The Short-Term Inhalation Study (STIS) as a Range Finder and Screening Tool in a Tiered Grouping Strategy

Part of the Current Topics in Environmental Health and Preventive Medicine book series (CTEHPM)


The rat short-term inhalation study (STIS; 5 days exposure, 6 h/day; approx. 3-week postexposure observation) allows assessing test material-induced early respiratory tract effects, the progression or reversibility of effects, pulmonary particle deposition, and potential test material translocation to extra-pulmonary tissues and the evolvement of systemic effects. This chapter provides details on the STIS study design focusing on aerosol characterization, performance of bronchoalveolar lavage in half a lung and preparation of the other half for histopathology. Five case studies (CSs) exemplify how the rat STIS can be used for initial safety assessments, e.g., within the previously published Decision-making framework for the grouping and testing of nanomaterials. This tiered framework allows grouping nanomaterials as soluble (CS 1: CuO, ZnO); high aspect ratio nanomaterials (CS 2: multiwall carbon nanotubes); passive (CS 3: BaSO4, ZrO2, graphite nanoplatelets); or active (CS 4: CeO2, TiO2). CS 5 addresses different amorphous SiO2 that are either soluble, passive, or active. In conclusion, the rat STIS and 28-day/90-day inhalation toxicity studies reveal comparable effects, and the rankings of no-observed adverse effect concentrations are very similar. Compared with 28-day and 90-day inhalation toxicity studies (OECD Test Guidelines 412 and 413), the rat STIS requires fewer animals and its duration is considerably shorter. Thereby, this test serves the 3Rs principle to replace, reduce, and refine animal testing. If 28-day and 90-day inhalation toxicity studies are mandatory for regulatory purposes, the rat STIS is a suitable range-finding study to select appropriate concentrations for the longer-term studies.


Engineered nanoparticles Short-term inhalation study (STIS) Pulmonary inflammation Pulmonary particle deposition Systemic uptake Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) Initial safety assessment 3Rs principle (replacement, reduction, refinement of animal testing) 



Dr. med. vet. Ursula G. Sauer (Scientific Consultancy—Animal Welfare, Germany) was hired as scientific writer of this chapter.


  1. 1.
    Arts JH, Muijser H, Duistermaat E, Junker K, Kuper C. 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. 2007;45(10):1856–67.PubMedCrossRefGoogle Scholar
  2. 2.
    Landsiedel R, Ma-Hock L, Hofmann T, Wiemann M, Strauss V, Treumann S, Wohlleben W, Gröters S, Wiench K, van Ravenzwaay B. Application of short-term inhalation studies to assess the inhalation toxicity of nanomaterials. Part Fibre Toxicol. 2014;11:16.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Ma-Hock L, Burkhardt S, Strauss V, Gamer AO, Wiench K, van Ravenzwaay B, Landsiedel R. Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance. Inhal Toxicol. 2009;21(2):102–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Ma-Hock L, Hofmann T, Landsiedel R, van Ravenzwaay B. A short-term inhalation study protocol: designed for testing of toxicity and fate of nanomaterials. Methods Mol Biol. 2014;1199:207–12.PubMedCrossRefGoogle Scholar
  5. 5.
    OECD. Organisation for Economic Co-operation and Development. Guideline for testing of chemicals no. 412. Subacute inhalation toxicity: 28-day study. Paris: OECD; 2017.Google Scholar
  6. 6.
    OECD. Organisation for Economic Co-operation and Development. Guideline for testing of chemicals no. 413. Subchronic inhalation toxicity: 90-day study. Paris: OECD; 2017.Google Scholar
  7. 7.
    Russell WMS, Burch RL. The principles of humane experimental technique. London: Methuen; 1959. Reprinted by UFAW, 1992, England, 238 pp.Google Scholar
  8. 8.
    Braakhuis HM, Cassee FR, Fokkens PH, de la Fonteyne LJ, Oomen AG, Krystek P, de Jong WH, van Loveren H, Park MV. Identification of the appropriate dose metric for pulmonary inflammation of silver nanoparticles in an inhalation toxicity study. Nanotoxicology. 2016;10(1):63–73.PubMedGoogle Scholar
  9. 9.
    Dekkers S, Ma-Hock L, Lynch I, Russ M, Miller MR, Schins RPF, Keller J, Römer I, Küttler K, Strauss V, de Jong WH, Landsiedel R, Cassee FR. Differences in the toxicity of nanomaterials after inhalation can be explained by lung deposition, animal species and nanoforms. The case of cerium dioxide. Inhal Toxicol. 2018;30(7-8):273–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Wohlleben W, Meier MW, Vogel S, Landsiedel R, Cox G, Hirth S, Tomović Ž. Elastic CNT-polyurethane nanocomposite: synthesis, performance and assessment of fragments released during use. Nanoscale. 2013;5(1):369–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Wohlleben W, Kuhlbusch T, Lehr C-M, Schnekenburger J. Safety of nanomaterials along their lifecycle: release, exposure and human hazards. Hoboken, NJ: Taylor & Francis; 2014. ISBN 978-1-46-656786-3, 472 pp.CrossRefGoogle Scholar
  12. 12.
    Wohlleben W, Driessen MD, Raesch S, Schaefer UF, Schulze C, Von Vacano B, Vennemann A, Wiemann M, Ruge CA, Platsch H, Mues S, Ossig R, Tomm JM, Schnekenburger J, Kuhlbusch TAJ, Luch A, Lehr C-M, Haase H. Influence of agglomeration and specific lung lining lipid/protein interaction on short-term inhalation toxicity. Nanotoxicology. 2016;10(7):970–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Wohlleben W, Mielke J, Bianchin A, Ghanem A, Freiberger H, Rauscher H, Gemeinert M, Hodoroaba VD. Reliable nanomaterial classification of powders using the volume-specific surface area method. J Nanopart Res. 2017;19(2):61.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Wohlleben W, Waindok H, Daumann B, Werle K, Drum M, Egenolf H. Composition, respirable fraction and dissolution rate of 24 stone wool MMVF with their binder. Part Fibre Toxicol. 2017;14:29.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Gandon A, Werle K, Neubauer N, Wohlleben W. Surface reactivity measurements as required for grouping and read-across: an advanced FRAS protocol. J Phys Conf Ser. 2017;838:012033.CrossRefGoogle Scholar
  16. 16.
    Ma-Hock L, Gamer AO, Landsiedel R, Leibold E, Frechen T, Sens B, Linsenbuehler M, van Ravenzwaay B. Generation and characterization of test atmospheres with nanomaterials. Inhal Toxicol. 2007;19:833–48.PubMedCrossRefGoogle Scholar
  17. 17.
    Mangum J, Bermudez E, Sar M, Everitt J. Osteopontin expression in particle-induced lung disease. Exp Lung Res. 2004;30(7):585–98.PubMedCrossRefGoogle Scholar
  18. 18.
    Ma-Hock L, Strauss V, Treumann S, Küttler K, Wohlleben W, Hofmann T, Gröters S, Wiench K, van Ravenzwaay B, Landsiedel R. Comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black. Part Fibre Toxicol. 2013;10:23.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Henderson RF, Driscoll KE, Harkema JR, Lindenschmidt RC, Chang I-Y, Maples KR, Barr EB. A comparison of the inflammatory response of the lung to inhaled versus instilled particles in F-344 rats. Fundam Appl Toxicol. 1995;24:183–97.PubMedCrossRefGoogle Scholar
  20. 20.
    Vennemann A, Alessandrini F, Wiemann M. Differential effects of surface functionalized zirconium oxide nanoparticles on alveolar makrophages, rat lung and a mouse model. Nanomaterials. 2017;7:280.PubMedCentralCrossRefGoogle Scholar
  21. 21.
    Wiemann M, Vennemann A, Blaske F, Sperling M, Karst U. Silver nanoparticle in the lung: toxic effects and focal accumulation of silver in remote organs. Nanomaterials. 2017;7:441.PubMedCentralCrossRefGoogle Scholar
  22. 22.
    Strauss V, Ma-Hock L, Rey Moreno MC, Groeters S, Landsiedel R, Wiemann M, van Ravenzwaay B. Validation of an appropriate lavage procedure of the left pulmonary lobe and accompanying histopathology in the frame of the draft OECD TG 413. In: The toxicologist: supplement to toxicological sciences, 156 (1), Society of Toxicology, 2017. Abstract no. 2385.Google Scholar
  23. 23.
    Arts JH, Hadi M, Irfan MA, Keene AM, Kreiling R, Lyon D, Maier M, Michel K, Petry T, Sauer UG, Warheit D, Wiench K, Wohlleben W, Landsiedel R. A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). Regul Toxicol Pharmacol. 2015;71(2 Suppl):S1–27.PubMedCrossRefGoogle Scholar
  24. 24.
    Arts JH, Irfan MA, Keene AM, Kreiling R, Lyon D, Maier M, Michel K, Neubauer N, Petry T, Sauer UG, Warheit D, Wiench K, Wohlleben W, Landsiedel R. Case studies putting the decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) into practice. Regul Toxicol Pharmacol. 2016;76:234–61.PubMedCrossRefGoogle Scholar
  25. 25.
    OECD. Organisation for Economic Co-operation and Development list of manufactured nanomaterials and list of endpoints for phase one of the sponsorship programme for the testing of manufactured nanomaterials: revision. Series on the safety of manufactured nanomaterials. ENV/JM/MONO(2010)46. Paris: OECD; 2010.Google Scholar
  26. 26.
    Bellmann B. DRF, 5-day nose-only inhalation toxicity study of Z-COTE® HP1 in Wistar WU rats (DRF study) 02 N 09 515 (Draft report). Hannover: Fraunhofer ITEM; 2009. Study owner: Cefic, Bruxelles.Google Scholar
  27. 27.
    Gosens I, Cassee FR, Zanella M, Manodori L, Brunelli A, Costa AL, Bokkers BG, de Jong WH, Brown D, Hristozov D, Stone V. Organ burden and pulmonary toxicity of nano-sized copper (II) oxide particles after short-term inhalation exposure. Nanotoxicology. 2016;10(8):1084–95.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Braakhuis HM, Gosens I, Krystek P, Boere JA, Cassee FR, Fokkens PH, Post JA, van Loveren H, Park MV. Particle size dependent deposition and pulmonary inflammation after short-term inhalation of silver nanoparticles. Part Fibre Toxicol. 2014;11:49.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Creutzenberg O. 14-Day nose-only inhalation toxicity study of Z-COTE HP1 in Wistar WU rats. 02 G 09 005. Hannover: Fraunhofer ITEM; 2013. Study owner: Cefic, Bruxelles.Google Scholar
  30. 30.
    Seiffert J, Buckley A, Leo B, Martin NG, Zhu J, Dai R, Hussain F, Guo C, Warren J, Hodgson A, Gong J, Ryan MP, Zhang JJ, Porter A, Tetley TD, Gow A, Smith R, Chung KF. Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague-Dawley rats. Respir Res. 2016;17(1):85.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Morimoto Y, Izumi H, Yoshiura Y, Tomonaga T, Oyabu T, Myojo T, Kawai K, Yatera K, Shimada M, Kubo M, Yamamoto K, Kitajima S, Kuroda E, Kawaguchi K, Sasaki T. Evaluation of pulmonary toxicity of zinc oxide nanoparticles following inhalation and intratracheal instillation. Int J Mol Sci. 2016;17(8):1241.PubMedCentralCrossRefGoogle Scholar
  32. 32.
    Creutzenberg O. 3-Month nose-only inhalation toxicity study of Z-COTE HP1 in Wister WU rats. 02 G 10 024. Hannover: Fraunhofer ITEM; 2013. Study owner: Cefic, Bruxelles.Google Scholar
  33. 33.
    Ahamed M, Akhtar MJ, Alhadlaq HA, Alrokayan SA. Assessment of the lung toxicity of copper oxide nanoparticles: current status. Nanomedicine (Lond). 2015;10(15):2365–77.CrossRefGoogle Scholar
  34. 34.
    WHO. WHO air quality guidelines for Europe. 2nd ed. Geneva: WHO; 2002. Available at
  35. 35.
    Donaldson K, Aitken R, Tran L, Stone V, Duffin R, Forrest G, Alexander A. Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety. Toxicol Sci. 2006;92:5–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Donaldson K, Murphy FA, Duffin R, Poland CA. Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part Fibre Toxicol. 2010;7:5.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Donaldson K, Murphy F, Schinwald A, Duffin R, Poland CA. Identifying the pulmonary hazard of high aspect ratio nanoparticles to enable their safety-by-design. Nanomedicine. 2011;6:143–56.PubMedCrossRefGoogle Scholar
  38. 38.
    Duke KS, Bonner JC. Mechanisms of carbon nanotube-induced pulmonary fibrosis: a physicochemical characteristic perspective. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2018;10:e1498. Scholar
  39. 39.
    Poulsen SS, Saber AT, Williams A, Andersen O, Købler C, Atluri R, Pozzebon ME, Mucelli SP, Simion M, Rickerby D, Mortensen A, Jackson P, Kyjovska ZO, Mølhave K, Jacobsen NR, Jensen KA, Yauk CL, Wallin H, Halappanavar S, Vogel U. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol. 2015;284:16–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, Macnee W, Donaldson K. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. 2008;3(7):423–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Fukushima S, Kasai T, Umeda Y, Ohnishi M, Sasaki T, Matsumoto M. Carcinogenicity of multi-walled carbon nanotubes: challenging issue on hazard assessment. J Occup Health. 2018;60(1):10–30.CrossRefGoogle Scholar
  42. 42.
    Kobayashi N, Izumi H, Morimoto Y. Review of toxicity studies of carbon nanotubes. J Occup Health. 2017;59(5):394–407.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Chernova T, Murphy FA, Galavotti S, Sun XM, Powley IR, Grosso S, Schinwald A, Zacarias-Cabeza J, Dudek KM, Dinsdale D, Le Quesne J, Bennett J, Nakas A, Greaves P, Poland CA, Donaldson K, Bushell M, Willis AE, MacFarlane M. Long-fiber carbon nanotubes replicate asbestos-induced mesothelioma with disruption of the tumor suppressor gene Cdkn2a (Ink4a/Arf). Curr Biol. 2017;27(21):3302–14. e6.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Ma-Hock L, Treumann S, Strauss V, Brill S, Luizi F, Mertler M, Wiench K, Gamer AO, van Ravenzwaay B, Landsiedel R. Inhalation toxicity of multi-wall carbon nanotubes in rats exposed for 3 months. Toxicol Sci. 2009;112:468–81.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Pothmann D, Simar S, Schuler D, Dony E, Gaering S, Le Net JL, Okazaki Y, Chabagno JM, Bessibes C, Beausoleil J, Nesslany F, Régnier JF. Lung inflammation and lack of genotoxicity in the comet and micronucleus assays of industrial multiwalled carbon nanotubes Graphistrength(©) C100 after a 90-day nose-only inhalation exposure of rats. Part Fibre Toxicol. 2015;12:21.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Régnier J-F, Pothmann-Krings D, Simar S, Dony E, Le Net J-L, Beausoleil J. Graphistrength© C100 multiwalled carbon nanotubes (MWCNT): thirteen-week inhalation toxicity study in rats with 13- and 52-week recovery periods combined with comet and micronucleus assays. J Phys Conf Series. 2017;838:012030.CrossRefGoogle Scholar
  47. 47.
    Pauluhn J. 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. 2010;113:226–42.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kasai T, Umeda Y, Ohnishi M, Mine T, Kondo H, Takeuchi T, Matsumoto M, Fukushima S. Lung carcinogenicity of inhaled multi-walled carbon nanotube in rats. Part Fibre Toxicol. 2016;13(1):53.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Sargent LM, Porter DW, Staska LM, Hubbs AF, Lowry DT, Battelli L, Siegrist KJ, Kashon ML, Mercer RR, Bauer AK, Chen BT, Salisbury JL, Frazer D, McKinney W, Andrew M, Tsuruoka S, Endo M, Fluharty KL, Castranova V, Reynolds SH. Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes. Part Fibre Toxicol. 2014;11:3.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kroll A, Dierker C, Rommel C, Hahn D, Wohlleben W, Schulze-Isfort C, Göbbert C, Voetz M, Hardinghaus F, Schnekenburger J. Cytotoxicity screening of 23 engineered nanomaterials using a test matrix of ten cell lines and three different assays. Part Fibre Toxicol. 2011;8:9.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Hofmann T, Ma-Hock L, Strauss V, Treumann S, Rey Moreno M, Neubauer N, Wohlleben W, Gröters S, Wiench K, Veith U, Teubner W, van Ravenzwaay B, Landsiedel R. Comparative short-term inhalation toxicity of five organic diketopyrrolopyrrole pigments and two inorganic iron-oxide-based pigments. Inhal Toxicol. 2016;7:1–17.Google Scholar
  52. 52.
    Bräu M, Ma-Hock L, Hesse C, Nicoleau L, Strauss V, Treumann S, Wiench K, Landsiedel R, Wohlleben W. Nanostructured calcium silicate hydrate seeds accelerate concrete hardening: a combined assessment of benefits and risks. Arch Toxicol. 2012;86(7):1077–87.PubMedCrossRefGoogle Scholar
  53. 53.
    Ma-Hock L, Landsiedel R, Wiench K, Geiger D, Strauss V, Gröters S, van Ravenzwaay B, Gerst M, Wohlleben W, Scherer G. Short-term rat inhalation study with aerosols of acrylic ester-based polymer dispersions containing a fraction of nanoparticles. Int J Toxicol. 2012;31:46–57.PubMedCrossRefGoogle Scholar
  54. 54.
    Kim YH, Jo MS, Kim JK, Shin JH, Baek JE, Park HS, An HJ, Lee JS, Kim BW, Kim HP, Ahn KH, Jeon K, Oh SM, Lee JH, Workman T, Faustman EM, Yu IJ. Short-term inhalation study of graphene oxide nanoplates. Nanotoxicology. 2018;1:1–15.Google Scholar
  55. 55.
    Konduru N, Keller J, Ma-Hock L, Gröters S, Landsiedel R, Donaghey TC, Brain JD, Wohlleben W, Molina RM. Biokinetics and effects of barium sulfate nanoparticles. Part Fibre Toxicol. 2014;11:55.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Schwotzer D, Ernst H, Schaudien D, Kock H, Pohlmann G, Dasenbrock C, Creutzenberg O. Effects from a 90-day inhalation toxicity study with cerium oxide and barium sulfate nanoparticles in rats. Part Fibre Toxicol. 2017;14:23.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Schwotzer D, Niehof M, Schaudien D, Kock H, Hansen T, Dasenbrock C, Creutzenberg O. Cerium oxide and barium sulfate nanoparticle inhalation affects gene expression in alveolar epithelial cells type II. J Nanobiotechnol. 2018;16(1):16.CrossRefGoogle Scholar
  58. 58.
    Cullen RT, Tran CL, Buchanan D, Davis JMG, Searl A, Jones AD, Donaldson K. Inhalation of poorly soluble particles. Differences in inflammatory response and clearance during exposure. Inhal Toxicol. 2000;12:1089–111.PubMedCrossRefGoogle Scholar
  59. 59.
    Tran CL, Buchanan D, Cullen RT, Searl A, Jones AD, Donaldson K. Inhalation of poorly soluble particles. II. Influence of particle surface area on inflammation and clearance. Inhal Toxicol. 2000;12:1113–26.PubMedCrossRefGoogle Scholar
  60. 60.
    Kim JK, Shin JH, Lee JS, Hwang JH, Lee JH, Baek JE, Kim TG, Kim BW, Kim JS, Lee GH, Ahn K, Han SG, Bello D, Yu IJ. 28-Day inhalation toxicity of graphene nanoplatelets in Sprague-Dawley rats. Nanotoxicology. 2016;10(7):891–901.PubMedCrossRefGoogle Scholar
  61. 61.
    Reuzel PG, Bruijntjes JP, Feron VJ, Woutersen RA. Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats. Food Chem Toxicol. 1991;29:341–54.PubMedCrossRefGoogle Scholar
  62. 62.
    Johnston CJ, Driscoll KE, Finkelstein JN, Baggs RF, O’Reilly MA, Carter J, Gelein R, Oberdörster G. Pulmonary chemokine and mutagenic responses in rats after subchronic inhalation of amorphous and crystalline silica. Toxicol Sci. 2000;56(2):405–13.PubMedCrossRefGoogle Scholar
  63. 63.
    Bermudez E, Mangum JB, Wong BA, Asgharian B, Hex PM, Warhead DB, Everett JI. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci. 2004;77(2):347–57.PubMedCrossRefGoogle Scholar
  64. 64.
    Heinrich U, Fuhst R, Rittinghausen S, Creutzenberg O, Bellmann B, Koch W, Levsen K. Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel exhaust, carbon black, and titanium dioxide. Inhal Toxicol. 1995;7:533–56.CrossRefGoogle Scholar
  65. 65.
    Disdier C, Chalansonnet M, Gagnaire F, Gaté L, Cosnier F, Devoy J, Saba W, Lund AK, Brun E, Mabondzo A. Brain inflammation, blood brain barrier dysfunction and neuronal synaptophysin decrease after inhalation exposure to titanium dioxide nano-aerosol in aging rats. Sci Rep. 2017;7(1):12196.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Oyabu T, Myojo T, Lee BW, Okada T, Izumi H, Yoshiura Y, Tomonaga T, Li YS, Kawai K, Shimada M, Kubo M, Yamamoto K, Kawaguchi K, Sasaki T, Morimoto Y. Biopersistence of NiO and TiO2 nanoparticles following intratracheal instillation and inhalation. Int J Mol Sci. 2017;18(12):2757.PubMedCentralCrossRefGoogle Scholar
  67. 67.
    Keller J, Wohlleben W, Ma-Hock L, Strauss V, Gröters S, Küttler K, Wiench K, Herden C, Oberdörster G, van Ravenzwaay B, Landsiedel R. Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-ceria. Arch Toxicol. 2014;88(11):2033–59.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Gosens I, Mathijssen LE, Bokkers BG, Muijser H, Cassee FR. Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats. Nanotoxicology. 2014;8(6):643–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Morimoto Y, Izumi H, Yoshiura Y, Tomonaga T, Oyabu T, Myojo T, Kawai K, Yatera K, Shimada M, Kubo M, Yamamoto K, Kitajima S, Kuroda E, Kawaguchi K, Sasaki T. Pulmonary toxicity of well-dispersed cerium oxide nanoparticles following intratracheal instillation and inhalation. J Nanopart Res. 2015;17(11):442.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Shin SH, Lim CH, Kim YS, Lee YH, Kim SH, Kim JC. Twenty-eight-day repeated inhalation toxicity study of nano-sized lanthanum oxide in male sprague-dawley rats. Environ Toxicol. 2017;32(4):1226–40.PubMedCrossRefGoogle Scholar
  71. 71.
    Kim YS, Lim CH, Shin SH, Kim JC. Twenty-eight-day repeated inhalation toxicity study of nano-sized neodymium oxide in male Sprague-Dawley rats. Toxicol Res. 2017;33(3):239–53.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Elder A, Gelein R, Finkelstein JN, Driscoll KE, Harkema J, Oberdörster G. Effects of subchronically inhaled carbon black in three species. Retention kinetics, lung inflammation and histopathology. Toxicol Sci. 2005;88(2):614–29.PubMedCrossRefGoogle Scholar
  73. 73.
    Lee KP, Trochimowicz HJ, Reinhardt CF. Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years. Toxicol Appl Pharmacol. 1985;79:179–92.PubMedCrossRefGoogle Scholar
  74. 74.
    Nikula KJ, Snipes MB, Barr EB, Griffith WC, Henderson RF, Mauderly JL. Comparative pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon black in F344 rats. Fundam Appl Toxicol. 1995;25:80–94.PubMedCrossRefGoogle Scholar
  75. 75.
    Groeters S, Ernst H, Ma-Hock L, Strauss V, Landsiedel R, Wiench K, van Ravenzwaay B. Long-term inhalation study with nano barium sulfate: unexpected morphological findings and lung-burden after 12 months of exposure. In: The Toxicologist: Supplement to Toxicological Sciences, 156(1), Society of Toxicology, 2017. Abstract no. 1328.Google Scholar
  76. 76.
    Hadjimichael OC, Brubaker RE. Evaluation of an occupational respiratory exposure to a zirconium-containing dust. J Occup Med. 1981;23(8):543–7.PubMedGoogle Scholar
  77. 77.
    Marcus RL, Turner S, Cherry NM. A study of lung function and chest radiographs in men exposed to zirconium compounds. Occup Med (Lond). 1996;46(2):109–13.CrossRefGoogle Scholar
  78. 78.
    Klein CL, Wiench K, Wiemann M, Ma-Hock L, van Ravenzwaay B, Landsiedel R. Hazard identification of inhaled nanomaterials: making use of short-term inhalation studies. Arch Toxicol. 2012;86(7):1137–51.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Wiemann M, Vennemann A, Sauer UG, Wiench K, Ma-Hock L, Landsiedel R. An alveolar macrophage assay for predicting the short-term inhalation toxicity of nanomaterials. J Nanobiotechnol. 2016;14:16.CrossRefGoogle Scholar
  80. 80.
    Van Ravenzwaay B, Landsiedel R, Fabian E, Burkhardt S, Strauss V, Ma-Hock L. Comparing fate and effects of three particles of different surface properties: nano-TiO2, pigmentary TiO2 and quartz. Toxicol Lett. 2009;186:152–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Ma-Hock L, Brill S, Wohlleben W, Farias PM, Chaves CR, Tenório DP, Fontes A, Santos BS, Landsiedel R, Strauss V, Treumann S, Ravenzwaay B. Short term inhalation toxicity of a liquid aerosol of CdS/Cd(OH)2 core shell quantum dots in male Wistar rats. Toxicol Lett. 2012;208(2):115–24.PubMedCrossRefGoogle Scholar
  82. 82.
    Ma-Hock L, Farias PM, Hofmann T, Andrade AC, Silva JN, Arnaud TM, Wohlleben W, Strauss V, Treumann S, Chaves CR, Gröters S, Landsiedel R, van Ravenzwaay B. Short term inhalation toxicity of a liquid aerosol of glutaraldehyde-coated CdS/Cd(OH)2 core shell quantum dots in rats. Toxicol Lett. 2014;225(1):20–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Kwon S, Yang YS, Yang HS, Lee J, Kang MS, Lee B, Lee K, Song CW. Nasal and pulmonary toxicity of titanium dioxide nanoparticles in rats. Toxicol Res. 2012;28(4):217–24.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Greim H, Ziegler-Skylakakis K. Risk assessment for biopersistent granular particles. Inhal Toxicol. 2007;19(Suppl 1):199–204.PubMedCrossRefGoogle Scholar
  85. 85.
    Creutzenberg O, Pohlmann G, Hansen T, Schuchardt S, Ernst H, Tillmann T, Schaudien D. CEFIC-LRI N1 project: inhalation toxicity of a synthetic amorphous silica (SAS) in rats. In: The toxicologist: supplement to toxicological sciences, 138 (1), Society of Toxicology, 2014. Abstract no. 600.Google Scholar
  86. 86.
    Shin JH, Jeon K, Kim JK, Kim Y, Jo MS, Lee JS, Baek JE, Park HS, An HJ, Park JD, Ahn K, Oh SM, Yu IJ. Subacute inhalation toxicity study of synthetic amorphous silica nanoparticles in Sprague-Dawley rats. Inhal Toxicol. 2017;29(12–14):567–76.PubMedCrossRefGoogle Scholar
  87. 87.
    Stöber W, Fink A, Bohn E. Controlled growth of monodisperse silica spheres in the micron size range. J Colloid Interface Sci. 1968;26:62–9.CrossRefGoogle Scholar
  88. 88.
    Wiemann M, Sauer UG, Vennemann A, Bäcker S, Keller J-G, Ma-Hock L, Wohlleben W, Landsiedel R. In vitro and in vivo short-term pulmonary toxicity of differently sized colloidal amorphous SiO2. Nanomaterials. 2018;8:160.PubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Product SafetyBASF SELudwigshafenGermany
  2. 2.Experimental Toxicology and EcologyBASF SELudwigshafenGermany

Personalised recommendations