Mechanisms of Silver Nanoparticle Release, Transformation and Toxicity: A Critical Review of Current Knowledge and Recommendations for Future Studies and Applications.

Nanosilver, due to its small particle size and enormous specific surface area, facilitates more rapid dissolution of ions than the equivalent bulk material; potentially leading to increased toxicity of nanosilver. This, coupled with their capacity to adsorb biomolecules and interact with biological receptors can mean that nanoparticles can reach sub-cellular locations leading to potentially higher localized concentrations of ions once those particles start to dissolve or degrade . Further complicating the story is the capacity for nanoparticles to generate reactive oxygen species, and to interact with, and potentially disturb the functioning of biomolecules such as proteins, enzymes and DNA.

Metabolomics in toxicology and preclinical research.

Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways.

Evaluation of selected biomarkers for the detection of chemical sensitization in human skin: a comparative study applying THP-1, MUTZ-3 and primary dendritic cells in culture.

Dendritic cells (DCs) exhibit the unique capacity to induce T cell differentiation and proliferation, two processes that are crucially involved in allergic reactions. By combining the exclusive potential of DCs as the only professional antigen-presenting cells of the human body with the well known handling advantages of cell lines, cell-based alternative methods aimed at detecting chemical sensitization in vitro commonly apply DC-like cells derived from myeloid cell lines. Here, we present the new biomarkers programmed death-ligand 1 (PD-L1), DC immunoreceptor (DCIR), IL-16, and neutrophil-activating protein-2 (NAP-2), all of which have been detectable in primary human DCs upon exposure to chemical contact allergens.

Effects of triclocarban on the transcription of estrogen, androgen and aryl hydrocarbon receptor responsive genes in human breast cancer cells.

Triclocarban (TCC) is an antimicrobial agent that is used in detergents, soaps and other personal hygiene products. Similarly to triclosan the widespread use of TCC has raised concerns about its endocrine potential. In luciferase-based reporter assays TCC has been shown to enhance estrogenic and androgenic activities following cellular coexposure with estrogen or dihydrotestosterone, respectively.

DNA quality control by a lesion sensor pocket of the xeroderma pigmentosum group D helicase subunit of TFIIH.

Background: Nucleotide excision repair is a versatile DNA repair reaction that removes bulky adducts generated by environmental mutagens such as the UV spectrum of sunlight or chemical carcinogens. Current multistep models of this excision repair pathway accommodate its broad substrate repertoire but fail to explain the stringent selectivity toward damaged nucleotides among excess native DNA. To understand the mechanism of bulky lesion recognition, we postulated that it is necessary to analyze the function of xeroderma pigmentosum group D (XPD) protein beyond its well-known role in the unwinding of double-stranded DNA.

Development of a manual method for the determination of mineral oil in foods and paperboard.

So far the majority of the measurements of mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH) were obtained from on-line high performance liquid chromatography-gas chromatography-flame ionization detection (on-line HPLC-GC-FID). Since this technique is not available in many laboratories, an alternative method with more easily available tools has been developed. Preseparation on a small conventional liquid chromatographic column was optimized to achieve robust separation between the MOSH and the MOAH, but also to keep out the wax esters from the MOAH fraction.

Esterase activity in excised and reconstructed human skin--biotransformation of prednicarbate and the model dye fluorescein diacetate.

Reconstructed human epidermis (RHE) is used in non-animal testing for hazard analysis and reconstructed human skin (RHS) gains growing interest in preclinical drug development. RHE and RHS have been characterised regarding their barrier function, but knowledge about biotransformation capacity in these constructs and in human skin remains rather poor. However, metabolising enzymes can be highly relevant for the efficacy of topical dermatics as well as genotoxicity and sensitisation.

Metabolically competent human skin models: activation and genotoxicity of benzo[a]pyrene.

The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) is metabolized into a complex pattern of BP derivatives, among which the ultimate carcinogen (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE) is formed to certain extents. Skin is frequently in contact with PAHs and data on the metabolic capacity of skin tissue toward these compounds are inconclusive. We compared BP metabolism in excised human skin, commercially available in vitro 3D skin models and primary 2D skin cell cultures, and analyzed the metabolically catalyzed occurrence of seven different BP follow-up products by means of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).

Human Langerhans cells control Th cells via programmed death-ligand 1 in response to bacterial stimuli and nickel-induced contact allergy.

Langerhans cells (LCs) are suspected to initiate inflammatory immune responses to contact allergens and pathogenic bacteria. In chronic infectious diseases, programmed death ligand (PD-L) 1 exhibits both inhibitory and costimulatory functions on T cell-mediated activation and tolerance. Here, we investigated the effects of contact allergens and bacterial stimuli on PD-L1 expression in LCs and the effects of altered PD-L1 expression on cytokine release of subsequently cocultured T cells.

Risk assessment of nanomaterials in cosmetics: a European union perspective.

In Europe, the data requirements for the hazard and exposure characterisation of chemicals are defined according to the REACH regulation and its guidance on information requirements and chemical safety assessment (Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), and its guidance documents; available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.

"Drugs on oxygen": an update and perspective on the role of cytochrome P450 testing in pharmacology.

Low hit rates for lead compounds and high attrition remain a major problem for drug development. The reasons for compound failure range from poor pharmacokinetics to toxic metabolites and adverse drug interactions; all of which are frequently mediated by cytochrome P450-dependent monooxygenases (CYPs). However, despite some 30 years of assay development and refinement, CYP metabolism remains a critical issue during drug development.

Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis.

In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[a]pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling.

On the role of low-dose effects and epigenetics in toxicology.

For a long time, scientists considered genotoxic effects as the major issue concerning the influence of environmental chemicals on human health. Over the last decades, a new layer superimposed the genome, i.e.

A personalized life: biomarker monitoring from cradle to grave.

Considering the holy grail of future medical treatment being personalized medicines, biomarker research will become more and more the focus for attention not only to develop new medical treatment regimes, based on changes in biomarker patterns, but also for nutritional advice to guarantee a lifelong optimized health condition. The current review gives an outline of how personalized medicine can become established for actual medical treatment using new biomarker concepts. Starting from the development of biomarker research using mainly immunological techniques, the review gives an overview about biomarkers of prediction evolved and focuses on new methodology for the identification of biomarkers using hyphenated analytical techniques like metabolomics and lipidomics.

Nanomaterials: a challenge for toxicological risk assessment?

Nanotechnology has emerged as one of the central technologies in the twenty-first century. This judgment becomes apparent by considering the increasing numbers of people employed in this area; the numbers of patents, of scientific publications, of products on the market; and the amounts of money invested in R&D. Prospects originating from different fields of nanoapplication seem unlimited.

Exposure to polycyclic aromatic hydrocarbons: bulky DNA adducts and cellular responses.

Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) have been intensively studied for decades. Although the genotoxicity of these compounds is well characterized (i.e.

Toxicologically relevant phthalates in food.

Various phthalates have been detected in a wide range of food products such as milk, dietary products, fat-enriched food, meat, fish, sea food, beverages, grains, and vegetables as well as in breast milk. Here we present an overview on toxicologically considerable phthalate levels in food reported in the literature. The most common phthalates detected are di-(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP).

Wind of change challenges toxicological regulators.

Background: In biomedical research, the past two decades have seen the advent of in vitro model systems based on stem cells, humanized cell lines, and engineered organotypic tissues, as well as numerous cellular assays based on primarily established tumor-derived cell lines and their genetically modified derivatives.

Objective: There are high hopes that these systems might replace the need for animal testing in regulatory toxicology. However, despite increasing pressure in recent years to reduce animal testing, regulators are still reluctant to adopt in vitro approaches on a large scale.

Neural differentiation of mouse embryonic stem cells as a tool to assess developmental neurotoxicity in vitro.

Mouse embryonic stem cells (mESCs) represent an attractive cellular system for in vitro studies in developmental biology as well as toxicology because of their potential to differentiate into all fetal cell lineages. The present study aims to establish an in vitro system for developmental neurotoxicity testing employing mESCs. We developed a robust and reproducible protocol for fast and efficient differentiation of the mESC line D3 into neural cells, optimized with regard to chemical testing.

Waterpipe smoking: the role of humectants in the release of toxic carbonyls.

In recent years, the number of waterpipe smokers has increased substantially worldwide. Here, we present a study on the identification and quantification of seven carbonylic compounds including formaldehyde, acetaldehyde and acrolein in the mainstream smoke of the waterpipe. Smoking was conducted with a smoking machine, and carbonyls were scavenged from the smoke with two impingers containing an acidic solution of 2,4-dinitrophenylhydrazine.

Drug-mediated toxicity: illuminating the 'bad' in the test tube by means of cellular assays?

Health problems are rising worldwide, be it as a consequence of lifestyle and longevity in increasingly affluent societies or due to a sharp rise in bacterial antibiotic resistance. The pharmaceutical industry is caught between high rates of attrition and the rather slow pace of a historically large regulatory system for pharmacological safety. Meanwhile, the past decade has seen a tremendous evolution of the biological toolbox, most notably of cellular assays, stem-cell differentiation and organ-mimicking systems.

Assaying embryotoxicity in the test tube: current limitations of the embryonic stem cell test (EST) challenging its applicability domain.

Testing for embryotoxicity in vitro is an attractive alternative to animal experimentation. The embryonic stem cell test (EST) is such a method, and it has been formally validated by the European Centre for the Validation of Alternative Methods. A number of recent studies have underscored the potential of this method.

CYP1B1 detection.

This unit describes procedures for measuring CYP1B1 gene expression by reverse transcription real-time PCR (qRT-PCR), CYP1B1 protein levels by western blotting, and CYP1B1 enzyme activity through conversion of 7-ethoxyresorufin substrate. To achieve specific measurement of CYP1B1 activity in the presence of CYP1A1 and CYP1A2, CYP1B1 inhibition and a subtractive approach have been adopted. 2,4,3',5'-Tetramethoxystilbene (TMS) is a potent and selective competitive inhibitor of CYP1B1 with an IC₅₀ of 3 nM for EROD and ~90 nM for E2 4-hydroxylation.

A novel type of silver nanoparticles and their advantages in toxicity testing in cell culture systems.

Silver nanoparticles (SNPs) are among the most commercialized nanoparticles worldwide. Often SNP are used because of their antibacterial properties. Besides that they possess unique optic and catalytic features, making them highly interesting for the creation of novel and advanced functional materials.