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: 6.99). 01/2014; 11(1):5. DOI: 10.1186/1743-8977-11-5
Source: PubMed

ABSTRACT 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 · 3.21 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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    Archive für Toxikologie 10/2014; 88(11). DOI:10.1007/s00204-014-1349-9 · 5.08 Impact Factor
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    • "Interestingly, Guadagnin et al. (2013), measuring the inflammatory markers GM-CSF, IL-6, IL-8 and IL-1b (determined by mRNA activity), reported the opposite, with bronchial epithelial cells generally being more sensitive than A549 cells following treatment with non-cytotoxic concentrations of P25 Evonik nano-TiO 2 ($70/30 anatase:rutile mix). Recently, Baisch et al. (2014) reported that an acute inflammatory response in F-344 rats, following intratracheal instillation with 25 nm predominantly anatase nano-TiO 2 , was driven primarily by MCP-1 in the lung. Increased MCP-1 production is observed in chronic pulmonary diseases such allergic asthma, bronchiolitis obliterans syndrome and idiopathic pulmonary fibrosis (Alam et al., 1996; Belperio, 2001; Inoshima, 2003); in this study, the 20% downward trend in its release 24 h post-treatment, suggests that the TT1 cellular response to nano- TiO 2 might be limited to an acute inflammatory response which could favour alveolar repair. "
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    ABSTRACT: Abstract There can be significant variability between bioreactivity studies of nanomaterials that are apparently the same, possibly reflecting differences in the models used and differing sources of experimental material. In this study, we have generated two crystal forms of titanium dioxide nanoparticles (nano-TiO2), pure anatase and pure rutile to address the hypothesis that the bioreactivity of these nanoparticles with human alveolar epithelium will depend on their crystal phase. We used a human alveolar type-I-like epithelial cell model (TT1; generated in-house from primary human alveolar epithelial type II cells); these cells cover 95% of the alveolar epithelial surface area and are an important target cell for inhaled nanomaterials. Using literature as a guide, we hypothesised that pure anatase nano-TiO2 would display greater bioreactivity with TT1 cells in comparison to pure rutile nano-TiO2. However, we found the profile and pattern of inflammatory mediator release was similar between these two nano-TiO2 formats, although pure rutile treatment caused a small, but consistently greater, response for IL-6, IL-8 and MCP-1. Interestingly, the temporal induction of oxidative stress (increased reactive oxygen species levels and depleted glutathione) varied markedly between the different nano-TiO2 formats. We have shown that a combination of using nanomaterials synthesised specifically for toxicological study and the use of a highly relevant, reproducible human lung cell model, offers a useful approach to delineating the physicochemical properties of nanomaterials that may be important in their cellular reactivity.
    Nanotoxicology 08/2014; 9(4):1-11. DOI:10.3109/17435390.2014.948518 · 7.34 Impact Factor
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