Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: The effect of dose rate on acute respiratory tract inflammation

Particle and Fibre Toxicology (Impact Factor: 7.11). 01/2014; 11(1):5. DOI: 10.1186/1743-8977-11-5
Source: PubMed


The increased production of nanomaterials has caused a corresponding increase in concern about human exposures in consumer and occupational settings. Studies in rodents have evaluated dose-response relationships following respiratory tract (RT) delivery of nanoparticles (NPs) in order to identify potential hazards. However, these studies often use bolus methods that deliver NPs at high dose rates that do not reflect real world exposures and do not measure the actual deposited dose of NPs. We hypothesize that the delivered dose rate is a key determinant of the inflammatory response in the RT when the deposited dose is constant.
F-344 rats were exposed to the same deposited doses of titanium dioxide (TiO2) NPs by single or repeated high dose rate intratracheal instillation or low dose rate whole body aerosol inhalation. Controls were exposed to saline or filtered air. Bronchoalveolar lavage fluid (BALF) neutrophils, biochemical parameters and inflammatory mediator release were quantified 4, 8, and 24 hr and 7 days after exposure.
Although the initial lung burdens of TiO2 were the same between the two methods, instillation resulted in greater short term retention than inhalation. There was a statistically significant increase in BALF neutrophils at 4, 8 and 24 hr after the single high dose TiO2 instillation compared to saline controls and to TiO2 inhalation, whereas TiO2 inhalation resulted in a modest, yet significant, increase in BALF neutrophils 24 hr after exposure. The acute inflammatory response following instillation was driven primarily by monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, mainly within the lung. Increases in heme oxygenase-1 in the lung were also higher following instillation than inhalation. TiO2 inhalation resulted in few time dependent changes in the inflammatory mediator release. The single low dose and repeated exposure scenarios had similar BALF cellular and mediator response trends, although the responses for single exposures were more robust.
High dose rate NP delivery elicits significantly greater inflammation compared to low dose rate delivery. Although high dose rate methods can be used for quantitative ranking of NP hazards, these data caution against their use for quantitative risk assessment.

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    • "In concordance, Li et al. (2010) indicated that after intratracheally installation of TiO 2 NPs once per-week for 4 consecutive weeks, NPs might translocated to the blood circulation and then to extrapulmonary tissues, and they were able to pass through the blood-brain barrier and induced to brain damage. In the latest study by Baisch et al. (2014), rats were exposed to TiO 2 NPs by intratracheal installation or whole body aerosol inhalation. The authors did not detect the TiO 2 NPs in the blood at 24 h or 7 days post exposure. "
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    ABSTRACT: Titanium dioxide nanoparticles (TiO2 NPs) have found many practical applications in industry and daily life. A widespread application of TiO2 NPs rises the question about safety of their use in the context of potential occupational, environmental and intentional exposure of humans and biota. TiO2 NPs easily enter the body through inhalation, cross blood-brain barrier and accumulate in the brain, especially in the cortex and hippocampus. Toxicity of these NPs and the molecular mechanisms of their action have been studied extensively in recent years. Studies showed that TiO2 NPs exposure resulted in microglia activation, reactive oxygen species production, activation of signaling pathways involved in inflammation and cell death, both in vitro and in vivo. Consequently, such action led to neuroinflammation, further brain injury. A, spatial recognition memory and locomotor activity impairment has been also observed. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Apr 2015 · Toxicology in Vitro
    • "For intratracheal instillation, one could assume the total bolus reaches the lungs, but in nose-only or whole-body chamber inhalation, the internal dose in the lungs should be measured. It should be noted that high dose rate methods such as intratracheal instillation, elicit significantly greater inflammation compared to low dose rate delivery such as nose-only or whole-body inhalation (Baisch et al., 2014). In the present study, based on the exposure concentration, surface area does bring the dose-response curves of the different particle sizes more towards each other, but the alveolar dose gives almost completely overlapping dose–response curves when surface area as a dose metric is used (Figure 7), showing the importance of using the alveolar dose instead of the external exposure concentrations. "
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    ABSTRACT: A number of studies have shown that induction of pulmonary toxicity by nanoparticles of the same chemical composition depends on particle size, which is likely in part due to differences in lung deposition. Particle size mostly determines whether nanoparticles reach the alveoli, and where they might induce toxicity. For the risk assessment of nanomaterials, there is need for a suitable dose metric that accounts for differences in effects between different sized nanoparticles of the same chemical composition. The aim of the present study is to determine the most suitable dose metric to describe the effects of silver nanoparticles after short-term inhalation. Rats were exposed to different concentrations (ranging from 41 to 1105 µg silver/m3 air) of 18, 34, 60 and 160 nm silver particles for four consecutive days and sacrificed at 24 h and 7 days after exposure. We observed a concentration-dependent increase in pulmonary toxicity parameters like cell counts and pro-inflammatory cytokines in the bronchoalveolar lavage fluid. All results were analysed using the measured exposure concentrations in air, the measured internal dose in the lung and the estimated alveolar dose. In addition, we analysed the results based on mass, particle number and particle surface area. Our study indicates that using the particle surface area as a dose metric in the alveoli, the dose–response effects of the different silver particle sizes overlap for most pulmonary toxicity parameters. We conclude that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation.
    No preview · Article · Feb 2015 · Nanotoxicology
    • "Studies that compare inhalation versus instillation of insoluble particles have shown that clearance of instilled particles is slower than that of inhaled particles (Pritchard et al., 1985) and that biological effects may be larger for instilled particles at the same delivered dose (Baisch et al., 2014). Instillation enables screening of a large number of compounds, at a range of doses, including high doses, rapidly and delivery of a readily quantifiable, known delivered dose (Driscoll et al., 2000). "
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    ABSTRACT: The growing use of silver nanoparticles (AgNPs) in consumer products raises concerns about potential health effects. This study investigated the persistence and clearance of two different size AgNPs (20 nm and 110 nm) delivered to rats by single nose-only aerosol exposures (6 hrs) of 7.2 and 5.4 mg/m(3), respectively. Rat lung tissue was assessed for silver accumulations using ICP-MS, autometallography and enhanced dark field microscopy. Involvement of tissue macrophages was assessed by scoring of silver staining in bronchoalveolar lavage fluid (BALF). Silver was abundant in most macrophages at 1 day post-exposure. The group exposed to 20 nm AgNP had the greatest number of silver positive BALF macrophages at 56 days post-exposure. While there was a significant decrease in the amount of silver in lung tissue at 56 days post-exposure compared to 1 day following exposure, at least 33% of the initial delivered dose was still present for both AgNPs. Regardless of particle size, silver was predominantly localized within the terminal bronchial/alveolar duct junction region of the lung associated with extracellular matrix and within epithelial cells. Inhalation of both 20nm and 110nm AgNPs resulted in a persistence of silver in the lung at 56 days post-exposure and local deposition as well as accumulation of silver at the terminal bronchiole alveolar duct junction. Further the smaller particles, 20nm AgNP, produced a greater silver burden in BALF macrophages as well as greater persistence of silver positive macrophages at later timepoints (21 and 56 days). © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email:
    No preview · Article · Jan 2015 · Toxicological Sciences
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