Abstract
Intratracheal (IT) instillation is a useful method for screening and hazard identification of inhaled materials, including manufactured nanomaterials. However, many variables regarding sample preparation, experimental equipment, and technical procedures influence results from studies involving IT instillation, and a standard procedure has not yet been validated internationally. These drawbacks prevent accurate comparison of hazard information obtained from different test facilities. In this chapter, we summarize representative IT instillation procedure and present acceptable ranges at which various procedural components do not affect the results. Issues requiring consideration prior to experimentation include the preparation of the dose suspension, appropriate vehicle, and delivery device. In addition, practical aspects of the testing procedure including appropriate forms of anesthesia, animal positioning during IT instillation, intubation methodology, and dosing volume, rate, and frequency are addressed, and recommended endpoints for hazard identification are described. Furthermore, an example recommended procedure for reproducible IT instillation is provided. Technical guidance for reproducible procedures, e.g., a Standard Operating Procedure, is pivotal for the standardization of IT instillation studies, and this chapter contributes validated technical information. In conclusion, IT instillation is poised to occupy an important position regarding hazard screening of manufactured nanomaterials.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Driscoll KE, Costa DL, Hatch G, Henderson R, Oberdorster G, Salem H. Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations. Toxicol Sci. 2000;55:24–35.
Oberdörster G, Oberdörster E, Oberdörster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005;113(7):823–39.
Shinohara N, Oshima Y, Kobayashi T, Imatanaka N, Nakai M, Ichinose T, Sasaki T, Kawaguchi K, Zhang G, Gamo M. Pulmonary clearance kinetics and extrapulmonary translocation of seven titanium dioxide nano- and submicron materials following intratracheal administration in rats. Nanotoxicology. 2015;9(8):1050–8.
van den Boogaard FE, Hofstra JJ, van‘t Veer C, Levi MM, Roelofs JJTH, van der Poll TS, Marcus J. Feasibility and safety of local treatment with recombinant human tissue factor pathway inhibitor in a rat model of Streptococcus pneumoniae pneumonia. PLoS One. 2015;10(5):e0127261.
Cho WS, Duffin R, Bradley M, Megson IL, MacNee W, Lee J, Jeong J, Donaldson K. Predictive value of in vitro assays depends on the mechanism of toxicity of metal oxide nanoparticles. Part Fibre Toxicol. 2013;10:55.
Morimoto Y, Izumi H, Yoshiura Y, Fujishima K, Yatera K, Yamamoto K. Usefulness of intratracheal instillation studies for estimating nanoparticle-induced pulmonary toxicity. Int J Mol Sci. 2016;17:165.
Nakanishi J, Morimoto Y, Ogura I, Kobayashi N, Naya M, Ema M, Endoh S, Shimada M, Ogami A, Myojyo T, Oyabu T, Gamo M, Kishimoto A, Igarashi T, Hanai S. Risk assessment of the carbon nanotube group. Risk Anal. 2015;35:1940–56.
OECD. Guidance on Sample Preparation and Dosimetry for Safety Testing of Manufactured Nanomaterials Series on the Safety of Manufactured Nanomaterials No. 36. ENV/JM/MONO(2012)40. 2012.
Dusinska M, Rundéen-Pran E, Schnekenburger J, Kanno J. Toxicity tests: in vitro and in vivo. In: Fadeel B, Pietroiusti A, Shvedova AA, editors. Adverse effects of engineered nanomaterials exposure, toxicology, and impact on human health. 2nd ed. London: Academic Press; 2017. https://doi.org/10.1016/B978-0-12-809199-9.00003-3.
Warheit DB, Laurence BR, Reed KL, Roach DH, Reynolds GM, Webb TR. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol Sci. 2004;77:117–25.
OECD. 2018. Guidance Document on Acute Inhalation Toxicity Testing. Series on testing and assessment no. 39. 2nd ed.
Hashizume N, Oshima Y, Nakai M, Kobayashi T, Sasaki T, Kawaguchi K, Honda K, Gamo M, Yamamoto K, Tsubokura Y, Ajimi S, Inoue Y, Imatanaka N. Categorization of nano-structured titanium dioxide according to physicochemical characteristics and pulmonary toxicity. Toxicol Rep. 2016;3:490–500.
Kobayashi T, Oshima Y, Tsubokura Y, Hashizume N, Ajimi S, Kayashima T, Nakai M, Sasaki T, Kawaguchi K, Imatanaka N. Effects of dose volume and delivery device on bronchoalveolar lavage parameters of intratracheally administered nano-sized TiO2 in rats. Regul Toxicol Pharmacol. 2016;81:233–41.
Höhr D, Steinfartz Y, Schins RP, Knaapen AM, Martra G, Fubini B, Borm PJ. The surface area rather than the surface coating determines the acute inflammatory response after instillation of fine and ultrafine TiO2 in the rat. Int J Hyg Environ Health. 2002;3:239–44.
Sager TM, Kommineni C, Castranova V. Pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide: role of particle surface area. Part Fibre Toxicol. 2008;5:17.
Krug HF. Nanosafety research—are we on the right track? Angew Chem Int Ed. 2014;53:12304–19.
Morimoto Y, Horie Y, Kitajima S, Fukushima S, Takebayashi T. Comparison of data between intratracheal instillation and inhalation studies for estimation of harmful effects of manufactured nanomaterials. Nippon Eiseigaku Zasshi. 2013;68:161–7 (in Japanese). https://doi.org/10.1265/jjh.68.161.
Morrow PE. Possible mechanism to explain dust overloading of the lungs. Fundam Appl Toxicol. 1988;10(3):369–84.
Borm PJ, Schins RP, Albrecht C. Inhaled particles and lung cancer, part B: paradigms and risk assessment. Int J Cancer. 2004;110:3–14.
Greim H, Borm P, Schins JA, Donaldson K, Driscoll KE, Hartwig A, Kuempel E, Oberdörster G, Speit G. Toxicity of fibers and particles—report of the workshop held in Munich, Germany, 26–27 October, 2000. Inhal Toxicol. 2001;13:737–54.
Pott F, Dungworth DL, Heinrich U, Muhle H, Kamino K, Germann PG, Roller M, Rippe RM, Mohr U. Lung tumours in rats after intratracheal instillation of dusts. Ann Occup Hyg. 1994;38(inhaled particles VII):357–63.
Borm P, Cassee FR, Oberdörster G. Lung particle overload: old school—new insights? Part Fibre Toxicol. 2015;12:10.
Hasegawa-Baba Y, Kubota H, Takata A, Miyagawa M. Intratracheal instillation methods and the distribution of administered material in the lung of the rat. J Toxicol Pathol. 2014;3(4):197–204.
Brain JD, Knudson DE, Sorokin SP, Davis MA. Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation. Environ Res. 1976;11:13–33.
Senoh H, Kano H, Suzuki M, Ohnishi M, Kondo H, Takanobu K, Umeda Y, Aiso S, Fukushima S. Comparison of single or multiple intratracheal administration for pulmonary toxic responses of nickel oxide nanoparticles in rats. J Occup Health. 2017;59:112–21.
Bergmann JD, Metker LW, McCain WC, Beall PA, Michie MW, Lee RB. Intratracheal instillation of zinc-cadmium sulfide (ZnCdS) in Fisher 344 rats. Inhal Toxicol. 2000;12:331–46.
Warheit DB, Webb TR, Sayes CM, Colvin VL, Reed KL. Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. Toxicol Sci. 2006;91(1):227–36.
Kobayashi N, Naya M, Endoh S, Maru J, Yamamoto K, Nakanishi J. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats: different short- and long-term post-instillation results. Toxicology. 2009;264:110–8.
OECD. Test Guideline 412. OECD Guideline for Testing of Chemicals. Subacute inhalation toxicity: 28-day study. 2017.
OECD. Test Guideline 413. OECD Guideline for Testing of Chemicals. Sub-chronic inhalation toxicity: 90-day study. 2017.
Tsubokura Y, Kobayashi T, Oshima Y, Hashizume N, Nakai M, Ajimi S, Imatanaka N. Effects of pentobarbital, isoflurane, or medetomidine– midazolam–butorphanol anesthesia on bronchoalveolar lavage fluid and blood chemistry in rats. J Toxicol Sci. 2016;41:595–604.
Kittel B, Ruehl-Fehlert C, Morawietz G, Klapwijk J, Elwell MR, Lenz B, O’Sullivan MG, Roth DR, Wadsworth PF. Revised guides for organ sampling and trimming in rats and mice—part 2. Exp Toxicol Pathol. 2004;55:413–31.
Shinohara N, Zhang G, Oshima Y, Kobayashi T, Imatanaka N, Nakai M, Sasaki T, Kawaguchi K, Gamo M. Kinetics and dissolution of intratracheally administered nickel oxide nanomaterials in rats. Part Fibre Toxicol. 2017;14:48.
Acknowledgements
This work is part of the research program “Development of innovative methodology for safety assessment of industrial nanomaterials” supported by the Ministry of Economy, Trade and Industry (METI) of Japan.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Kobayashi, T. et al. (2019). Standardization of Intratracheal Instillation Study of Manufactured Nanomaterials. In: Takebayashi, T., Landsiedel, R., Gamo, M. (eds) In Vivo Inhalation Toxicity Screening Methods for Manufactured Nanomaterials. Current Topics in Environmental Health and Preventive Medicine. Springer, Singapore. https://doi.org/10.1007/978-981-13-8433-2_6
Download citation
DOI: https://doi.org/10.1007/978-981-13-8433-2_6
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-13-8432-5
Online ISBN: 978-981-13-8433-2
eBook Packages: MedicineMedicine (R0)