Fate of aerosolized Nanoparticles: The influence of surface active substances on lung deposition and respiratory effects (NANOaers)
Programme: PNCDI III - P3 - International Cooperation– SIINN ERA-NET
Contract nr. 12 / 07.04.2016
Duration: 07.04.2016 - 06.04.2019
Total project value (euro) : 1.724.740 euro
Total PNCDI III value: 121.477 euro( 546.646,5 lei)
Federal Institute for Risk Assessment (BfR) - Germany / Coordinator
National Research and Development Institute for Textile and Leather (INCDTP) - Romania / Partner
Technical University of Dresden (TU Dresden) - Germany / Partner
TU Graz, Institute of Fluid Mechanics and Heat Transfer (TU Graz) - Austria / Partner
Fundación Gaiker (Gaiker) - Spain / Partner
Harvard School of Public Health (Harvard) - USA / Partner
National Institute of Standards and Technology (NIST) - USA - Asociated Partner
- Publishable abstract
The use of manufactured nanomaterials (MNM) in particulate form is increasing steadily, but little is known about their fate and effects after release into the airborne state and subsequent deposition in the respiratory tract. Especially the influence of matrix effects in liquid formulations on MNM fate, e.g. their ability to absorb other substances and serving as a carrier to otherwise inaccessible sites in the lungs of organisms still remains to be investigated. Toxicological properties of MNM are determined by short term aging processes in daily life scenarios, which are unknown to a large extent. The project NANOaers combines physicochemical and toxicological in vitro - 3D cell models and precision cut lung slices (PCLS) - and in vivo experiments with modelling approach. This widespread approach is used to identify essential parameters for determining the fate and short and long-term effects of MNM after aerosolization of formulations as a basis for further regulatory and normative needs.
- Summary of the project
MNM are released into the air and deposited on human airway epithelia by several scenarios. Little is known about the aging processes of these materials, above all under the potential influence of chemical matrices. These aspects are necessary for assessing their potential effects on living organisms as MNM are hardly exposed to human or the environment without being altered by any chemical sub-stances, either coming from the products they are used in or by reactions in the atmosphere. For adder-ssing the open questions, an approach is being designed to describe exemplarily the different fates of two representative classes of MNM relevant for inhalation exposure: 1) soluble particles with a substance-specific toxicity using the example of Ag nanoparticles, 2) granular biodurable particles (GBP) using the example of CeO2 nanoparticles. Both particle types will be investigated in a test system which addresses the aerosol generation from liquid formulations under the influence of chemi-cal substances. An experiment will be established which will enable the release of MNM from liquid matrices into the airborne state and which allows for a controlled variation of parameters influencing the aerosol formation. The fate of MNM will then be investigated after deposition on airway epithelia and abiotic surfaces. The aging process in the aerosol may change the morphology, density, size range and distribution of the particles. The aging process is assumed to be affected by physicochemical properties of the MNM, interaction with substances, and the releasing process parameters.
The aging process of MNM during aerosol transport will be investigated producing defined suspen-sions of different concentrations of nano-Ag and -CeO2, using a range of active ingredients such as fluorocarbon resins and silanes. The suspensions will be atomized into aerosol states by standardized procedures. The presence of MNM and their size distribution in the generated aerosol will be measured at different time instants and measuring sites within the aerosol. At the same positions, sampling grids, monolayer cultures of alveolar and bronchial origin, 3D cell culture models, PCLS, as well as textile samples will be used for collecting solid particles from the aerosols, which will then be characterized i.a. by electron microscopy and Time of Flight – Secondary Ion Mass Spectrometry (ToF-SIMS). The particle sampling will be size selective by using a cascade impactor and a Nano- Differential Mobility Analyser (DMA). Samples of the airway epithelium model will be cultivated and analyzed for investigating cellular influences on particle fate. For determining effects, in vitro tests will be conducted addressing the epithelial barrier integrity, cytotoxicity and inflammation. Furthermore, biokinetic studies on mice will be conducted to determine their lung clearance and to evaluate the influence of surface modify-cations due to chemical surroundings of MNM on their pulmonary toxicity. All data obtained will form the basis for a standard model allowing the process from the state of formation of the particle-laden droplets to the end of the drying process to be described. The model will include the prediction of particle deposition on lung tissue for real-life situations, using an approach developed within the BMBF-project NanoGEM. To specify the nano-effect, all experiments and investigations will addi-tionnally be conducted with micro-sized particles. Five main steps will be established to close the knowledge gap within the MNM fate:
1) Production of formulation (WP PC): Generation of liquid formulations with different MNM
2) Aerial Fate (WP E): Experimental analysis of MNM release from liquids under the influence of auxiliary substances
3) Fate on lung tissue and abiotic surfaces (WP E): Analysis of MNM reaching the airway
epithelium and textiles as an example for abiotic surfaces
4) Effects of aerosolized MNM (WP T-A/B): In vitro toxicity and in vivo tests covering respiratory cell types and endpoints including cytotoxicity, pro-inflammatory cytokine expression, hemolytic capacity, lung clearance over time, extrapulmonary retention and elimination kinetics, and the analysis of intracellular dose
5) Modelling (WP M): Development of an experimentally based model for predicting MNM fate during spraying and aerosol transport.