic data.

Background: Integrating transcriptomic experiments within drug development is increasingly advocated for the early detection of toxicity. This is partly to reduce costs related to drug failures in the late, and expensive phases of clinical trials. Such an approach has proven useful both in the study of toxicology and carcinogenicity.

Release of (and lessons learned from mining) a pioneering large toxicogenomics database.

Aim: We release the Janssen Toxicogenomics database. This rat liver gene-expression database was generated using Codelink microarrays, and has been used over the past years within Janssen to derive signatures for multiple end points and to classify proprietary compounds.

Materials & Methods: The release consists of gene-expression responses to 124 compounds, selected to give a broad coverage of liver-active compounds.

Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants.

Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression.

Evaluation of miR-122 and other biomarkers in distinct acute liver injury in rats.

The detection of drug-induced hepatotoxicity remains an important safety issue in drug development. A liver-specific microRNA species, microRNA-122 (miR-122), has recently shown potential for predicting liver injury in addition to the standard hepatic injury biomarkers. The objective of this study was to measure miR-122 together with several other liver markers in distinct settings of acute liver toxicity in rats to determine the value of miR-122 as a biomarker for liver injury in this species.

Phospholipidosis in rats treated with amiodarone: serum biochemistry and whole genome micro-array analysis supporting the lipid traffic jam hypothesis and the subsequent rise of the biomarker BMP.

To provide mechanistic insight in the induction of phospholipidosis and the appearance of the proposed biomarker di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP), rats were treated with 150 mg/kg amiodarone for 12 consecutive days and analyzed at three different time points (day 4, 9, and 12). Biochemical analysis of the serum revealed a significant increase in cholesterol and phospholipids at the three time points. Bio-analysis on the serum and urine detected a time-dependent increase in BMP, as high as 10-fold compared to vehicle-treated animals on day 12.

Preservation of hepatocellular functionality in cultures of primary rat hepatocytes upon exposure to 4-Me2N-BAVAH, a hydroxamate-based HDAC-inhibitor.

Great efforts are being put in the development/optimization of reliable and highly predictive models for high-throughput screening of efficacy and toxicity of promising drug candidates. The use of primary hepatocyte cultures, however, is still limited by the occurrence of phenotypic alterations, including loss of xenobiotic biotransformation capacity. In the present study, the differentiation-stabilizing effect of a new histone deacetylase inhibitor 5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamide (4-Me(2)N-BAVAH), a structural Trichostatin A (TSA)-analogue with a more favourable pharmaco-toxicological profile, was studied at a genome-wide scale by means of microarray analysis.

Screening for phospholipidosis induced by central nervous drugs: comparing the predictivity of an in vitro assay to high throughput in silico assays.

Drug-induced phospholipidosis is a side effect for which drug candidates can be screened in the drug discovery phase. The numerous in silico models that have been developed as a first line of screening are based on the characteristic physicochemical properties of phospholipidosis-inducing drugs, e.g.

MUTZ-3-derived dendritic cells as an in vitro alternative model to CD34+ progenitor-derived dendritic cells for testing of chemical sensitizers.

The cytokine-dependent CD34(+) human acute myeloid leukaemia cell line MUTZ-3 was used to generate immature dendritic-like cells (MUTZ-3 DC) and their validity as an alternative to primary CD34(+) progenitor-derived DC (CD34-DC) for testing chemical-induced sensitization was assessed. Expression levels of the DC maturation markers HLA-DR, CD86, CD83 and CD11c were studied using flow cytometry after 24 and 48 h exposure to the model compound nickel sulphate (100 and 300 microM). No maturation of MUTZ-3 DC was observed, whereas significantly upregulated expression levels of CD83 and CD86 were noticed in CD34-DC after 24h treatment with 300 microM nickel sulphate compared to control cells.

A 96-well flow cytometric screening assay for detecting in vitro phospholipidosis-induction in the drug discovery phase.

Drug-induced phospholipidosis is caused by lysosomal accumulation of the drug, resulting in the disturbance of phospholipid degradation and a consequent excessive phospholipid accumulation. Depending on the type and number of tissues affected, phospholipidosis occurrence in test animals can raise safety issues, which may be critical for the risk assessment. Safety profiling of potential phospholipidosis-inducing drugs in the drug discovery phase can predict these late obstructions of drug development.

Automated analysis of contractility in the embryonic stem cell test, a novel approach to assess embryotoxicity.

The embryonic stem cell test (EST) is an ECVAM-validated assay to detect embryotoxicity. The output of the assay is the effect of test compounds on the differentiation of murine-derived embryonic stem cells (D3 cells), recorded by visual analysis of contracting cardiomyocyte-like cells. Incorporation of a system to assess the contractility in an automated manner is proposed, to increase the throughput in the EST independent of observer bias.

Evaluation of the embryotoxic potency of compounds in a newly revised high throughput embryonic stem cell test.

The ability of murine-derived embryonic stem cells (D3) to differentiate into cardiomyocytes is the basis of the embryonic stem cell test (EST). With the EST, chemicals and pharmaceuticals can be assessed for their embryotoxic potency early on in the development process. In order to come to a higher throughput EST, a 96-well based method was developed based on low attachment well plates that allow for the formation of embryonic bodies from which the stem cells can differentiate.

Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization.

The assessment of the skin sensitising capacity of chemicals is up to now investigated using in vivo animal tests. However there has been an increasing public and governmental concern regarding the use of animals for chemical screening. This has raised the need for the development of validated in vitro alternatives.

Respiratory immunotoxicity: an in vitro assessment.

As yet, in vitro assessment of the immunotoxic potency of respiratory agents is not possible. The complexity of the endpoint and the respiratory tract, and the limited availability of well-documented respiratory agents are the main reasons. The evidence that epithelial cells (ECs) are triggered by compounds to express in vitro surface proteins and soluble mediators, has stimulated their use for developing tests for respiratory immunotoxicity.

Gene expression signatures in CD34+-progenitor-derived dendritic cells exposed to the chemical contact allergen nickel sulfate.

The detection of the sensitizing potential of chemicals is of great importance to industry. A promising in vitro alternative to the currently applied animal assays for sensitization testing makes use of dendritic cells (DCs) that have the capability to process and present antigens to naive T cells and induce their proliferation. Here, we studied changes in gene expression profiles after exposing DCs to the contact allergen nickel sulfate.

Interactions between dendritic cells and epithelial cells in allergic disease.

Dendritic cells (DCs) play a crucial role in the sensitisation process. Upon encounter with an allergen, DCs require interactions with other cells and factors for triggering a primary or secondary immune response. Epithelial cells (ECs) express features of accessory cells, such as expression of HLA-DR, co-stimulatory molecules, functional FcgammaR, molecules of the antigen-processing machinery, and display an ability to internalise antigen.