Skip to main content

Advertisement

SpringerLink
Log in

Hazard identification of inhaled nanomaterials: making use of short-term inhalation studies

  • Inorganic compounds
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

A major health concern for nanomaterials is their potential toxic effect after inhalation of dusts. Correspondingly, the core element of tier 1 in the currently proposed integrated testing strategy (ITS) is a short-term rat inhalation study (STIS) for this route of exposure. STIS comprises a comprehensive scheme of biological effects and marker determination in order to generate appropriate information on early key elements of pathogenesis, such as inflammatory reactions in the lung and indications of effects in other organs. Within the STIS information on the persistence, progression and/or regression of effects is obtained. The STIS also addresses organ burden in the lung and potential translocation to other tissues. Up to now, STIS was performed in research projects and routine testing of nanomaterials. Meanwhile, rat STIS results for more than 20 nanomaterials are available including the representative nanomaterials listed by the Organization for Economic Cooperation and Development (OECD) working party on manufactured nanomaterials (WPMN), which has endorsed a list of representative manufactured nanomaterials (MN) as well as a set of relevant endpoints to be addressed. Here, results of STIS carried out with different nanomaterials are discussed as case studies. The ranking of different nanomaterials potential to induce adverse effects and the ranking of the respective NOAEC are the same among the STIS and the corresponding subchronic and chronic studies. In another case study, a translocation of a coated silica nanomaterial was judged critical for its safety assessment. Thus, STIS enables application of the proposed ITS, as long as reliable and relevant in vitro methods for the tier 1 testing are still missing. Compared to traditional subacute and subchronic inhalation testing (according to OECD test guidelines 412 and 413), STIS uses less animals and resources and offers additional information on organ burden and progression or regression of potential effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Arts JH, Muijser H, Duistermaat E, Junker K, Kuper C (2007) Five-day inhalation toxicity study of three types of synthetic amorphous silicas in Wistar rats and post-exposure evaluations for up to 3 months. Food Chem Toxicol 45(10):1856–1867

    Article  PubMed  CAS  Google Scholar 

  • Bermudez E, Mangum JB, Asgharian B, Wong BA, Reverdy EE, Janszen DB, Hext PM, Warhead DB, Everitt JI (2002) Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. Toxicol Sci 70(1):86–97

    Article  PubMed  CAS  Google Scholar 

  • Bermudez E, Mangum JB, Wong BA, Asgharian B, Hex PM, Warhead DB, Everett JI (2004) Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci 77(2):347–357

    Article  PubMed  CAS  Google Scholar 

  • Cullen RT, Tran CL, Buchanan D, Davis JMG, Searl A, Jones AD, Donaldson K (2000) Inhalation of poorly soluble particles. Differences in inflammatory response and clearance during exposure. Inhal Toxicol 12:1089–1111

    Article  PubMed  CAS  Google Scholar 

  • Donaldson K, Aitken R, Tran L, Stone V, Duffin R, Forrest G, Alexander A (2006) Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety. Toxicol Sci 92(1):5–22

    Article  PubMed  CAS  Google Scholar 

  • Driscoll KE, Carter JM, Howard BW, Hassenbein DG, Pepelko W, Baggs RB, Oberdörster G (1996) Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black. Toxicol Appl Pharmacol 136(2):372–380

    Article  PubMed  CAS  Google Scholar 

  • Geiser M, Rothen-Rutishauser B, Kapp N, Schurch S, Kreyling W, Schulz H, Semmler M, Im HV, Heyder J, Gehr P (2005) Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ Health Perspect 113(11):1555–1560

    Google Scholar 

  • Geiser M, Casaulta M, Kupferschmid B, Schulz H, Semmler-Behnke M, Kreyling W (2008) The role of macrophages in the clearance of inhaled ultrafine titanium dioxide particles. Am J Respir Cell Mol Biol 38(3):371–376

    Google Scholar 

  • Elder A, Gelein R, Finkelstein JN, Driscoll KE, Harkema J, Oberdörster G (2005) Effects of subchronically inhaled carbon black in three species. Retention kinetics, lung inflammation and histopathology. Toxicol Sci 88(2):614–629

    Article  PubMed  CAS  Google Scholar 

  • Ferin J, Oberdörster G, Penney DP (1992) Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 6(5):535–542

    PubMed  CAS  Google Scholar 

  • Hadjimichael OC, Brubaker RE (1981) Evaluation of an occupational respiratory exposure to a zirconium-containing dust. J Occup Med 23(8):543–547

    PubMed  CAS  Google Scholar 

  • Heinrich U, Fuhst R, Rittinghausen S, Creutzenberg O, Bellmann B, Koch W, Levsen K (1995) Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel exhaust, carbon black, and titanium dioxide. Inhal Toxicol 7:533–556

    Article  CAS  Google Scholar 

  • Johnson NF, Smith DM, Sebring RF, Holland LM (1987) Silica-induced alveolar cell tumors in rats. Am J Ind Med 11(1):93–107

    Article  PubMed  CAS  Google Scholar 

  • Johnston CJ, Driscoll KE, Finkelstein JN, Baggs RF, O’Reilly MA, Carter J, Gelein R, Oberdörster G (2000) Pulmonary chemokine and mutagenic responses in rats after subchronic inhalation of amorphous and crystalline silica. Toxicol Sci 56(2):405–413

    Article  PubMed  CAS  Google Scholar 

  • Kreyling W, Geiser M (2010) Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol 7:2

    Article  PubMed  Google Scholar 

  • Landsiedel R, Ma-Hock L, Kroll A, Hahn D, Schnekenburger J, Wiench K, Wohlleben W (2010) Testing metal-oxide nanomaterials for human safety. Adv Mater 22:2601–2627

    Article  PubMed  CAS  Google Scholar 

  • Lee KP, Trochimowicz HJ, Reinhardt CF (1985) Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years. Toxicol Appl Pharmacol 79(2):179–192

    Article  PubMed  CAS  Google Scholar 

  • Ma-Hock L, Gamer A, Landsiedel R, Leibold E, Frechen T, Sens B, Huber G, van Ravenzwaay B (2007) Generation and characterization of test atmospheres with nanomaterials. Inhal Toxicol 19:833–848

    Article  PubMed  CAS  Google Scholar 

  • Ma-Hock L, Burkhardt S, Strauss V, Gamer A, Wiench K, van Ravenzwaay B, Landsiedel R (2009a) Development of a short-term inhalation test in rats using nano-titanium dioxide as a model substance. Inhal Toxicol 21:102–118

    Article  PubMed  CAS  Google Scholar 

  • Ma-Hock L, Treumann S, Strauss V, Brill S, Luizi F, Mertler M, Wiench K, Gamer AO, van Ravenzwaay B, Landsiedel R (2009b) Inhalation toxicity of multi-wall carbon nanotubes in rats exposed for 3 months. Toxicol Sci 112:468–481

    Article  PubMed  CAS  Google Scholar 

  • Mangum J, Bermudez E, Sar M, Everitt J (2004) Osteopontin expression in particle-induced lung disease. Exp Lung Res 30(7):585–598

    Article  PubMed  CAS  Google Scholar 

  • Marcus RL, Turner S, Cherry NM (1996) A study of lung function and chest radiographs in men exposed to zirconium compounds. Occup Med (Lond) 46(2):109–113

    Google Scholar 

  • Merget R, Bauer T, Küpper HU, Philippou S, Bauer HD, Breitstadt R, Bruening T (2002) Health hazards due to the inhalation of amorphous silica. Arch Toxicol 75:625–634

    Article  PubMed  CAS  Google Scholar 

  • Muhle H, Kittel B, Ernst H, Mohr U, Mermelstein R (1995) Neoplastic lung lesions in rat after chronic exposure to crystalline silica. Scand J Work Environ Health 21(Suppl 2):27–29

    PubMed  CAS  Google Scholar 

  • Oberdörster G, Ferin J, Gelein R, Soderholm SC, Finkelstein J (1992) Role of the alveolar macrophage in lung injury: studies with ultrafine particles. Environ Health Perspect 97:193–199

    PubMed  Google Scholar 

  • Oberdörster G, Ferin J, Lehnert BE (1994) Correlation between particle size, in vivo particle persistence, and lung injury. Environ Health Perspect 102(Suppl 5):173–179

    Article  PubMed  Google Scholar 

  • Pauluhn J (2010) Subchronic 13-week inhalation exposure of rats to multiwalled carbon nanotubes: toxic effects are determined by density of agglomerate structures, not fibrillar structures. Toxicol Sci 113:226–242

    Article  PubMed  CAS  Google Scholar 

  • Plitzko S (2009) Workplace exposure to engineered nanoparticles. Inhal Toxicol 21(Suppl. 1):25–29

    Article  PubMed  CAS  Google Scholar 

  • Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, Macnee W, Donaldson K (2008) Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol 3(7):423–428

    Article  PubMed  CAS  Google Scholar 

  • Reiser KM, Last JA (1979) Silicosis and fibrogenesis: fact and artifact. Toxicology 13(1):51–72

    PubMed  CAS  Google Scholar 

  • Reuzel PG, Bruijntjes JP, Feron VJ, Woutersen RA (1991) Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats. Food Chem Toxicol 29:341–354

    Article  PubMed  CAS  Google Scholar 

  • Roller M (2008) Untersuchungen zur krebserzeugenden Wirkung von Nanopartikeln und anderen Stäuben 1. Auflage. Bundesanstalt für Arbeitsschutz und Arbeitsmedizin, Dortmund, ISBN: 978-3-88261-069-7

  • Sauer UG (2010) Conference report, nanotoxicology session at the 16th congress on alternatives to animal testing, Linz, Austria. ALTEX 27:318–322

    Google Scholar 

  • Schneider et al (2007) Evaluation and control of occupational health risks from nanoparticles. TemaNord:581. http://www.norden.org/en/publications/publications/2007-581. ISBN 978-92-893-1563-0

  • Seaton A, Ruckley VA, Addison J, Brown WR (1986) Silicosis in barium miners. Thorax 41(8):591–595

    Article  PubMed  CAS  Google Scholar 

  • Tran CL, Buchanan D, Cullen RT, Searl A, Jones AD, Donaldson K (2000) Inhalation of poorly soluble particles. II. Influence of particle surface area on inflammation and clearance. Inhal Toxicol 12:1113–1126

    Article  PubMed  CAS  Google Scholar 

  • van Ravenzwaay B, Landsiedel R, Fabian E, Burkhardt S, Strauss V, Ma-Hock L (2009) Comparing fate and effects of three particles of different surface properties: Nano-TiO2, pigmentary TiO2 and quartz. Toxicol Lett 186(3):152–159

    Article  PubMed  Google Scholar 

  • Voloudaki A, Ergazakis N, Gourtsoyiannis N (2003) Late changes in barium sulfate aspiration: HRCT features. Eur Radiol 13(9):2226–2229

    Article  PubMed  CAS  Google Scholar 

  • Warheit DB, Webb TR, Reed KL, Frerichs S, Sayes CM (2007) Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential responses related to surface properties. Toxicology 230(1):90–104

    Google Scholar 

  • Warheit DB, Reed KL, Sayes CM (2009) A role for nanoparticle surface reactivity in facilitating pulmonary toxicity and development of a base set of hazard assays as a component of nanoparticle risk management. Inhal Toxicol 21(Suppl 1):61–67

    Google Scholar 

Download references

Acknowledgments

Parts of the work presented here were performed within the German nanoCare (BMBF) project and the European NanoSafe2 (FP6) project. This paper was initiated by the OECD Working Party on Manufactured Nanomaterials SG7: The Role of Alternative Methods in Nano Toxicology.

Conflict of interest

Some of the authors are employees of BASF SE, a company producing and marketing nanomaterials. BASF has sponsored parts of this work.

Author information

Authors and Affiliations

  1. BASF SE, Ludwigshafen am Rhein, Germany

    Karin Wiench, Lan Ma-Hock, Ben van Ravenzwaay & Robert Landsiedel

  2. European Commission, Joint Research Centre (JRC), Institute for Health and Consumer Protection (IHCP), Ispra, Italy

    Christoph L. Klein

  3. IBE R&D gGmbH, Muenster, Germany

    Martin Wiemann

Authors
  1. Christoph L. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karin Wiench
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Wiemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lan Ma-Hock
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ben van Ravenzwaay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert Landsiedel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Landsiedel.

Additional information

This article is published as a part of the Special Issue “Nanotoxicology II” on the ECETOC Satellite workshop, Dresden 2010 (Innovation through Nanotechnology and Nanomaterials + Current Aspects of Safety Assessment and Regulation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klein, C.L., Wiench, K., Wiemann, M. et al. Hazard identification of inhaled nanomaterials: making use of short-term inhalation studies. Arch Toxicol 86, 1137–1151 (2012). https://doi.org/10.1007/s00204-012-0834-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-012-0834-2

Keywords

Search

Navigation