Inhalation exposure to multi-walled carbon nanotubes alters the pulmonary allergic response of mice to house dust mite allergen.

Background: Increasing evidence from rodent studies indicates that inhaled multi-walled carbon nanotubes (MWCNTs) have harmful effects on the lungs. In this study, we examined the effects of inhalation exposure to MWCNTs on allergen-induced airway inflammation and fibrosis. We hypothesized that inhalation pre-exposure to MWCNTs would render mice susceptible to developing allergic lung disease induced by house dust mite (HDM) allergen. Methods: Male B6C3F1/N mice were exposed by whole-body inhalation for 6 h a day, 5 d a week, for 30 d to air control or 0.06, 0.2, and 0.6 mg/m3 of MWCNTs. The exposure atmospheres were agglomerates (1.4-1.8 µm) composed of MWCNTs (average diameter 16 nm; average length 2.4 µm; 0.52% Ni). Mice then received 25 µg of HDM extract by intranasal instillation 6 times over 3 weeks. Necropsy was performed at 3 and 30 d after the final HDM dose to collect serum, bronchoalveolar lavage fluid (BALF), and lung tissue for histopathology. Results: MWCNT exposure at the highest dose inhibited HDM-induced serum IgE levels, IL-13 protein levels in BALF, and airway mucus production. However, perivascular and peribronchiolar inflammatory lesions were observed in the lungs of mice at 3 d with MWCNT and HDM, but not MWCNT or HDM alone. Moreover, combined HDM and MWCNT exposure increased airway fibrosis in the lungs of mice. Conclusions: Inhalation pre-exposure to MWCNTs inhibited HDM-induced TH2 immune responses, yet this combined exposure resulted in vascular inflammation and airway fibrosis, indicating that MWCNT pre-exposure alters the immune response to allergens.

Evaluation of the respiratory tract toxicity of ortho-phthalaldehyde, a proposed alternative for the chemical disinfectant glutaraldehyde.

ortho-Phthalaldehyde (OPA) is a high-level chemical disinfectant that is commonly used for chemical sterilization of dental and medical instruments as an alternative to glutaraldehyde, a known skin and respiratory sensitizer. Concern for safe levels of human exposure remains due to a lack of toxicity data as well as human case reports of skin and respiratory sensitization following OPA exposure. The present study evaluated the inhalational toxicity of OPA in Harlan Sprague-Dawley rats and B6C3F1/N mice. Groups of 10 male and female rats and mice were exposed to OPA by whole-body inhalation for 3 months at concentrations of 0 (control), 0.44, 0.88, 1.75, 3.5, or 7.0 ppm. Rats and mice developed a spectrum of lesions at sites of contact throughout the respiratory tract (nose, larynx, trachea, lung), as well as in the skin and eye, consistent with a severe irritant response. In general, histologic lesions (necrosis, inflammation, regeneration, hyperplasia and metaplasia) occurred at deeper sites within the respiratory tract with increasing exposure concentration. As a first site of contact, the nose exhibited the greatest response to OPA exposure and resulted in an increased incidence, severity and variety of lesions compared to a previous study of glutaraldehyde exposure at similar exposure concentrations. This increased response in the nasal cavity, combined with extensive lesions throughout the respiratory tract, provides concern for use of OPA as a replacement for glutaraldehyde as a high-level disinfectant.

Lung deposition and clearance of microparticle and nanoparticle C60 fullerene aggregates in B6C3F1 mice and Wistar Han rats following nose-only inhalation for 13 weeks.

C60 fullerenes (C60) are spherical structures consisting of 60 carbon atoms that are generated via combustion from both natural and anthropogenic sources. C60 are also synthesized intentionally for industrial applications. Individual C60 structures have an approximate diameter of 1nm; however, C60 readily forms aggregates and typically exist as larger particles that range from nanometers to micrometers in diameter. In this report, lung and extrapulmonary tissue deposition and lung clearance of C60 nanoparticles (nano-C60, 50nm) and microparticles (micro-C60, 1µm) were examined in Wistar Han rats and B6C3F1/N mice after nose-only inhalation for 90 days. Exposure concentrations were 0.5 and 2mg/m(3) (nano-C60) and 2, 15, and 30mg/m(3) (micro-C60). For both C60 particle sizes, the C60 lung burden increased proportionally to exposure concentration. The C60 lung burden was greater in both species at all time points following exposure to nano-C60 particle exposure compared to micro-C60 exposure at the common exposure concentration 2mg/m(3). The calculated C60 particle lung retention half-times were similar for both nano-C60 and micro-C60 exposure at 2mg/m(3) in male mice (15-16 days). In contrast, in male rats, the half-time of C60 particles following nano-C60 exposure (61 days) was roughly twice as long as the half-time following micro-C60 exposure (27 days) at the same exposure concentration (2mg/m(3)) and was similar to the clearance following micro-C60 exposure at higher exposure concentrations (15 and 30mg/m(3)). C60 was detected in bronchial lymph nodes but the burden was not quantified due to the high variability in the data. C60 concentrations were below the experimental limit of quantitation (ELOQ) in liver, spleen, blood, brain and kidney tissues. These tissue burden data provide information for comparison between nanometer and micrometer sized C60 particle exposure and will aid in the interpretation of toxicity data.

Comparative toxicity and carcinogenicity of soluble and insoluble cobalt compounds.

Occupational exposure to cobalt is of widespread concern due to its use in a variety of industrial processes and the occurrence of occupational disease. Due to the lack of toxicity and carcinogenicity data following exposure to cobalt, and questions regarding bioavailability following exposure to different forms of cobalt, the NTP conducted two chronic inhalation exposure studies in rats and mice, one on soluble cobalt sulfate heptahydrate, and a more recent study on insoluble cobalt metal. Herein, we compare and contrast the toxicity profiles following whole-body inhalation exposures to these two forms of cobalt. In general, both forms were genotoxic in the Salmonella T98 strain in the absence of effects on micronuclei. The major sites of toxicity and carcinogenicity in both chronic inhalation studies were the respiratory tract in rats and mice, and the adrenal gland in rats. In addition, there were distinct sites of toxicity and carcinogenicity noted following exposure to cobalt metal. In rats, carcinogenicity was observed in the blood, and pancreas, and toxicity was observed in the testes of rats and mice. Taken together, these findings suggest that both forms of cobalt, soluble and insoluble, appear to be multi-site rodent carcinogens following inhalation exposure.