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Nanosized TiO2 caused minor airflow limitation in the murine airways

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Abstract

The use of nanotechnology is increasing exponentially, whereas the possible adverse health effects of engineered nanoparticles (NPs) are so far less known. Standardized mouse bioassay was used to study sensory and pulmonary irritation, airflow limitation, and inflammation potency of nanosized TiO2. Single exposure (0.5 h) to in situ generated TiO2 (primary particle size 20 nm; geometric mean diameters of 91, 113, and 130 nm at mass concentrations of 8, 20, and 30 mg/m3, respectively; crystal phase anatase + brookite (3:1)) caused airflow limitation in the conducting airways at each studied exposure concentration, which was shown as a reduction in expiratory flow, being at the lowest 73% of baseline. The response was not dose dependent. Repeated exposures (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) to TiO2 at mass concentration of 30 mg/m3 caused as intense airflow limitation effect as the single exposures, and the extent of the responses stayed about the same along the exposure days. Sensory irritation was fairly minor. Pulmonary irritation was more pronounced during the latter part of the repeated exposures compared to the single exposures and the beginning of the repeated exposures. Sensory and pulmonary irritation were observed also in the control group, and, therefore, reaction by-products (NO2 and C3H6) may have contributed to the irritation effects. TiO2 NPs accumulated mainly in the pulmonary macrophages, and they did not cause nasal or pulmonary inflammation. In conclusion, the irritation and inflammation potencies of studied TiO2 seemed to be low.

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References

  • Aitken RJ, Creely KS, Tran CL (2004) Nanoparticle: an occupational hygiene review. Research report 274. Institute of Occupational Medicine, Edinburgh

    Google Scholar 

  • Alarie Y (1998) Computer-based bioassay for evaluation of sensory irritation of airborne chemicals and its limit of detection. Arch Tocicol 72:277–282

    Article  CAS  Google Scholar 

  • Alarie Y (2001) Computerized animal bioassay to evaluate the effects of airborne chemicals on the respiratory tract. In: Spengler JD, Samet JM, McCarthy JF (eds) Indoor air quality handbook. MC-Graw-Hill, New York

    Google Scholar 

  • Alarie Y, Nielsen GD, Schaper MM (2001) Animal bioassays for evaluation of indoor air quality. In: Spengler JD, Samet JM, McCarthy JF (eds) Indoor air quality handbook. MC-Graw-Hill, New York

    Google Scholar 

  • Andersen I, Lundqvist GR, Proctor DF, Swift DL (1979) Human response to controlled levels of inert dust. Am Rev Respir Dis 119:619–627

    PubMed  CAS  Google Scholar 

  • Andersen I, Mølhave L, Proctor DF (1981) Human response to controlled levels of combinations of sulfur dioxide and inert dust. Scand J Work Environ Health 7:1–7

    PubMed  CAS  Google Scholar 

  • Anderson RC, Anderson JH (1999a) Acute respiratory effects of diaper emissions. Arch Environ Health 54:353–358

    Article  PubMed  CAS  Google Scholar 

  • Anderson RC, Anderson JH (1999b) Respiratory toxicity in mice exposed to mattress covers. Arch Environ Health 54:202–209

    Article  PubMed  CAS  Google Scholar 

  • Anderson RC, Anderson JH (2000) Respiratory toxicity of mattress emissions in mice. Arch Environ Health 55:38–43

    Article  PubMed  CAS  Google Scholar 

  • ASTM, American Society for Testing and Materials (1984) Designation E981-84. Philadelphia, PA

  • Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Cagliano V (2006) Carcinogenicity of carbon black, titanium dioxide, and talc. Lancet Oncol 7:295–296

    Article  PubMed  Google Scholar 

  • Backman U, Tapper U, Jokiniemi JK (2004) An aerosol method to synthesize supported metal catalyst nanoparticles. Synth Met 142:169–176

    Article  CAS  Google Scholar 

  • Baggs RB, Ferin J, Öberdörster G (1997) Regression of pulmonary lesions produced by inhaled titanium dioxide in rats. Vet Pathol 34:592–597

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Boffetta P, Soutar A, Cherrie JW, Granath F, Andersen A, Anttila A, Blettner M, Gaborieau V, Klug SJ, Langard S, Luce D, Merletti F, Miller B, Mirabelli D, Pukkala E, Adami H-O, Weider E (2004) Mortality among workers employed in the titanium dioxide production industry in Europe. Cancer Causes Control 15:697–706

    Article  PubMed  Google Scholar 

  • Boylstein LA, Anderson SJ, Thomson RD, Alarie Y (1995) Characterization of the effects of an airborne mixture of chemicals on the respiratory tract and smoothing polynomial spline analysis of the data. Arch Toxicol 69:579–589

    Article  PubMed  CAS  Google Scholar 

  • Boylstein LA, Luo J, Stock MF, Alarie Y (1996) An attempt to define a just detectable effect for airborne chemicals on the respiratory tract in mice. Arch Toxicol 70:567–578

    Article  PubMed  CAS  Google Scholar 

  • Chen H-W, Su S-F, Chien C-T, Lin W-H, Yu S-L, Chou C-C, Chen JJW, Yang P-C (2006) Titanium dioxide nanoparticles induce emphysema-like lung injury in mice. FASEB J 20:1732–1741

    Google Scholar 

  • Fond AM, Meyer GJ (2006) Biotoxicity of metal oxide nanoparticles. In: Kumar CSSR (ed) Nanomaterials—toxicity, health and environmental issues. Nanotechnologies for the life sciences, vol 5. WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

    Google Scholar 

  • Fryzek JP, Chadda B, Marano D, White K, Schweitzer S, McLaughlin JK, Blot WJ (2003) A cohort mortality study among titanium dioxide manufacturing workers in the United States. J Occup Environ Med 45:400–409

    Article  PubMed  CAS  Google Scholar 

  • Grassian VH, O’Shaugnessy PT, Adamcakova-Dodd A, Pettibone JM, Thorne PS (2007a) Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 nm. Environ Health Perspect 115:397–402

    Article  PubMed  CAS  Google Scholar 

  • Grassian VH, Adamcakova-Dodd A, Pettibone JM, O’Shaughnessy PI, Thorne PS (2007b) Inflammatory response of mice to manufactured titanium dioxide nanoparticles: comparison of size effects through different exposure routes. Nanotoxicology 1:211–226

    Article  CAS  Google Scholar 

  • Hemmilä M, Hihkiö M, Kasanen J-P, Turunen M, Hautamäki M, Pasanen A-L, Linnainmaa K (2007) In vivo and in vitro evaluation of the acute toxicity, the genotoxicity, and the irritation potency of two hexachloroethane-based pyrotechnic smokes. J Toxicol Environ Health A 70:1167–1181

    Article  PubMed  Google Scholar 

  • Hext PM, Tomenson JA, Thompson P (2005) Titanium dioxide: inhalation toxicology and epidemiology. Ann Occup Hyg 49:461–472

    Article  PubMed  CAS  Google Scholar 

  • Kasanen J-P, Pasanen A-L, Pasanen P, Liesivuori J, Kosma V-M, Alarie Y (1998) Stereospecificity of the sensory irritation receptor for nonreactive chemicals illustrated by pinene enantiomers. Arch Toxicol 72:514–523

    Article  PubMed  CAS  Google Scholar 

  • Korpi A, Kasanen J-P, Alarie Y, Kosma V-M, Pasanen A-L (1999) Sensory irritating potency of some microbial volatile organic compouds (MVOCs) and a mixture of five MVOCs. Arch Environ Health 54:347–352

    Article  PubMed  CAS  Google Scholar 

  • Korpi A, Kasanen J-P, Kosma V-M, Rylander R, Pasanen A-L (2003a) Slight respiratory irritation but not inflammation in mice exposed to (1 → 3)-β-d-glucan aerosols. Mediators Inflamm 12:139–146

    Article  PubMed  CAS  Google Scholar 

  • Korpi A, Kasanen J-P, Raunio P, Pasanen A-L (2003b) Acute effects of Aspergillus versicolor aerosols on murine airways. Indoor Air 13:260–266

    Article  PubMed  CAS  Google Scholar 

  • Larsen ST, Nielsen GD (2000) Effects of methacrolein on the respiratory tract in mice. Toxicol Lett 114:197–202

    Article  PubMed  CAS  Google Scholar 

  • Larsen ST, Hougaard KS, Hammer M, Alarie Y, Wolkoff P, Clausen PA, Wilkins CK, Nielsen GD (2000) Effects of R-(+)- and S-(−)-limonene on the respiratory tract in mice. Hum Exp Toxicol 19:457–466

    Article  PubMed  CAS  Google Scholar 

  • Larsen ST, Hansen JS, Hammer M, Alarie Y, Nielsen GD (2004) Effects of mono-2-ethylhexyl phthalate on the respiratory tract in BALB/c mice. Hum Exp Toxicol 23:537–545

    Article  PubMed  CAS  Google Scholar 

  • Li J, Li Q, Xu J, Li J, Cai X, Liu R, Li Y, Ma J, Li W (2007a) Comparative study on the acute pulmonary toxicity induced by 3 and 20 nm TiO2 primary particles in mice. Environ Toxicol Pharmacol 24:239–244

    Article  Google Scholar 

  • Li J-G, Ishigaki T, Sun X (2007b) Anatase, brookite, and rutile nanocrystals via redox reactions under mild hydrothermal conditions: phase-selective synthesis and physicochemical properties. J Phys Chem C 111:4969–4976

    Article  CAS  Google Scholar 

  • Lux Research (2010) Nanomaterials State of the Market Q3 2008: Stealth Success, Broad Impact. http://portal.luxresearchinc.com/research/document_excerpt/3735. Accessed 5 Feb 2010

  • Lyyränen J, Backman U, Tapper U, Auvinen A, Jokiniemi J (2009) A size selective nanoparticle collection device based on diffusion and thermophoresis. J Phys: Conference Series 170, p 11 

  • Miettinen M, Riikonen J, Tapper U, Backman U, Joutsensaari J, Auvinen A, Lehto V-P, Jokiniemi J (2009) Development of a highly controlled gas-phase nanoparticle generator for inhalation exposure studies. Hum Exp Toxicol 28:413–419

    Article  PubMed  CAS  Google Scholar 

  • Ministry of Social Affairs and Health (2009) HTP-arvot 2009 [in Finnish]. Sosiaali- ja terveysministeriön julkaisuja 2009:11. Helsinki

  • Neuberger T, Schöpf B, Hofmann H, Hofmann M, von Rechenberg B (2005) Superparamagnetic nanoparticles for biomedical applications: possibilities and limitations of a new drug delivery system. J Magn Magn Mater 293:483–496

    Article  CAS  Google Scholar 

  • Nielsen GD, Hougaard KS, Larsen ST, Hammer M, Wolkoff P, Clausen PA, Wilkins CK, Alarie Y (1999) Acute airway effects of formaldehyde and ozone in BALB/c mice. Hum Exp Toxicol 18:400–409

    Article  PubMed  CAS  Google Scholar 

  • Nielsen GD, Larsen ST, Hougaard KS, Hammer M, Wolkoff P, Clausen PA, Wilkins CK, Alarie Y (2005) Mechanisms of acute inhalation effects of (+) and (−)-α-pinene in BALB/c mice. Basic Clin Pharmacol Toxicol 96:420–428

    Article  PubMed  CAS  Google Scholar 

  • Nørgaard AW, Larsen ST, Hammer M, Poulsen SS, Jensen KA, Nielsen GD, Wolkoff P (2010) Lung damage in mice after inhalation of nanofilm spray products: the role of perfluorination and free hydroxyl groups. Toxicol Sci 116:216–224

    Article  PubMed  Google Scholar 

  • Otani N, Ishimatsu S, Mochizuki T (2008) Acute group poisoning by titanium dioxide: inhalation exposure may cause metal fume fever. Am J Emerg Med 26:608–611

    Article  PubMed  Google Scholar 

  • Popp JA, Monteiro-Riviere NA (1985) Macroscopic, microscopic, and ultra-structural anatomy of the nasal cavity, rat; the upper respiratory system (nares, larynxs, trachea). In: Jones TC, Mohr U, Hunt RD (eds) Monographs on pathology of laboratory animals, sponsored by the international life sciences institute 3–4. Respiratory system. Springer-Verlag, Berlin

    Google Scholar 

  • Pottenger LH, Malley LA, Bogdanffy MS, Donner EM, Upton PB, Li Y, Walker VE, Harkema JR, Banton MI, Swenberg JA (2007) Evaluation of effects from repeated inhalation exposure of F344 rats to high concentration of propylene. Toxicol Sci 97:336–347

    Article  PubMed  CAS  Google Scholar 

  • Rohr AC, Wilkins CK, Clausen PA, Hammer M, Nielsen GD, Wolkoff P, Spengler JD (2002) Upper airway and pulmonary effects of oxidation products of (+)-α-pinene, d-limonene, and isoprene in BALB/c mice. Inhal Toxicol 14:663–684

    Article  PubMed  CAS  Google Scholar 

  • Rossi EM, Pylkkänen L, Koivisto AJ, Vippola M, Jensen KA, Miettinen M, Sirola K, Nykäsenoja H, Karisola P, Stjernvall T, Vanhala E, Kiilunen M, Pasanen P, Mäkinen M, Hämeri K, Joutsensaari J, Tuomi T, Jokiniemi J, Wolff H, Savolainen K, Matikainen S, Alenius H (2010) Airway exposure to silica coated TiO2 nanoparticles induces pulmonary neutrophilia in mice. Toxicol Sci 113:422–433

    Article  PubMed  CAS  Google Scholar 

  • Schaper M (1993) Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am Ind Hyg Assoc J 54:488–544

    Article  PubMed  CAS  Google Scholar 

  • Schaper MM, Thompson RD, Detwiler-Okabayashi KA (1994) Respiratory responses of mice exposed to thermal decomposition products from polymers heated at and above workplace processing temperatures. Am Ind Hyg Assoc J 55:924–934

    Article  PubMed  CAS  Google Scholar 

  • Schneider T et al (2007) Evaluation and control of occupational health risks from nanoparticles. TemaNord 2007, vol 581. Copenhagen

  • Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AI, Tyurina YY, Gorelik O, Arepalli S, Schwegler-Berry D, Hubbs AF, Antonini J, Evans DE, Ku B-K, Ramsey D, Maynard A, Kagan VE, Castranova V, Baron P (2005) Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol 289:L698–L708

    Article  PubMed  CAS  Google Scholar 

  • Sippula O, Hokkinen J, Puustinen H, Yli-Pirilä P, Jokiniemi J (2009) Particle emissions from small wood-fired district heating units. Energy Fuels 23:2974–2982

    Article  CAS  Google Scholar 

  • Thorne PS, DeKoster JA (1996) Pulmonary effects of machining fluids in guinea pigs and mice. AIHA J 57:1168–1172

    Article  CAS  Google Scholar 

  • Vijayaraghavan R, Schaper M, Thompson R, Stock MF, Alarie Y (1993) Characteristic modifications of the breathing pattern of mice to evaluate the effects of airborne chemicals on the respiratory tract. Arch Toxicol 67:478–490

    Article  PubMed  CAS  Google Scholar 

  • Vijayaraghavan R, Schaper M, Thompson R, Stock MF, Boylstein LA, Luo JE, Alarie Y (1994) Computer assisted recognition and quantification of the effects of airborne chemicals acting at different areas of the respiratory tract in mice. Arch Toxicol 68:490–499

    Article  PubMed  CAS  Google Scholar 

  • Warheit DB, Webb TR, Sayes CM, Colvin VL, Reed KL (2006) Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. Toxicol Sci 91:227–236

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Warheit DB, Hoke RA, Finlay C, Donner EM, Reed KL, Sayes CM (2007b) Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicol Lett 171:99–110

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Banfield JF (2000) Understanding polymorphic phase transformation behavior during growth of nanocrystalline aggregates: insights from TiO2. J Phys Chem B 104:3481–3487

    Article  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the financial support from the Academy of Finland, FinNano program (grants 117924 and 118114). Also the personnel of the National Laboratory Animal Centre, especially senior laboratory technician Minna Törrönen, is acknowledged for technical help, and statistics expert Marja-Leena Hannila from the Statistical services unit at the University of Eastern Finland for the advice on statistics. Søren Thor Larsen and Maria Hammer from the National Research Centre for the Working Environment, Copenhagen are greatly acknowledged for their generous tips on the Notocord program and data handling. The authors thank also MSc Eveliina Repo from Laboratory of Applied Environmental Chemistry, University of Eastern Finland for the help with zeta potential measurements, and maintenance engineer Pentti Willman from the Department of Environmental Science, University of Eastern Finland, for the assistance with OC/EC analysis.

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The authors declare that they have no conflict of interest.

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Correspondence to Maija Leppänen.

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Leppänen, M., Korpi, A., Miettinen, M. et al. Nanosized TiO2 caused minor airflow limitation in the murine airways. Arch Toxicol 85, 827–839 (2011). https://doi.org/10.1007/s00204-011-0644-y

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