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

Abstract

BackgroundThe 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.MethodsF-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.ResultsAlthough 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.ConclusionsHigh 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.

Titán-dioxid nanorészecskék szubakut légúti adagolásával kiváltott elektrofiziológiai eltérések és általános toxicitás patkányban

“…According to the measured tissue Ti levels, most of the amount applied remained in the lungs but the load measured in the brain and other organ samples was also considerably higher than in the rats without nano-TiO 2 exposure. The high degree of deposition of TiO 2 NPs in the lungs was in similar to the observation in 7 that a single amount instilled in the trachea of rats was completely retained in the lungs for 7 days.…”

“…In some experiments, access of TiO 2 NPs to the rat brain after application to the airways was verified, together with damage to the blood-brain barrier 6 ; the same authors also reported dose-and time-dependent toxicity of the identical TiO 2 NPs on rat astrocytes in vitro. Others, however, found that most of the nano-TiO 2 remained in the lungs 7 . Functional alterations, possibly resulting from access of TiO 2 NPs to the brain, have been described at the level of electrophysiological changes only a few times up to now.…”

Toward achieving harmonization in a nanocytotoxicity assay measurement through an interlaboratory comparison study

“…8). Figure 8B shows there is less than 5% variability between pipette volumes within a pipette step over all rounds performed no effect in the lungs of the rats (Baisch et al, 2014). Further studies may be required to clarify which physiologically relevant parameters of an in vivo system are captured in actual in vitro experiments.…”

Biokinetics of engineered nano-TiO2 in rats administered by different exposure routes: implications for human health

“…These factors have had a significant impact in vitro (DeLoid et al, 2015(DeLoid et al, , 2017Pal et al, 2015;Watson et al, 2016). More recent comparative work has shown that IT dose rate and mode of administration impact considerably the study outcomes (Baisch et al, 2014;Silva et al, 2014). What effects did such dispersions have during their subsequent use in IT and IV applications?…”