Comparative lung toxicity of engineered nanomaterials utilizing in vitro, ex vivo and in vivo approaches

Journal of Nanobiotechnology

M Ian Gilmour³  Katelyn Lavrich¹  Tina Stevens²  Elizabeth Boykin³  Yong Ho Kim¹ 

[1] Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Research Triangle Park Division, National Center for Environmental Assessment, United States Environmental Protection Agency, Research Triangle Park, NC, USA;Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC, USA

关键词: Alternative toxicity testing;    Lung toxicity;    Engineered nanomaterials;   

Others  :  1139418
DOI  :  10.1186/s12951-014-0047-3

 received in 2014-08-05, accepted in 2014-10-23,  发布年份 2014

【 摘 要 】

Background

Although engineered nanomaterials (ENM) are currently regulated either in the context of a new chemical, or as a new use of an existing chemical, hazard assessment is still to a large extent reliant on information from historical toxicity studies of the parent compound, and may not take into account special properties related to the small size and high surface area of ENM. While it is important to properly screen and predict the potential toxicity of ENM, there is also concern that current toxicity tests will require even heavier use of experimental animals, and reliable alternatives should be developed and validated. Here we assessed the comparative respiratory toxicity of ENM in three different methods which employed in vivo, in vitro and ex vivo toxicity testing approaches.

Methods

Toxicity of five ENM (SiO₂ (10), CeO₂ (23), CeO₂ (88), TiO₂ (10), and TiO₂ (200); parentheses indicate average ENM diameter in nm) were tested in this study. CD-1 mice were exposed to the ENM by oropharyngeal aspiration at a dose of 100 μg. Mouse lung tissue slices and alveolar macrophages were also exposed to the ENM at concentrations of 22–132 and 3.1-100 μg/mL, respectively. Biomarkers of lung injury and inflammation were assessed at 4 and/or 24 hr post-exposure.

Results

Small-sized ENM (SiO₂ (10), CeO₂ (23), but not TiO₂ (10)) significantly elicited pro-inflammatory responses in mice (in vivo), suggesting that the observed toxicity in the lungs was dependent on size and chemical composition. Similarly, SiO₂ (10) and/or CeO₂ (23) were also more toxic in the lung tissue slices (ex vivo) and alveolar macrophages (in vitro) compared to other ENM. A similar pattern of inflammatory response (e.g., interleukin-6) was observed in both ex vivo and in vitro when a dose metric based on cell surface area (μg/cm²), but not culture medium volume (μg/mL) was employed.

Conclusion

Exposure to ENM induced acute lung inflammatory effects in a size- and chemical composition-dependent manner. The cell culture and lung slice techniques provided similar profiles of effect and help bridge the gap in our understanding of in vivo, ex vivo, and in vitro toxicity outcomes.

【 授权许可】

   
2014 Kim et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Jud C, Clift MJ, Petri-Fink A, Rothen-Rutishauser B: Nanomaterials and the human lung: what is known and what must be deciphered to realise their potential advantages? Swiss Med Wkly 2013, 143:w13758.
• [2]Maynard AD, Aitken RJ, Butz T, Colvin V, Donaldson K, Oberdorster G, Philbert MA, Ryan J, Seaton A, Stone V, Tinkle SS, Tran L, Walker NJ, Warheit DB: Safe handling of nanotechnology. Nature 2006, 444(7117):267-269.
• [3]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(2):301-324.
• [4]Kreyling W, Semmler-Behnke M, Möller W: Health implications of nanoparticles. J Nanoparticle Res 2006, 8(5):543-562.
• [5]Madl AK, Pinkerton KE: Health effects of inhaled engineered and incidental nanoparticles. Crit Rev Toxicol 2009, 39(8):629-658.
• [6]Oberdorster G, Oberdorster E, Oberdorster J: Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 2005, 113(7):823-839.
• [7]Phillips JI, Green FY, Davies JC, Murray J: Pulmonary and systemic toxicity following exposure to nickel nanoparticles. Am J Ind Med 2010, 53(8):763-767.
• [8]Hendren CO, Mesnard X, Dröge J, Wiesner MR: Estimating production data for five engineered nanomaterials as a basis for exposure assessment. Environ Sci Technol 2011, 45(7):2562-2569.
• [9]Cassee FR, van Balen EC, Singh C, Green D, Muijser H, Weinstein J, Dreher K: Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. Crit Rev Toxicol 2011, 41(3):213-229.
• [10]Shi H, Magaye R, Castranova V, Zhao J: Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol 2013, 10:15. BioMed Central Full Text
• [11]Chen J, Patil S, Seal S, McGinnis JF: Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. Nat Nanotechnol 2006, 1(2):142-150.
• [12]Korsvik C, Patil S, Seal S, Self WT: Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem Commun 2007, 10:1056-1058.
• [13]Tang L, Cheng J: Nonporous silica nanoparticles for nanomedicine application. Nano Today 2013, 8(3):290-312.
• [14]Hiraiwa K, van Eeden SF: Contribution of lung macrophages to the inflammatory responses induced by exposure to air pollutants. Mediators Inflamm 2013, 2013:619523.
• [15]Sanders K, Degn LL, Mundy WR, Zucker RM, Dreher K, Zhao B, Roberts JE, Boyes WK: In vitro phototoxicity and hazard identification of nano-scale titanium dioxide. Toxicol Appl Pharmacol 2012, 258(2):226-236.
• [16]Haynes WM: CRC Handbook of Chemistry and Physics. 94th edition. CRC Press/Taylor & Francis Group, Boca Raton, FL; 2013.
• [17]DeLoid G, Cohen JM, Darrah T, Derk R, Rojanasakul L, Pyrgiotakis G, Wohlleben W, Demokritou P: Estimating the effective density of engineered nanomaterials for in vitro dosimetry. Nat Commun 2014, 5:3514.
• [18]Cohen JM, Teeguarden JG, Demokritou P: An integrated approach for the in vitro dosimetry of engineered nanomaterials. Part Fibre Toxicol 2014, 11:20. BioMed Central Full Text
• [19]Sterling MC Jr, Bonner JS, Ernest AN, Page CA, Autenrieth RL: Application of fractal flocculation and vertical transport model to aquatic sol-sediment systems. Water Res 2005, 39(9):1818-1830.
• [20]Hinderliter PM, Minard KR, Orr G, Chrisler WB, Thrall BD, Pounds JG, Teeguarden JG: ISDD: a computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies. Part Fibre Toxicol 2010, 7(1):36. BioMed Central Full Text
• [21]Diaz B, Sanchez-Espinel C, Arruebo M, Faro J, de Miguel E, Magadan S, Yague C, Fernandez-Pacheco R, Ibarra MR, Santamaria J, Gonzalez-Fernandez A: Assessing methods for blood cell cytotoxic responses to inorganic nanoparticles and nanoparticle aggregates. Small 2008, 4(11):2025-2034.
• [22]Fazlollahi F, Kim YH, Sipos A, Hamm-Alvarez SF, Borok Z, Kim KJ, Crandall ED: Nanoparticle translocation across mouse alveolar epithelial cell monolayers: species-specific mechanisms. Nanomedicine 2013, 9(6):786-794.
• [23]Brunner TJ, Wick P, Manser P, Spohn P, Grass RN, Limbach LK, Bruinink A, Stark WJ: In vitro cytotoxicity of oxide nanoparticles: comparison to asbestos, silica, and the effect of particle solubility. Environ Sci Technol 2006, 40(14):4374-4381.
• [24]Kim YH, Fazlollahi F, Kennedy IM, Yacobi NR, Hamm-Alvarez SF, Borok Z, Kim KJ, Crandall ED: Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure. Am J Respir Crit Care Med 2010, 182(11):1398-1409.
• [25]Xia T, Kovochich M, Liong M, Madler L, Gilbert B, Shi H, Yeh JI, Zink JI, Nel AE: Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano 2008, 2(10):2121-2134.
• [26]Napierska D, Thomassen LC, Lison D, Martens JA, Hoet PH: The nanosilica hazard: another variable entity. Part Fibre Toxicol 2010, 7(1):39. BioMed Central Full Text
• [27]Zhang H, Ji Z, Xia T, Meng H, Low-Kam C, Liu R, Pokhrel S, Lin S, Wang X, Liao YP, Wang M, Li L, Rallo R, Damoiseaux R, Telesca D, Madler L, Cohen Y, Zink JI, Nel AE: Use of metal oxide nanoparticle band gap to develop a predictive paradigm for oxidative stress and acute pulmonary inflammation. ACS Nano 2012, 6(5):4349-4368.
• [28]Cho WS, Choi M, Han BS, Cho M, Oh J, Park K, Kim SJ, Kim SH, Jeong J: Inflammatory mediators induced by intratracheal instillation of ultrafine amorphous silica particles. Toxicol Lett 2007, 175(1–3):24-33.
• [29]Aalapati S, Ganapathy S, Manapuram S, Anumolu G, Prakya BM: Toxicity and bio-accumulation of inhaled cerium oxide nanoparticles in CD1 mice. Nanotoxicology 2014, 8(7):786-798.
• [30]Ma JY, Zhao H, Mercer RR, Barger M, Rao M, Meighan T, Schwegler-Berry D, Castranova V, Ma JK: Cerium oxide nanoparticle-induced pulmonary inflammation and alveolar macrophage functional change in rats. Nanotoxicology 2011, 5(3):312-325.
• [31]Srinivas A, Rao PJ, Selvam G, Murthy PB, Reddy PN: Acute inhalation toxicity of cerium oxide nanoparticles in rats. Toxicol Lett 2011, 205(2):105-115.
• [32]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):643-653.
• [33]McDonald JW, Ghio AJ, Sheehan CE, Bernhardt PF, Roggli VL: Rare earth (cerium oxide) pneumoconiosis: analytical scanning electron microscopy and literature review. Mod Pathol 1995, 8(8):859-865.
• [34]Vocaturo G, Colombo F, Zanoni M, Rodi F, Sabbioni E, Pietra R: Human exposure to heavy metals. Rare earth pneumoconiosis in occupational workers. Chest 1983, 83(5):780-783.
• [35]Bonner JC, Silva RM, Taylor AJ, Brown JM, Hilderbrand SC, Castranova V, Porter D, Elder A, Oberdorster G, Harkema JR, Bramble LA, Kavanagh TJ, Botta D, Nel A, Pinkerton KE: Interlaboratory evaluation of rodent pulmonary responses to engineered nanomaterials: the NIEHS Nano GO Consortium. Environ Health Perspect 2013, 121(6):676-682.
• [36]Joris F, Manshian BB, Peynshaert K, De Smedt SC, Braeckmans K, Soenen SJ: Assessing nanoparticle toxicity in cell-based assays: influence of cell culture parameters and optimized models for bridging the in vitro-in vivo gap. Chem Soc Rev 2013, 42(21):8339-8359.
• [37]Teeguarden JG, Hinderliter PM, Orr G, Thrall BD, Pounds JG: Particokinetics in vitro: dosimetry considerations for in vitro nanoparticle toxicity assessments. Toxicol Sci 2007, 95(2):300-312.
• [38]Baisch BL, Corson NM, Wade-Mercer P, Gelein R, Kennell AJ, Oberdorster G, Elder A: Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: the effect of dose rate on acute respiratory tract inflammation. Part Fibre Toxicol 2014, 11:5. BioMed Central Full Text
• [39]Rivera-Gil P, Jimenez de Aberasturi D, Wulf V, Pelaz B, del Pino P, Zhao Y, de la Fuente JM, Ruiz de Larramendi I, Rojo T, Liang XJ, Parak WJ: The challenge to relate the physicochemical properties of colloidal nanoparticles to their cytotoxicity. Acc Chem Res 2013, 46(3):743-749.
• [40]Kim YH, Tong H, Daniels M, Boykin E, Krantz QT, McGee J, Hays M, Kovalcik K, Dye JA, Gilmour MI: Cardiopulmonary toxicity of peat wildfire partcualte matter and the predictive utility of precision cut lung slices. Part Fibre Toxicol 2014, 11:29. BioMed Central Full Text
• [41]Neuhaus V, Schwarz K, Klee A, Seehase S, Forster C, Pfennig O, Jonigk D, Fieguth HG, Koch W, Warnecke G, Yusibov V, Sewald K, Braun A: Functional testing of an inhalable nanoparticle based influenza vaccine using a human precision cut lung slice technique. PLoS One 2013, 8(8):e71728.
• [42]Sauer UG, Vogel S, Aumann A, Hess A, Kolle SN, Ma-Hock L, Wohlleben W, Dammann M, Strauss V, Treumann S, Groters S, Wiench K, van Ravenzwaay B, Landsiedel R: Applicability of rat precision-cut lung slices in evaluating nanomaterial cytotoxicity, apoptosis, oxidative stress, and inflammation. Toxicol Appl Pharmacol 2014, 276(1):1-20.
• [43]Losa Garcia JE, Rodriguez FM, de Cabo MR M, Garcia Salgado MJ, Losada JP, Villaron LG, Lopez AJ, Arellano JL: Evaluation of inflammatory cytokine secretion by human alveolar macrophages. Mediators Inflamm 1999, 8(1):43-51.
• [44]Sayes C, Reed K, Subramoney S, Abrams L, Warheit D: Can in vitro assays substitute for in vivo studies in assessing the pulmonary hazards of fine and nanoscale materials? J Nanoparticle Res 2009, 11(2):421-431.
• [45]Sayes CM, Reed KL, Warheit DB: Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 2007, 97(1):163-180.
• [46]Gilmour MI, McGee J, Duvall RM, Dailey L, Daniels M, Boykin E, Cho SH, Doerfler D, Gordon T, Devlin RB: Comparative toxicity of size-fractionated airborne particulate matter obtained from different cities in the United States. Inhal Toxicol 2007, 19(Suppl 1):7-16.
• [47]Schmidt-Nielsen K: Animal Physiology: Adaptation and Environment. 5th edition. Cambridge University Press, Cambridge, UK; 1997.
• [48]Whitehead GS, Grasman KA, Kimmel EC: Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: comparison to a rodent model of acute lung injury. Toxicology 2003, 183(1–3):175-197.