Usefulness of Intratracheal Instillation Studies for Estimating Nanoparticle-Induced Pulmonary Toxicity

Abstract

Inhalation studies are the gold standard for the estimation of the harmful effects of respirable chemical substances, while there is limited evidence of the harmful effects of chemical substances by intratracheal instillation. We reviewed the effectiveness of intratracheal instillation studies for estimating the hazards of nanoparticles, mainly using papers in which both inhalation and intratracheal instillation studies were performed using the same nanoparticles. Compared to inhalation studies, there is a tendency in intratracheal instillation studies that pulmonary inflammation lasted longer in the lungs. A difference in pulmonary inflammation between high and low toxicity nanoparticles was observed in the intratracheal instillation studies, as in the inhalation studies. Among the endpoints of pulmonary toxicity, the kinetics of neutrophil counts, percentage of neutrophils, and chemokines for neutrophils and macrophages, heme oxygenase-1 (HO-1) in bronchoalveolar lavage fluid (BALF), reflected pulmonary inflammation, suggesting that these markers may be considered the predictive markers of pulmonary toxicity in both types of study. When comparing pulmonary inflammation between intratracheal instillation and inhalation studies under the same initial lung burden, there is a tendency that the inflammatory response following the intratracheal instillation of nanoparticles is greater than or equal to that following the inhalation of nanoparticles. If the difference in clearance in both studies is not large, the estimations of pulmonary toxicity are close. We suggest that intratracheal instillation studies can be useful for ranking the hazard of nanoparticles through pulmonary inflammation.

A 104-week pulmonary toxicity assessment of long and short single-wall carbon nanotubes after a single intratracheal instillation in rats

“…As shown in the TEM images, a considerable amount of SWCNTs remained in the rat lungs, suggesting that an overload of the materials might have occurred to some extent. It has been said that one should be careful to avoid overly high dosages, which might give rise to artificial biological effects (Morimoto et al, 2016).…”

The curious case of how mimicking physiological complexity in in vitro models of the human respiratory system influences the inflammatory responses. A preliminary study focused on gold nanoparticles

“…Such inflammatory mechanisms have been thoroughly investigated and elucidated. To date, it is commonly accepted that the NPs physico-chemical properties (such as composition, size, surface charge, and agglomeration) (Braakhuis, Park, Gosens, De Jong, & Cassee, 2014;Kim et al, 2016;Kreyling, Semmler-Behnke, Takenaka, & Moller, 2013;Madl, Plummer, Carosino, & Pinkerton, 2014;Rotoli et al, 2015), as well as the timing (acute vs. chronic) and route (e.g., intratracheal or intranasal) of administration (Landsiedel, Sauer, Ma-Hock, Schnekenburger, & Wiemann, 2014;Morimoto et al, 2016), strongly influence the lung inflammatory response to NPs (Mohamud et al, 2014). Most of these paradigms have been extrapolated from the data originating from animal studies, which are widely used for evaluating inflammatory responses in inhalation toxicology studies.…”

“…In addition, there are significant differences in the distribution of epithelial cell populations along the respiratory tract and in the histology of the connective The curious case of in vitro complexity Dania Movia et al tissue. Finally, although intratracheal instillation is widely accepted as a useful method of animal exposure in nanosafety research Morimoto et al, 2016), it produces a NPs lung deposition that is heterogeneous and far from physiological (Oberdorster, 2010). Lung inflammation is indeed affected by the architecture of the respiratory system and by NPs deposition pattern.…”

Comparison of the local pulmonary distribution of nanoparticles administered intratracheally to rats via gavage needle or microsprayer delivery devices

“…As applications for nanoparticles (NPs) continue to spread across fields, concerns about their safety have been raised. Intratracheal administration methods have been used for the toxicological assessment of inhaled NPs (Driscoll et al, 2000;Morimoto et al, 2016). These methods include gavage needles ( Jacobsen et al, 2015;Yoshiura et al, 2015) and microsprayers (Shinohara et al, 2014;Tada et al, 2013).…”