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N5-FRAU: Histopathology of rats exposed to Barium sulfate nanoparticles by life-time inhalation exposure – Effects and Biokinetics

Principal Investigator

PhD, Dipl. ACVP Dirk Schaudien

Fraunhofer Institute for Toxicology and Experimental Medicine

Nikolai-Fuchs-Strasse 1

30625 Hannover, Germany

Tel: +49 (511) 5350-324

E-mail: Dirk.schaudien@item.fraunhofer.de

Collaborators

1. Dr. med. vet. Heinrich Ernst, FTA Pathol, Fraunhofer ITEM, Germany
2. Dr. med. vet. Sibylle Gröters, Dipl. ECVP, BASF SE, Germany
3. Prof. Joseph D. Brain, MD, Harvard T. H. Chan School of Public Health, USA
4. Prof. Günter Oberdörster, DVM, Ph.D., University of Rochester Medical Center, USA

Description

A lot of data are known regarding acute and subacute toxicity of nanomaterials, whereas the long term outcome of inhalation exposure to nanomaterials is still unclear. Long-term inhalation exposure data are only available for nano-TiO2 and Carbon black particles at high aerosol concentrations. These studies indicated a chronic inflammation and subsequent tumor formation in the lungs (Heinrich et al., 1995).

Within the European project NANoREG (7th framework programme) a co-operation project was set up between the BMU (The Federal Environment Ministry, Germany) BASF SE, Germany and competent authorities as BAuA; (Federal Institute for Occupational Safety and Health), BfR (Federal Institute for Risk Assessment) and UBA (Federal Environment Agency) for conducting and evaluation of a chronic inhalation study with nanomaterials. Goal of this study is to derive profound conclusions based on the outcome of long term inhalation exposure with selected nanomaterials. The ongoing inhalation study with nanomaterials is the first and only study providing data on the type and potency of long-term exposure to nanoparticles. The outcome of the study will be a basis of future regulations of nanomaterials. The test compounds are Ceroxid (CeO2) at several dose levels, and bariumsulfate (BaSO4) at one high dose. The two particles are expected to cover a wider range of different biokinetic behaviours and toxicological responses with bariumsulfate being more rapidly cleared and less toxic. The proposed project has an immediate impact on the regulation of nanomaterials: the results of the project will be the basis of future regulations of nanomaterials both on occupational exposure levels and cancer classifications. Therefore it is of tremendous importance to guarantee a scientific justifiable and defendable result.

The chronic BaSO4 exposed animals (12 month interim sacrifice) within this combined Chronic Toxicity\Carcinogenicity Study (OECD 453) are already sacrificed and first investigations (bronchoalveolar lavage, organ burden, histopathology) are performed and published by BASF (Keller et al., 2014). Some unexpected results after 52 weeks of BaSO4 exposure might be solved in the context of this proposal after life-time exposure. Previous work with very high technical standards and harmonized histopathologic nomenclature over several studies (1 week, 4 week, 13 week, 52 week of exposure) is already done by the applicants, therefore from a scientific point of view it seems very valuable to follow this strategy.

In addition to the possible carcinogenic potential of long-term exposure, the biokinetic part of this proposal has a very high importance to understand and follow up the possible distribution of nanoparticles in the body. It will be important to compare the chemical signatures, size, crystallinity and structural characteristics such as shape and density of the starting materials (as-synthesized BaSO4 NPs) with those particles that translocate to the lung, liver and bone tissues at various time frames. E.g. high resolution TEM/STEM coupled with electron energy loss spectroscopy (EELS) allows for the detection of nanometer and sub-nanometer particles in tissue materials, giving insights into chemical composition and structural properties after nanoparticle uptake.

The objective of this project is the investigation of the (i) effects and (ii) biokinetics of nanoparticulate barium sulfate inhaled for a life-time in experimental animals; to contribute to hazard prediction and risk assessment of inhaled nanoparticles in man.

Timeline: August 2015 > July 2017

LRI funding: € 280.000

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