Inhalation studies for the safety assessment of nanomaterials: Status quo and the way forward

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology

Volumn 4, Issue 4, 2012, Pages 399-413

  Landsiedel, Robert ^a   Ma Hock, Lan ^a   Haussmann, Hans Juergen ^b   van Ravenzwaay, Ben ^a   Kayser, Martin ^a   Wiench, Karin ^a  

^a BASF SE   (Germany)

^b Toxicology Consultant ^*  (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ADVERSE HEALTH EFFECTS; AMBIENT AIR POLLUTION; BIOKINETICS; BIOLOGICAL EFFECTS; CARDIO-VASCULAR DISEASE; CHRONIC DISEASE; ENGINEERED NANOMATERIALS; ENVIRONMENTAL EXPOSURE; IN-VITRO; INHALATION STUDIES; ORGANIZATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT; RESEARCH STUDIES; SAFETY ASSESSMENTS; STATUS QUO; SUBCHRONIC; TEST MATERIALS; TOXICOKINETICS;

DISEASES; INTERNATIONAL COOPERATION; NANOSTRUCTURED MATERIALS;

SAFETY ENGINEERING;

ALUMINUM OXIDE; CERIUM; DENDRIMER; FULLERENE DERIVATIVE; GOLD; IRON; MULTI WALLED NANOTUBE; NANOMATERIAL; SILICON DIOXIDE; SILVER; SINGLE WALLED NANOTUBE; TITANIUM DIOXIDE; ZINC OXIDE; ZIRCONIUM;

ACUTE TOXICITY; AEROSOL; AIR POLLUTION; AMBIENT AIR; CARCINOGENICITY; CARDIOVASCULAR DISEASE; CENTRAL NERVOUS SYSTEM; CHRONIC DISEASE; CHRONIC TOXICITY; CONCENTRATION (PARAMETERS); ENVIRONMENTAL EXPOSURE; ENVIRONMENTAL MONITORING; GENOTOXICITY; HAZARD ASSESSMENT; HUMAN; INHALATION; NEBULIZER; NONHUMAN; PHYSICAL CHEMISTRY; PRACTICE GUIDELINE; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; TOXICOKINETICS;

ANIMALS; HUMANS; INHALATION EXPOSURE; NANOSTRUCTURES; NANOTECHNOLOGY;

EID: 84862673700     PISSN: 19395116     EISSN: 19390041     Source Type: Journal    
DOI: 10.1002/wnan.1173     Document Type: Review

References (76)

1. Oberdörster G, Oberdörster E, Oberdörster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 2005, 113:823-839.
2. Oberdörster G, Elder A, Rinderknecht A. Nanoparticles and the brain: cause for concern? J Nanosci Nanotechnol 2009, 9:4996-5007.
3. Möller W, Felten K, Sommerer K, Scheuch G, Meyer G, Meyer P, Haussinger K, Kreyling WG. Deposition, retention, and translocation of ultrafine particles from the central airways and lung periphery. Am J Respir Crit Care Med 2008, 177:426-432.
4. Pauluhn J. Comparative pulmonary response to inhaled nanostructures: considerations on test design and endpoints. Inhal Toxicol 2009, 21 (suppl 1):40-54.
5. Driscoll KE, Costa DL, Hatch G, Henderson R, Oberdorster G, Salem H, Schlesinger RB. Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations. Toxicol Sci 2000, 55:24-35.
6. Warheit DB. Assessing health risks of inhaled nanomaterials: development of pulmonary bioassay hazard studies. Anal Bioanal Chem 2010, 398:607-612.
7. 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. Nanomed 2011, 6:143-156.
8. Rückerl R, Schneider A, Breitner S, Cyrys J, Peters A. Health effects of particulate air pollution: a review of epidemiological evidence. Inhal Toxicol 2011, 23:555-592.
9. Madl AK, Teague SV, Qu Y, Masiel D, Evans JE, Guo T, Pinkerton KE. Aerosolization system for experimental inhalation studies of carbon-based nanomaterials. Aerosol Sci Technol 2012, 46:94-107.
10. 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, 19:833-848.
11. Schmoll LH, Elzey S, Grassian VH, O'Shaughnessy PT. Nanoparticle aerosol generation methods from bulk powders for inhalation exposure studies. Nanotoxicology 2009, 3:265-275.
12. Sayes CM, Warheit DB. Characterization of nanomaterials for toxicity assessment. WIREs Nanomed Nanobiotechnol 2009, 1:660-670.
13. Organization 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. ENV/JM/MONO (2010)46. 2010. Series on the Safety of Manufactured Nanomaterials, 19-9-2011.
14. Landsiedel R, Ma-Hock L, Kroll A, Hahn D, Schnekenburger J, Wiench K, Wohlleben W. Testing metal-oxide nanomaterials for human safety. Adv Mater 2010, 22:2601-2627.
15. Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci 2004, 77:347-357.
16. Elder A, Gelein R, Finkelstein JN, Driscoll KE, Harkema J, Oberdörster G. Effects of subchronically inhaled carbon back in three species. I. retention kinetics, lung inflammation, and histopathology. Toxicol Sci 2005, 88:614-629.
17. International Life Science Institute. The relevance of the rat lung response to particle overload for human risk assessment: a workshop consensus report. Inhal Toxicol 2000, 12:1-17.
18. van Eijl S, van Oorschot R, Olivier B, Nijkamp FP, Bloksma N. Stress and hypothermia in mice in a nose-only cigarette smoke exposure system. Inhal Toxicol 2006, 18:911-918.
19. Bowers SL, Bilbo SD, Dhabhar FS, Nelson RJ. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun 2008, 22:105-113.
20. Jansson AH, Eriksson C, Wang X. Effects of budesonide and N-acetylcysteine on acute lung hyperinflation, inflammation and injury in rats. Vasc Pharmacol 2005, 43:101-111.
21. Droms KA, Malkinson A. Mechanisms of glucocorticoid involvement in mouse lung tumorigenesis. Exp Lung Res 1991, 17:359-370.
22. Sutherland MA, Shome GP, Hulbert LE, Krebs N, Wachtel M, McGlone JJ. Acute stress affects the physiology and behavior of allergic mice. Physiol Behav 2009, 98:281-287.
23. Shvedova AA, Kisin E, Murray AR, Johnson VJ, Gorelik O, Arepalli S, Hubbs AF, Mercer RR, Keohavong P, Sussman N, et al. Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis. Am J Physiol Lung Cell Mol Physiol 2008, 295:L552-L565.
24. 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, 113:226-242.
25. 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, 21:102-118.
26. Haussmann H-J, Gerstenberg B, Göcke W, Kuhl P, Schepers G, Stabbert R, Stinn W, Teredesai A, Tewes FJ. 12-month inhalation study on room-aged cigarette sidestream smoke in rats. Inhal Toxicol 1998, 10:663-697.
27. Oberdörster G. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. J Intern Med 2010, 267:89-105.
28. Hubbs AF, Mercer RR, Benkovic SA, Harkema J, Sriram K, Schwegler-Berry D, Goravanahally MP, Nurkiewicz TR, Castranova V, Sargent LM. Nanotoxicology-a pathologist's perspective. Toxicol Pathol 2011, 39:301-324.
29. Pauluhn J. Poorly soluble particulates: searching for a unifying denominator of nanoparticles and fine particles for DNEL estimation. Toxicology 2011, 279:176-188.
30. Pauluhn J. Common mechanism-based study design for inhalation toxicity testing of poorly soluble (nano-/ultrafine-) particles: are new testing strategies and interpretation guidelines needed? NanoCon, Brno, Czech Republic. 2011, 15-11-2011.
31. Geiser M, Kreyling W. Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol 2010, 7:2.
32. International Commission on Radiological Protection. ICRP publication 66: human respiratory tract model for radiological protection. Ann ICRP 1994, 24:1-3.
33. National Institute for Public Health and the Environment (RIVM). Multiple path particle dosimetry model. A model for human and rat airway particle dosimetry. RIVA Report 650010030. 2002. Bilthoven, The Netherlands, 20-9-2011.
34. Geiser M. Update on macrophage clearance of inhaled micro- and nanoparticles. J Aerosol Med Pulm Drug Deliv 2010, 23:207-217.
35. 2 and quartz. Toxicol Lett 2009, 186:152-159.
36. Riviere JE. Pharmacokinetics of nanomaterials: an overview of carbon nanotubes, fullerenes and quantum dots. WIREs Nanomed Nanobiotechnol 2009, 1:26-34.
37. Takenaka S, Karg E, Kreyling WG, Lentner B, Schulz H, Ziesenis A, Schramel P, Heyder J. Fate and toxic effects of inhaled ultrafine cadmium oxide particles in the rat lung. Inhal Toxicol 2004, 16(suppl 1):83-92.
38. Kreyling WG, Semmler-Behnke M, Seitz J, Scymczak W, Wenk A, Mayer P, Takenaka S, Oberdörster G. Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs. Inhal Toxicol 2009, 21:55-60.
39. Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 2002, 65:1531-1543.
40. 2 caused minor airflow limitation in the murine airways. Arch Toxicol 2011, 85:827-839.
41. Ryman-Rasmussen JP, Tewksbury EW, Moss OR, Cesta MF, Wong BA, Bonner JC. Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthma. Am J Respir Cell Mol Biol 2009, 40:349-358.
42. Maier KL, Alessandrini F, Beck-Speier I, Hofer TPJ, Diabate S, Bitterle E, Stöger T, Jakob T, Behrendt H, Horsch M, et al. Health effects of ambient particulate matter - biological mechanisms and inflammatory responses to in vitro and in vivo particle exposures. Inhal Toxicol 2008, 20:319-337.
43. Warheit DB, McHugh TA, Hartsky MA. Differential pulmonary responses in rats inhaling crystalline, colloidal or amorphous silica dusts. Scand J Work Environ Health 1995, 21:19-21.
44. Reuzel PG, Bruijntjes JP, Feron VJ, Woutersen RA. Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats. Food Chem Toxicol 1991, 29:341-354.
45. Johnston CJ, Driscoll KE, Finkelstein JN, Baggs R, 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, 56:405-413.
46. Arts JH, Muijser H, Duistermaat E, Junker K, Kuper CF. 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, 45:1856-1867.
47. 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 multiwall carbon nanotubes in rats exposed for 3 months. Toxicol Sci 2009, 112:468-481.
48. Ferin J, Oberdörster G, Penney DP. Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 1992, 6:535-542.
49. Carter JM, Corson N, Driscoll KE, Elder A, Finkelstein JN, Harkema JR, Gelein R, Wade-Mercer P, Nguyen K, Oberdörster G. A comparative dose-related response of several key pro- and antiinflammatory mediators in the lungs of rats, mice, and hamsters after subchronic inhalation of carbon black. J Occup Environ Med 2006, 48:1265-1278.
50. Pauluhn J. Pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminum oxyhydroxides following 4-week inhalation exposure of rats: toxic effects are determined by agglomerated, not primary particle size. Toxicol Sci 2009, 109:152-167.
51. Johnston HJ, Hutchison G, Christensen FM, Peters S, Hankin S, Stone V. A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity. Crit Rev Toxicol 2010, 40:328-346.
52. 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 engine exhaust, carbon black, and titanium dioxide. Inhal Toxicol 1995, 7:533-556.
53. Baan RA. Carcinogenic hazards from inhaled carbon black, titanium dioxide, and talc not containing asbestos or asbestiform fibers: recent evaluations by an IARC Monographs Working Group. Inhal Toxicol 2007, 19(suppl 1):213-228.
54. Borm PJA, Tran L, Donaldson K. The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism. Crit Rev Toxicol 2011, 41:756-770.
55. Wang ZL, Kong XY, Ding Y, Gao P, Hughes WL, Yang R, Zhang Y. Semiconducting and piezoelectric oxide nanostructures induced by polar surfaces. Adv Funct Mater 2004, 14:943-956.
56. Upadhyay S, Stoeger T, Harder V, Thomas RF, Schladweiler MC, Semmler-Behnke M, Takenaka S, Karg E, Reitmeir P, Bader M, et al. Exposure to ultrafine carbon particles at levels below detectable pulmonary inflammation affects cardiovascular performance in spontaneously hypertensive rats. Part Fibre Toxicol 2008, 5:19.
57. Ellinger-Ziegelbauer H, Pauluhn J. Pulmonary toxicity of multi-walled carbon nanotubes (Baytubes) relative to α-quartz following a single 6h inhalation exposure of rats and a 3 months post-exposure period. Toxicology 2009, 266:16-29.
58. Morimoto Y, Oyabu T, Ogami A, Myojo T, Kuroda E, Hirohashi M, Shimada M, Lenggoro W, Okuyama K, Tanaka I. Investigation of gene expression of MMP-2 and TIMP-2 mRNA in rat lung in inhaled nickel oxide and titanium dioxide nanoparticles. Ind Health 2011, 49:344-352.
59. Pacurari M, Qian Y, Porter DW, Wolfarth M, Wan Y, Luo D, Ding M, Castranova V, Guo NL. Multi-walled carbon nanotube-induced gene expression in the mouse lung: association with lung pathology. Toxicol Appl Pharmacol 2011, 255:18-31.
60. Sellamuthu R, Umbright C, Roberts JR, Chapman R, Young SH, Richardson D, Leonard H, McKinney W, Chen B, Frazer D, et al. Blood gene expression profiling detects silica exposure and toxicity. Toxicol Sci 2011, 122:253-264.
61. Teeguarden JG, Webb-Robertson BJ, Waters KM, Murray AR, Kisin ER, Varnum SM, Jacobs JM, Pounds JG, Zanger RC, Shvedova AA. Comparative proteomics and pulmonary toxicity of instilled single-walled carbon nanotubes, crocidolite asbestos, and ultrafine carbon black in mice. Toxicol Sci 2011, 120:123-135.
62. Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter JM, Potter R, Maynard A, Ito Y, Finkelstein J, et al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 2006, 114:1172-1178.
63. Kang GS, Gillespie PA, Gunnison A, Moreira AL, Tchou-Wong KM, Chen LC. Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model. Environ Health Perspect 2011, 119:176-181.
64. Niwa Y, Hiura Y, Murayama T, Yokode M, Iwai N. Nano-sized carbon black exposure exacerbates atherosclerosis in LDL-receptor knockout mice. Circ J 2007, 71:1157-1161.
65. Li Z, Hulderman T, Salmen R, Chapman R, Leonard SS, Young SH, Shvedova A, Luster MI, Simeonova PP. Cardiovascular effects of pulmonary exposure to single-wall carbon nanotubes. Environ Health Perspect 2007, 115:377-382.
66. LeBlanc AJ, Moseley AM, Chen BT, Frazer D, Castranova V, Nurkiewicz TR. Nanoparticle inhalation impairs coronary microvascular reactivity via a local reactive oxygen species-dependent mechanism. Cardiovasc Toxicol 2010, 10:27-36.
67. LeBlanc AJ, Cumpston JL, Chen BT, Frazer D, Castranova V, Nurkiewicz TR. Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles. J Toxicol Environ Health A 2009, 72:1576-1584.
68. Nurkiewicz TR, Porter DW, Hubbs AF, Cumpston JL, Chen BT, Frazer DG, Castranova V. Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction. Part Fibre Toxicol 2008, 5:1.
69. Khandoga A, Stoeger T, Khandoga AG, Bihari P, Karg E, Ettehadieh D, Lakatos S, Fent J, Schulz H, Krombach F. Platelet adhesion and fibrinogen deposition in murine microvessels upon inhalation of nanosized carbon particles. J Thromb Haemost 2010, 8:1632-1640.
70. Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdörster G. Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains. Inhal Toxicol 2004, 16:461-471.
71. Kodavanti UP, Schladweiler MC, Ledbetter AD, Hauser R, Christiani DC, McGee J, Richards JR, Costa DL. Temporal association between pulmonary and systemic effects of particulate matter in healthy and cardiovascular compromised rats. J Toxicol Environ Health A 2002, 65:1545-1569.
72. Roller M. Carcinogenicity of inhaled nanoparticles. Inhal Toxicol 2009, 21(suppl 1):144-157.
73. Tsuda H, Xu J, Sakai Y, Futakuchi M, Fukamachi K. Toxicology of engineered nanomaterials - a review of carcinogenic potential. Asian Pac J Cancer Prev 2009, 10:975-980.
74. Engineered Nanoparticles-Review of Health and Environmental Safety (ENRHES Project). 2009. Available at: (Accessed April 15, 2011).
75. European Commission Scientific Committee on Emerging and Newly Identified Health Risks, Risk Assessment of Products of Nanotechnologies. 2009. Available at:
76. Maynard AD, Warheit DB, Philbert MA. The new toxicology of sophisticated materials: nanotoxicology and beyond. Toxicol Sci 2011, 120(S1):S109-S129. Available at: