Time-course comparison of pulmonary inflammation induced by intratracheal instillation of four different nickel oxide nanoparticles in male Fischer rats

Abstract

Occupational exposure to nickel oxide (NiO) is an important cause of respiratory tract cancer. Toxicity is known to be associated with the dissociated component, i.e. nickel (II) ions. To address the relationship between physicochemical properties, including solubility in artificial lysosomal fluid, of NiO and time-course changes in the pulmonary response, we conducted an intratracheal instillation study in male Fischer rats using four different well-characterized NiO products, US3352 (NiO A), NovaWireNi01 (NiO B), I small particle (NiO C), and 637130 (NiO D). The NiOs were suspended in purified water and instilled once intratracheally into male F344 rats (12 weeks old) at 0 (vehicle control), 0.67, 2, and 6 mg/kg body weight. The animals were euthanized on days 3, 28, or 91 after instillation, and blood analysis, bronchoalveolar lavage fluid (BALF) testing, and histopathological examination were performed. The most soluble product, NiO B, caused the most severe systemic toxicity, leading to a high mortality rate, but the response was transient and surviving animals recovered. The second-most-soluble material, NiO D, and the third, NiO A, caused evident pulmonary inflammation, and the responses persisted for at least 91 days with collagen proliferation. In contrast, NiO C induced barely detectable inflammation in the BALF examination, and no marked changes were noted on histopathology. These results indicate that the early phase toxic potential of NiO products, but not the persistence of pulmonary inflammation, is associated with their solubility.

Time‐course analysis of pulmonary inflammation induced by intratracheal instillation of nanosized crystalline silica particles in F344 rats

“…MS5-a silica product that is frequently used for toxicological research (IARC, 1997;WHO, 2000)-is well known to cause biphasic inflammation, consisting of an early-stage response and later granuloma formation, in rats (Langley et al, 2004). These granulomas can be induced in rats by inhalation of or intratracheal exposure to MS5 (Langley et al, 2010;Porter, 2004;Zhang et al, 1996) Generally, pulmonary inflammation induced by intratracheal instillation is accompanied by an increase in the number of alveolar macrophages (Kobayashi et al, 2021). However, in the present study, the recruitment of macrophages did not occur in response to MS5, and SPB_C-treated-animals showed a decrease in macrophage numbers.…”

“…These decrease in SPB_C can be explained by the abovementioned macrophage toxicity, although the stable number in the MS5-derivative groups is less straightforward. Then possible inapplicability of the instrument could be raised although, we believe that the measurement methods were reliable because (1) the instrument was the same as that used in our previous report examining NiO, in which an increased macrophage number was observed (Kobayashi et al, 2021); (2) the outcomes of the BALF lactate dehydrogenase activity, which indicate general cytotoxicity, showed similar trend to the total cell number in BALF (Figure S3); and (3) unusual appearance of the BALF cytology was not detected at the cell differentiation using Giemsa-stained slides.…”

“…Generally, pulmonary inflammation induced by intratracheal instillation is accompanied by an increase in the number of alveolar macrophages (Kobayashi et al, 2021). However, in the present study, the recruitment of macrophages did not occur in response to MS5, and SPB_C‐treated‐animals showed a decrease in macrophage numbers.…”

“…However, these novel physicochemical properties can cause unexpected health hazards; therefore, numerous studies have been conducted to investigate the relationships between physicochemical properties and hazard potential (Cho et al, 2013; Oberdörster et al, 2005). Previously, we reported the relationship between the physicochemical properties and the hazard potentials induced by intratracheal instillation of seven types of titanium dioxide (Hashizume et al, 2016; Shinohara et al, 2014) and four types of nickel oxide (Kobayashi et al, 2021; Shinohara et al, 2017). Briefly, acute pulmonary inflammation was revealed to be associated with the particle size or surface coating of titanium dioxide (Hashizume et al, 2016), whereas inflammatory responses induced by nickel oxide were thought to be associated with its solubility (Kobayashi et al, 2021).…”

Acute Toxicity in the Rat Lung Induced by Intratracheal Instillation of Glycolic Acid

“…It has recently been reported that the intratracheal instillation test can be useful for acidic compounds that are difficult to test with the inhalation test (30). In addition, many studies on the toxic effects of nanomaterials using intratracheal instillation have been published (31)(32)(33). One study reported that the intratracheal instillation experiment can be used to rank the harmfulness of nanomaterials (34).…”