CarboTox

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CarboTox – Development of screening methods to analyse cancerogenous potential of carbon nano tubes

 

As part of the joint project CarboTox, tailor-made multi-walled carbon nanotubes (MWCNT) with different lengths, diameters and shapes, produced by our cooperation partner (IFW, Dresden), were tested both in vivo and in vitro for their toxic and carcinogenic potential.

A carcinogenicity study was performed to evaluate the carcinogenic potential of multi-walled CNT over a test duration of 2 years. To this end, rats were treated once with the test item (2 dose groups with 50 animals/group: 1 x 109 and 5 x 109 WHO fibers*/rat, amosite as reference fiber, dose: 0.1 x 109 WHO fibers*/rat) by intraperitoneal injection. In parallel, a screening test was developed with the aim to identify markers for chronic adverse effects detectable already after shorter observation periods. All multi-walled carbon nanotubes, independent of their length and diameter, caused tumors (mesothelioma) typically associated with fibers after intraperitoneal injection, but multi-walled carbon nanotubes with more needle-like morphology showed a stronger tumorigenic effect than the coiled carbon nanotubes.

MWCNT

Length
WHO-Fibers* (µm)

Diameter
WHO-Fibers* (µm)

Shape
Amosit 13,95 0,394 Needle-like
MWCNT A 8,57 0,085 Needle-like
MWCNT B 9,30 0,062 Curved
MWCNT C 10,24 0,040 Curved
MWCNT D 7,91 0,037 Coiled

*WHO fibers: length > 5 µm, diameter < 3 µm; length/diameter ratio > 3/1

 

Measuring the thickness of the diaphragm covering the peritoneum was found to be a well suited endpoint for an in vivo screening test with observation periods of 3 and 6 months. Equally valid is the determination of the ratio of proliferated cells compared to non-proliferated cells in the peritoneum using the BrdU method (chem. Bromodeoxyuridine). An increase in proliferated cells indicates the beginning of possibly uncontrolled cell division. A simultaneously performed subchronic inhalation test with the same multi-walled carbon nanotubes is aimed at detecting and quantifying the migration of multi-walled CNT to the pleura. With the currently available results, however, it is not yet possible to answer these questions

In vitro assays with primary mesothelial cell cultures showed that multi-walled CNT, depending on their morphology, inhibit cell proliferation, lead to damage of membranes, cytoskeleton and DNA, and cause cellular senescence. The strongest biological effects were induced by multi-walled carbon nanotubes with needle-like morphology.

Interestingly, the effects of different multi-walled carbon nanotubes observed in cell cultures correlated with tumor development in rats, so that certain cell culture methods might be suitable for use as screening tests to assess the adverse, carcinogenic potential of new multi-walled CNT.

Grant Number: BMBF - FKZ 03X0109
Duration: 01.09.2010 - 31.08.2013 (extended to 31.12.2013)

Project Lead

Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Logo
Anja Hackbarth, Fraunhofer-Institute for Toxicology and Experimental Medicine (ITEM), Hannover (DE)

Project Partners

Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Logo
Fraunhofer-Institute for Toxicology and Experimental Medicine (ITEM), Hannover (DE)
Leibniz IFW Dresden Logo English
Leibniz Institute for Solid State and Materials Research Dresden (IFW), Dresden (DE)
ayer Material-Science Logo
Bayer Material Science AG (since 2015 Covestro AG), Leverkusen (DE)

Publications

2014

  • Rittinghausen S., Hackbarth A., Creutzenberg O., Ernst H., Heinrich U., Leonhardt A., Schaudien D. (2014). The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats. Part Fibre Toxicol, 11(1): 59.

2013

  • Hackbarth A., Schaudien D., Bellmann B., Ernst H., Ziemann C., Leonhardt A., Heinrich U., Rittinghausen S. (2013). Toxic effects of multiwall carbon nanotubes (MWCNT) in vivo and in vitro. Scientific Symposium "Good Particles - Bad Particles - Interaction of (Carbon) Nano Particles with Lung Cells", 23.-24.10.2013, Borstel, Deutschland. Pneumologie 67 (12): S.695
 

2014

  • Hackbarth A., Schaudien D., Bellmann B., Ernst H., Leonhardt A., Steinberg P., Rittinghausen S. (2014). BrdU screening - short-time test for reliable prediction of carcinogenicity for MWCNT. DGPT Jahrestagung 2014, 01.-03.04.2012, Hannover, Germany. Naunyn Schmiedebergs Arch. Pharmacol. 387, Suppl. 1: S46, Abstract 180.
  • Reamon-Buettner SM, Bellmann B, Hackbarth A, Leonhardt A, Niehof M, Ziemann C (2014). Multiwalled carbon nanotubes (MWCNT) induce DNA damage and cellular senescence in human peritoneal mesothelial LP9 cells. DGPT Jahrestagung 2014, 01.-03.04.2012, Hannover, Germany. Naunyn Schmiedebergs Arch. Pharmacol. 387, Suppl. 1: S23, Abstract 087.
  • Rittinghausen S., Bellmann B., Hackbarth A., Ernst H., Heinrich U., Leonhardt A.; Schaudien D. (2014). Histopathological analysis of malignant tumors induced by intraperitoneal injection of carbon nanotubes. SOT 2014 - 53rd Annual Meeting and ToxExpo, 23.-27.03.2014, Phoenix, USA. The Toxicologist 138 (2014), Nr.1, S.525, PS 1990.

2013

  • Schlichting A, Ziemann C, Leonhardt A, Rittinghausen S, Schaudien D, Bellmann B (2013). Toxic Effects of MWCNT In Vivo and In Vitro. SOT 2013 - 52nd Annual Meeting and ToxExpoTM, 10.-14.03.2013, San Antonio, USA. The Toxicologist 132 (1): PS 460.
  • Ziemann C, Reamon-Buettner SM, Hackbarth A, Brockmeyer H, Rahmer H, Bellmann B (2013). Human Pleural Mesothelial MeT-5A Cells are a limited in vitro Model for Detection of Potential Asbestos-like Genotoxic Effects of Multiwall Carbon Nanotubes. SOT 2013 - 52nd Annual Meeting and ToxExpoTM, 10.-14.03.2013, San Antonio, USA. The Toxicologist 132 (1): PS 434.
  • Hackbarth A, Ziemann C, Leonhardt A, Steinberg P, Bellmann B (2013). Multiwall carbon nanotubes exhibit a cytotoxic but not directly DNA-damaging potential in human LP9/TERT-1 peritoneal mesothelial cells. DGPT Jahrestagung 2013, 05.-07.03.2013, Halle, Germany. Naunyn Schmiedebergs Arch. Pharmacol. 386, Suppl. 1: S30, Abstract 113.
  • Reamon-Buettner S, Hackbarth A, Voepel IR, Brockmeyer H, Leonhardt A, Bellmann B, Ziemann C (2013). Human peritoneal mesothelial LP9 cells as a model system to determine the toxic and genotoxic potential of multiwall carbon nanotubes (MWCNTs). DGPT Jahrestagung 2013, 05.-07.03.2013, Halle, Germany. Naunyn Schmiedebergs Arch. Pharmacol. 386, Suppl. 1: S65, Abstract 262.

2012

  • Ziemann C, Reamon-Buettner SM, Schlichting A, Brockmeyer H, Rahmer H, Bellmann B (2012). Human pleural mesothelial MeT-5A cells are a limited in vitro model system in determining potential asbestos-like effects of multiwall carbon nanotubes. DGPT Jahrestagung 2012, 19.-22.03.2012, Dresden, Germany. Naunyn Schmiedebergs Arch. Pharmacol. 385, Suppl. 1: S107, Abstract 473.
  • Heinrich U, Schlichting A, Ziemann C, Seyock S, Haase D, Leonhardt A, Bellmann B (2012). Suspension of MWCNT for toxicological in vivo and in vitro studies. SOT 2012 - 51st Annual Meeting and ToxExpoTM, 11.-15.03.2012, San Francisco, USA. The Toxicologist 126 (1): PS 661.

All available final scientific reports of the CarboTOX consortium can be accessed via the TIB Hannover website https://www.tib.eu/en/  
  • Fraunhofer-Institute for Toxicology and Experimental Medicine (ITEM) (2014). Entwicklung von Screening-Verfahren zur Untersuchung eines möglichen kanzerogenen Potentials von Carbon Nanotubes : Endbericht des Teilvorhabens; Projektleitung: Anja Hackbarth, Fraunhofer ITEM, FKZ 03X0109A, TIB Hannover.
  • Leibniz Institute for Solid State and Materials Research Dresden (IFW) (2014). CarboTox - Entwicklung von Screening-Verfahren zur Untersuchung eines möglichen kanzerogenen Potentials von Carbon Nanotubes : Teilvorhaben ; Schlussbericht; Leibniz-Institut für Festkörper- und Werkstoffforschung Dresden; FKZ 03X0109B, TIB Hannover.
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