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.
    Toxicology in Vitro 04/2015; 29(5). DOI:10.1016/j.tiv.2015.04.004 · 2.90 Impact Factor
    • "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.
    Nanotoxicology 02/2015; DOI:10.3109/17435390.2015.1012184 · 6.41 Impact Factor
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    • "After single intratracheal instillation of 0.15, 0.5, 1.3, 5, and 7 mg/ kg in male Sprague–Dawley rats, Ceria caused concentration-dependent alveolar macrophage functional change, significant lung inflammation, and cytotoxicity, indicating a potential shift from a proinflammatory environment to final pulmonary fibrosis (Ma et al. 2011). However, instillation studies usually have a bolus of high dose and high dose rate in the lung and are therefore less suitable to determine the exposure concentrations, biokinetics, and biological effects toward the design of a long-term inhalation study (Baisch et al. 2014). The majority of the published studies indicate an inflammatory potential of Ceria but lack appropriate dose metrics and biokinetic information (Cassee et al. 2011; Becker et al. 2011). "
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    ABSTRACT: Two Ceria nanomaterials (NM-211 and NM-212) were tested for inhalation toxicity and organ burdens in order to design a chronic and carcinogenicity inhalation study (OECD TG No. 453). Rats inhaled aerosol concentrations of 0.5, 5, and 25 mg/m(3) by whole-body exposure for 6 h/day on 5 consecutive days for 1 or 4 weeks with a post-exposure period of 24 or 129 days, respectively. Lungs were examined by bronchoalveolar lavage and histopathology. Inhaled Ceria is deposited in the lung and cleared with a half-time of 40 days; at aerosol concentrations higher than 0.5 mg/m(3), this clearance was impaired resulting in a half-time above 200 days (25 mg/m(3)). After 5 days, Ceria (>0.5 mg/m(3)) induced an early inflammatory reaction by increases of neutrophils in the lung which decreased with time, with sustained exposure, and also after the exposure was terminated (during the post-exposure period). The neutrophil number observed in bronchoalveolar lavage fluid (BALF) was decreasing and supplemented by mononuclear cells, especially macrophages which were visible in histopathology but not in BALF. Further progression to granulomatous inflammation was observed 4 weeks post-exposure. The surface area of the particles provided a dose metrics with the best correlation of the two Ceria's inflammatory responses; hence, the inflammation appears to be directed by the particle surface rather than mass or volume in the lung. Observing the time course of lung burden and inflammation, it appears that the dose rate of particle deposition drove an initial inflammatory reaction by neutrophils. The later phase (after 4 weeks) was dominated by mononuclear cells, especially macrophages. The progression toward the subsequent granulomatous reaction was driven by the duration and amount of the particles in the lung. The further progression of the biological response will be determined in the ongoing long-term study.
    Archive für Toxikologie 10/2014; 88(11). DOI:10.1007/s00204-014-1349-9 · 5.98 Impact Factor
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