Project

MetalSafety

MetalSafety – Development of evaluation concepts for fibrous and granular metal compounds – bioavailability, toxicological efficacy profiles and comparative in vitro, ex vivo and in vivo studies

Metals and their compounds are ubiquitously present in our daily life, for example as components of stainless steel, catalysts, and pigments. Furthermore, metal compounds are being used in numerous innovative processes such as inks for 3D printing or as semiconductors in electronic engineering and medical devices. Apart from granular compounds of different particle sizes, the use of metal-based fibrous materials, so-called nanowires, in various products is increasing. However, many metals and their compounds reveal inflammatory and/or even carcinogenic potentials. Hereby, the toxicity often depends on the respective metal species; decisive factors are oxidation state and solubility and – in case of metal particles – their size (nano-/micro-scaled) as well as structure (granular or fibrous).

The aim of the scientific project MetalSafety is to design comparatively easy-to-use in vitro models for the toxicological evaluation and grouping of different metal-based compounds, which differ in their solubility and bioavailability. One main focus within this project lies on metal-based nanowires, since their toxicological potentials are hardly known. The toxicological profiles of these fibrous structures will be compared to the respective nano-scaled granular as well as water-soluble compounds.

For this purpose, an air-liquid interface (ALI) exposure system will be established to apply fibrous as well as granular structures on in vitro cellular models and to directly measure the deposited mass of the respective compound. The toxicological “finger prints” will be assessed using gene expression profiles, complemented by solubility, uptake and genotoxicity studies.

Afterwards, the results will be compared to complex ex vivo as well as in vivo studies and evaluated with regard to their predictability of the toxicological potential, the mode of action and the dose-response relationship. Species differences between human and rat with respect to toxicodynamic interactions will be obtained on the level of cell culture and precision cut lung slices (PCLS). The respective results will finally compared with data from in vivo studies in rats.

Altogether, the identification of relevant modes of actions by different metals and their compounds is an important prerequisite for a scientific-based derivation of workplace and environmental exposure limit values, including new, innovative metal fibres and granular metal compounds.

NanoCELL

NanoCELL – Comprehensive characterization and human toxicological assessment of nanocellulose along its life cycle for reliable risk assessment and safe use in environmentally friendly packaging materials

Project report

The NanoCELL project addressed the synthesis, physico-chemical characterization, application, and human-toxicological assessment of nanocellulose across its life cycle. Particular focus was on crystalline nanocellulose (CNC) and its application in environmentally friendly packaging materials as important building block of a modern circular economy.

The most important developments and findings within NanoCELL are:

• Development of a process for the lab-scale synthesis of hydrophilic CNC from different raw materials (a.o., cotton, birch, spruce) including successful CNC spray-drying; upscaling of the CNC synthesis process requires adaptations of the reactor design though.
• Successful surface functionalization of CNC (fluorescence labelling, silanization).
• Successful coating of different foil substrates (Polylactic acid, polypropylene, paper) with high composite adhesion and improved barrier effect against oxygen but need further studies necessary regarding coating reproducibility and barrier effect against mineral oils.
• Comprehensive physico-chemical characterization of CNC (size/number distribution, Zeta potential, agglomeration) in complex matrices (a.o., cell culture medium, digestive juices) by multi-detector field-flow fractionation (FFF) and electron microscopy.
• Successful development of different in vitro (GIT-model, 3D lung models) and ex vivo (porcine mucus, intestinal tissue) to study potentially toxic effects of CNC after oral and pulmonal exposure.
• CNC-transport studies in in vitro and ex vivo models under static and dynamic conditions show CNC-transport across the mucus layer, but not across the intestinal tissue; no toxic effects could be observed under these conditions.
• Successful preliminary work for an in silico transport model for CNC across biological barriers.

CERASAFE

CERASAFE – Safe production and use of nanomaterials in the ceramic industry

CERASAFE aims to assess and improve environmental health and safety (EHS) in the ceramic industry. The project’s objective is to study industrial processes and activities, which may generate nanoparticle emissions into workplace air, and to assess worker exposure by evaluating the particle release processes, characterizing the particles emitted, and understanding their toxicity. Finally, mitigation measures to minimize exposure will be proposed.

CERASAFE will also develop a tool to discriminate engineered nanoceramic particles from background aerosols, thus innovating in the field of characterisation methods relevant for EHS. The project will establish a set of Good Manufacturing and Use Practices for nanoceramic materials. Results will be collected in a public database complemented with risk assessment and including recommendations for industry, users and stakeholders to ensure the safe production process for nanoceramic materials.

Project Website:www.cerasafe.eu

NanoToxClass

NanoToxClass – Establishing nanomaterial grouping / classification strategies according to toxicity and biological effects for supporting risk assessment

Nanotechnology is regarded as one of the most significant innovations of the 21^st century, featuring a large industrial and medical potential. Already by now, nanomaterials are used in a variety of different products. Currently, commercialised nanomaterials comprise only a fraction of the chemical space. However, due to substance combinations as well as variations in size, shape and surface modification an almost unlimited number of nanomaterials is possible. Despite extensive research over the past two decades, it has not been possible to formulate any generalised conclusions on the potential health hazards of nanomaterials. Unlike for conventional bulk chemicals there are only very few nanomaterial grouping strategies available. In consequence, nanomaterials are usually still subject to experimental testing and risk evaluation on a case by case basis, which is very time- and cost intense.

NanoToxClass aims to facilitate the respective health hazard evaluation by developing new grouping approaches for a selection of industrially relevant nanomaterials. Importantly, the approach will integrate existing data from literature and the public domain together with extensive new data from a modern systems biology approach in combination with established toxicological endpoints. NanoToxClass will perform transcriptomics, metabolomics and proteomics studies in vitro as well as in vivo.

The project will thus make use of most comprehensive datasets, allowing to unravel mechanisms of action of nanomaterials and concomitantly develop new grouping strategies based on mode of action. Furthermore, our approach will significantly contribute to the establishment of in vitro / in vivo correlations and hence support the development of new integrated testing strategies. Moreover, selected nanomaterials will be examined not only in their original form but also at representative stages of their life cycle, i.e. after thermal aging or after release from a composite material. Finally, newly identified grouping criteria will be validated using additional nanomaterials.

To achieve these objectives, NanoToxClass combines expert knowledge from academia, federal authorities and industry. The development of nanomaterial grouping strategies is of high importance in Europe as well as internationally.

Project Website: www.nanotoxclass.eu/project.html

NanoBEL

NanoBEL – Biological Elimination of Complex Diagnostic Nanoparticles

NanoBEL medical applications (c) NanoBEL Consortium

Nanotechnology is one of the key technologies of the 21st century that developed from a basic research to a worldwide important discipline in the last years with an enormous importance in life sciences and medicine. Magnetic nanoparticles play an important role in diagnostic imaging for prevention, therapeutic monitoring and therapy.

Whereas the toxicological effects of acute nanoparticle expositions were widely described in the last years, long-term risks depending on the structure of the nanomaterials and the disease state of the patients have not been systematically investigated.

NanoBEL is focused on the risk assessment of the long-term effects of magnetic nanoparticle exposition particularly after repeated administrations, as well as the role of degradation and elimination in the life-cycle of the nanoparticles in diseases like cancer and inflammation. Innovative magnetic nanoparticle formulations with a high relevance for future diagnostic applications are taken into consideration. Beside the development and optimization of magnetic nanoparticles,

NanoBEL contributes to the development and validation of new alternatives to animal-based methods (cell cultures, hen’s egg models) to be applied in an integrated safety assessment of the long-term administration of nanoparticles. In close collaboration with DaNa^2.0, the systematic collection of the data in a data base accomplish the categorization of nanomaterials, the identification of relevant endpoints, and the risk management.