Toxicokinetics and toxicity of nanoparticles in the course of inhalation exposure
More details
Hide details
Zakład Biologii Molekularnej i Badań Translacyjnych, Instytut Medycyny Wsi w Lublinie
Berta Fal   

Zakład Biologii Molekularnej i Badań Translacyjnych, Instytut Medycyny Wsi w Lublinie
Med Og Nauk Zdr. 2020;26(3):221–229
The modern dynamic development of nanotechnology provides many benefits to society. Due to almost unlimited manipulations of the matter at the nanoscale, nanomaterials (NMs) are created, which show different physicochemical properties compared to their counterparts of larger sizes.

The aim of this study is presentation of the factors determining the toxicokinetic behaviour of NPs due to inhalation exposure, and the potential fate of NPs in the respiratory system, as well as the toxic effects of their interaction with biological structures. The latest progress and limitations related to the assessment and management of risk of exposure to NPs are discussed.

Brief description of the state of knowledge:
The ability to give NMs the desired characteristics translates into a wide range of applications of these materials in almost every area of life. This entails an increasing risk of human exposure to NMs, including NPs, which should not be treated analogously to other chemical pollutants. NPs exceed the protective barriers of the body by the dermal, ingestion and inhalation routes; however, the latter is of the greatest importance in relation to the toxic effects of exposure. Many engineered NPs have the ability to overcome the physical, biochemical and cellular barriers of the respiratory system and pass through the respiratory surface into the bloodstream.

Toxicological risk assessment of exposure to NMs should occur simultaneously with the development of new NMs to ensure human health and safety, and environmental protection. A thorough study of the toxicokinetics of inhaled NPs, therefore, is of great importance for a reliable exposure risk assessment.

Hobson DW, Roberts SM, Shvedova AA, Warheit DB, Hinkley GK, Guy RC. Applied nanotoxicology. Int J Toxicol. 2016; 35(1): 5–16.
Hougaard KS, Campagnolo L, Chavatte-Palmer P, Tarrade A, Rousseau--Ralliard D, Valentino S, et al. A perspective on the developmental toxicity of inhaled nanoparticles. Reprod Toxicol. 2015; 56: 118–140.
Ding Y, Kuhlbusch TAJ, Van Tongeren M, Jiménez AS, Tuinman I, Chen R, et al. Airborne engineered nanomaterials in the workplace – a review of release and worker exposure during nanomaterial production and handling processes. J Hazard Mater. 2017; 322(Pt A): 17–28.
Donaldson K, Seaton A. A short history of the toxicology of inhaled particles. Part Fibre Toxicol. 2012; 9: 13.
Song Y, Tang S. Nanoexposure, unusual diseases, and new health and safety concerns. Sci World J. 2011; 11: 1821–1828.
Iyer R, Hsia CCW, Nguyen KT. Nano-therapeutics for the lung: state--of-the-art and future perspectives. Curr Pharm Des. 2015; 21(36): 5233–5244.
Hidalgo A, Cruz A, Pérez-Gil J. Pulmonary surfactant and nanocarriers: Toxicity versus combined nanomedical applications. Biochim Biophys Acta Biomembr. 2017; 1859(9): 1740 –174.
8. Hayes AJ, Bakand S. Toxicological perspectives of inhaled therapeu-tics and nanoparticles. Expert Opin Drug Metab Toxicol. 2014; 10(7): 933–947.
DeLoid GM, Cohen JM, Pyrgiotakis G, Demokritou P. Preparation, characterization, and in vitro dosimetry of dispersed, engineered na-nomaterials. Nat Protoc. 2017; 12(2): 355–371.
Graczyk H, Riediker M. Occupational exposure to inhaled nanopar-ticles: Are young workers being left in the dust? J Occup Health. 2019; 61(5): 333–338.
Kuhlbusch TAJ, Asbach C, Fissan H, Göhler D, Stintz M. Nanoparticle exposure at nanotechnology workplaces: A review. Part Fibre Toxicol. 2011; 8: 22.
Schulte PA, Kuempel ED, Drew NM. Characterizing risk assessments for the development of occupational exposure limits for engineered nanomaterials. Regul Toxicol Pharmacol. 2018; 95: 207–219. ht t ps://
Calderón L, Han TT, McGilvery CM, Yang L, Subramaniam P, Lee KB, et al. Release of airborne particles and Ag and Zn compounds from nanotechnology-enabled consumer sprays: Implications for inhalation exposure. Atmos Environ. 2017; 155: 85–96.
Kendall M, Holgate S. Health impact and toxicological effects of na-nomaterials in the lung. Respirology. 2012; 17(5): 743–758. ht t ps:// /10.1111/j.14 40 -1843.2012 .02171.x.
De Matteis V, Rinaldi R. Toxicity assessment in the nanoparticle era. Adv Exp Med Biol. 2018; 1048: 1–19. 41-8 _1.
John AC, Küpper M, Manders-Groot AMM, Debray B, Lacome JM, Kuhlbusch TAJ. Emissions and possible environmental implication of engineered nanomaterials (ENMs) in the atmosphere. Atmosphere--Basel. 2017; 8(5): 84.
Bressot C, Manier N, Pagnoux C, Aguerre-Chariol O, Morgeneyer M. Environmental release of engineered nanomaterials from commercial tiles under standardized abrasion conditions. J Hazard Mater. 2017; 322(Pt A): 276–283.
Keller AA, McFerran S, Lazareva A, Suh S. Global life cycle releases of engineered nanomaterials. J Nanopart Res. 2013; 15(6): 1–17. ht t ps://
Kumar S, Verma MK, Srivastava AK. Ultrafine particles in urban ambient air and their health perspectives. Rev Environ Health. 2013; 28(2–3): 117–128.
Becker H, Herzberg F, Schulte A, Kolossa-Gehring M. The carcinogenic potential of nanomaterials, their release from products and options for regulating them. Int J Hyg Environ Health. 2011; 214(3): 231–238.
Stone V, Miller MR, Clift MJD, Elder A, Mills NL, Möller P, et al. Nano-materials versus ambient ultrafine particles: an opportunity to exchange toxicology knowledge. Environ Health Perspect. 2017; 125(10): 106002.
Carvalho TC, Peters JI, Williams RO 3rd. Influence of particle size on regional lung deposition – what evidence is there? Int J Pharm. 2011; 406(1–2): 1–10.
Smith JR, Birchall A, Etherington G, Ishigure N, Bailey MR. A revised model for the deposition and clearance of inhaled particles in human extra-thoracic airways. Radiat Prot Dosimetry. 2014; 158(2): 135–147.
Hidalgo A, Cruz A, Pérez-Gil J. Barrier or carrier? Pulmonary surfactant and drug delivery. Eur J Pharm Biopharm. 2015; 95(Pt A): 117–127.
Fröhlich E, Salar-Behzadi S. Toxicological assessment of inhaled nanoparticles: role of in vivo, ex vivo, in vitro, and in silico stu-dies. Int J Mol Sci. 2014; 15(3): 4795–4822.
Garcia-Mouton C, Hidalgo A, Cruz A, Pérez-Gil J. The Lord of the Lungs: The essential role of pulmonary surfactant upon inhalation of nanoparticles. Eur J Pharm Biopharm. 2019; 144: 230–243. ht t ps://
Pearson JP, Chater PI, Wilcox MD. The properties of the mucus barrier, a unique gel – how can nanoparticles cross it? Ther Deliv. 2016; 7(4): 229–244.
Kuhn DA, Vanhecke D, Michen B, Blank F, Gehr P, Petri-Fink A, et al. Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages. Beilstein J Nanotechnol. 2014; 5: 1625–1636.
Shaw CA, Mortimer GM, Deng ZJ, Carter ES, Connell SP, Miller MR, et al. Protein corona formation in bronchoalveolar fluid enhances diesel exhaust nanoparticle uptake and pro-inflammatory responses in macrophages. Nanotoxicology. 2016; 10(7): 981–991.
Nakayama M. Macrophage recognition of crystals and nanoparticles. Front Immunol. 2018; 9: 103.
Liegeois M, Legrand C, Desmet CJ, Marichal T, Bureau F. The in-terstitial macrophage: A long-neglected piece in the puzzle of lung immunity. Cell Immunol. 2018; 330: 91–96.
Donaldson K, Schinwald A, Murphy F, Cho WS, Duffin R, Tran L, et al. The biologically effective dose in inhalation nanotoxicology. Acc Chem Res. 2013; 46(3): 723–732.
Gwinn WM, Qu W, Bousquet RW, Price H, Shines CJ, Taylor GJ, et al. Macrophage solubilization and cytotoxicity of indium-containing par-ticles as in vitro correlates to pulmonary toxicity in vivo. Toxicol Sci. 2015; 144(1): 17–26.
Ortega R, Bresson C, Darolles C, Gautier C, Roudeau S, Perrin L, et al. Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells. Part Fibre Toxicol. 2014; 11: 14.
Misra SK, Dybowska A, Berhanu D, Luoma SN, Valsami-Jones E. The complexity of nanoparticle dissolution and its importance in nanoto-xicological studies. Sci Total Environ. 2012; 438: 225–232. ht t ps://
Wang X, Ji Z, Chang CH, Zhang H, Wang M, Liao YP, et al. Use of coated silver nanoparticles to understand the relationship of particle dissolution and bioavailability to cell and lung toxicological potential. Small. 2014; 10(2): 385–98.
Gunawan C, Lim M, Marquis CP, Amal R. Nanoparticle-protein corona complexes govern the biological fates and functions of nanopartic-les. J Mater Chem B. 2014; 2(15): 2060–2083.
Hamilton RF, Buckingham S, Holian A. The effect of size on Ag na-nosphere toxicity in macrophage cell models and lung epithelial cell lines is dependent on particle dissolution. Int J Mol Sci. 2014; 15(4): 6815–6830.
Accomasso L, Gallina C, Turinetto V, Giachino C. Stem cell tracking with nanoparticles for regenerative medicine purposes: An overview. Stem Cells Int. 2016; 2016: 7920358.
Bakand S, Hayes A, Dechsakulthorn F. Nanoparticles: a review of particle toxicology following inhalation exposure. Inhal Toxicol. 2012; 24(2): 125–135.
Puri A. Nanoparticles: crossing barriers and membrane interactions. Mol Membr Biol. 2010; 27(7): 213–214.
Adjei IM, Sharma B, Labhasetwar V. Nanoparticles: cellular upta-ke and cytotoxicity. Adv Exp Med Biol. 2014; 811: 73–91. ht t ps:// 5.
Khalili Fard J, Jafari S, Eghbal MA. A review of molecular mechanis-ms involved in toxicity of nanoparticles. Adv Pharm Bull. 2015; 5(4): 447–454.
Chithrani DB. Intracellular uptake, transport, and processing of gold nanostructures. Mol Membr Biol. 2010; 27(7): 299–311.
Fenoglio I, Fubini B, Ghibaudi EM, Turci F. Multiple aspects of the interaction of biomacromolecules with inorganic surfaces. Adv Drug Deliv Rev. 2011; 63(13): 1186–1209.
Sanganeria P, Sachar S, Chandra S, Bahadur D, Ray P, Khanna A. Cellu-lar internalization and detailed toxicity analysis of protein-immobilized iron oxide nanoparticles. J Biomed Mater Res B Appl Biomater. 2015; 103(1): 125–134.
McShan D, Ray PC, Yu H. Molecular toxicity mechanism of nanosil-ver. J Food Drug Anal. 2014; 22(1): 116–127.
Dubey P, Matai I, Kumar SU, Sachdev A, Bhushan B, Gopinath P. Per-turbation of cellular mechanistic system by silver nanoparticle toxicity: Cytotoxic, genotoxic and epigenetic potentials. Adv Colloid Interface Sci. 2015; 221: 4–21.
Kim IY, Joachim E, Choi H, Kim K. Toxicity of silica nanoparticles de-pends on size, dose, and cell type. Nanomedicine. 2015; 11(6): 1407–1416.
Thit A, Selck H, Bjerregaard HF. Toxic mechanisms of copper oxide nanoparticles in epithelial kidney cells. Toxicol in Vitro. 2015; 29(5): 1053–1059.
Hussain S, Vanoirbeek JA, Hoet PH. Interactions of nanomaterials with the immune system. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012; 4(2): 169–183. Epub 2011 Dec 5.
Kabir E, Kumar V, Kim KH, Yip ACK, Sohn JR. Environmental impacts of nanomaterials. J Environ Manage. 2018; 225: 261–271. ht t ps://
Męczyńska-Wielgosz S, Wojewódzka M, Matysiak-Kucharek M, Czajka M, Jodłowska-Jędrych B, Kruszewski M, Kapka-Skrzypczak L. Suscepti-bility of HepG2 cells to silver nanoparticles in combination with other metal/metal oxide nanoparticles. Materials (Basel). 2020; 13(10): 2221.
Morimoto Y, Horie M, Kobayashi N, Shinohara N, Shimada M. Inhala-tion toxicity assessment of carbon-based nanoparticles. Acc Chem Res. 2013; 46(3): 770–781.
Puisney C, Baeza-Squiban A, Boland S. Mechanisms of uptake and translocation of nanomaterials in the lung. Adv Exp Med Biol. 2018; 1048: 21–36. _ 2.
Sajid M, Ilyas M, Basheer C, Tariq M, Daud M, Baig N, et al. Impact of nanoparticles on human and environment: review of toxicity factors, exposures, control strategies, and future prospects. Environ Sci Pollut Res Int. 2015; 22(6): 4122–4143. -1.
ISO. ISO/TR 13121. Nanotechnologies – Nanomaterial Risk Evaluation. Genewa: Międzynarodowa Organizacja Normalizacyjna; 2011.
Geiser M, Jeannet N, Fierz M, Burtscher H. Evaluating adverse effects of inhaled nanoparticles by realistic in vitro technology. Nanomaterials (Basel). 2017; 7(2): 49.
Anderson SR, Parmiter D, Baxa U, Nagashima K. Immunoelectron microscopy for visualization of nanoparticles. Methods Mol Biol. 2018; 1682: 65–71.
Savage DT, Hilt JZ, Dziubla TD. In vitro methods for assessing na-noparticle toxicity. Methods Mol Biol. 2019; 1894: 1–29. /10.10 07/978-1-4939-8916 -4 _1.
Wysokińska E, Cichos J, Zioło E, Bednarkiewicz A, Strządała L, Karbowiak M, et al. Cytotoxic interactions of bare and coated NaGdF4:Yb(3+):Er(3+) nanoparticles with macrophage and fibro-blast cells. Toxicol In Vitro. 2016; 32: 16–25.
Foldbjerg R, Dang DA, Autrup H. Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549. Arch Toxicol. 2011; 85(7): 743–750.
Alarcon EI, Vulesevic B, Argawal A, Ross A, Bejjani P, Podrebarac J, et al. Coloured cornea replacements with anti-infective properties: expanding the safe use of silver nanoparticles in regenerative medicine. Nanoscale. 2016; 8(12): 6484–6489.
Zhang YN, Poon W, Tavares AJ, McGilvray ID, Chan WCW. Nano-particle-liver interactions: Cellular uptake and hepatobiliary elimina-tion. J Control Release. 2016; 240: 332–348.
ISO. ISO/TS 12901-1. Nanotechnologies – Occupational Risk Mana-gement Applied to Engineered Nanomaterial – Part 1: Principles and Approaches. Genewa: Międzynarodowa Organizacja Normalizacyjna; 2012.
ISO. ISO/TS 12901-2. Nanotechnologies – Occupational Risk Ma-nagement Applied to Engineered Nanomaterial – Part 2: Use of the Control Banding Approach. Genewa: Międzynarodowa Organizacja Normalizacyjna; 2014.
Ramachandran G, Ostraat M, Evans DE, Methner MM, O’Shaughnessy P, D’Arcy J, et al. A strategy for assessing workplace exposures to na-nomaterials. J Occup Environ Hyg. 2011; 8(11): 673–685.