Assessment of cyclohexanone toxicity in inhalation-exposed F344 rats and B6C3F1 mice: applications in occupational health.

BACKGROUND: Cyclohexanone is a chemical used in various industries and many workers are exposed to it. Therefore, in this study, we determined the toxicity of cyclohexanone in inhalation-exposed F344 rats and B6C3F1 mice, so as to apply the findings in hazard and risk assessments. METHODS: Ten male and 10 female rats and mice per test group were exposed to cyclohexanone vapors at 0, 100, 250, and 625 ppm concentrations for 6 h per day, 5 d per week, and for 13 weeks. All rats and mice were killed after the exposure period. Clinical signs, body weight, feed intake, and ophthalmoscopy findings were recorded during the exposure period, and hematology, blood biochemistry, organ weights, gross findings, and histopathology were evaluated thereafter. RESULTS: The following findings were noted in cyclohexanone-exposed F344 rats: increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increased liver weight, and bile duct hyperplasia in the males exposed to 250 and 625 ppm cyclohexanone, increased ALT levels and bile duct hyperplasia in the females exposed to 625 ppm cyclohexanone, and increased blood urea nitrogen (BUN) and tubular basophilia in the renal cortex in the males exposed to 625 ppm cyclohexanone. On the other hand, B6C3F1 mice exposed to cyclohexanone showed no obvious exposure-related effects. CONCLUSION: Based on the findings, the no-observed-adverse-effect level (NOAEL) was determined to be 100 ppm in F344 rats and >625 ppm in B6C3F1 mice. Therefore, 2 ppm was revealed as the derived no-effect level (DNEL) for cyclohexanone.

Reactive oxygen species by isoflurane mediates inhibition of nuclear factor κB activation in lipopolysaccharide-induced acute inflammation of the lung.

BACKGROUND: Although anesthetic-induced inhibition of lipopolysaccharide (LPS)-induced lung injury has been recognized, the underlying mechanism is obscure. Some studies suggest that reactive oxygen species (ROS) by isoflurane play a crucial role for anesthetic-induced protective effects on the brain or the heart; however, it still remains controversial. In this study, we examined the role of isoflurane-derived ROS in isoflurane-induced inhibition of lung injury and nuclear factor κB (NFκB) activation in LPS-challenged rat lungs. METHODS: Male Sprague-Dawley rats were subjected to inhalation of 1.0 minimum alveolar concentration of isoflurane for 60 minutes, and intratracheal LPS 0.1 mg was administered 60 minutes later. In some cases, ROS scavenger, 2-mercaptopropinyl glycine or N-acetylcysteine was given 30 minutes before isoflurane. ROS generation was measured by fluorometer before LPS challenge and 4 hours after. Isoflurane's preconditioning effect was assessed by histologic examination, protein content, neutrophil recruitment, and determination of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels in bronchoalveolar lavage fluid and lung tissue. Western blotting measured phosphorylation of inhibitory κB α (ser 32/36), NFκB p65, and inducible nitric oxide synthase (iNOS). TNF-α and IL-6 mRNA expression and immunofluorescence staining for iNOS were also assessed. RESULTS: Isoflurane preconditioning reduced inflammatory lung injury and TNF-α, IL-1ß, and IL-6 release in the lung. Isoflurane upregulated ROS generation before LPS but inhibited a ROS burst after LPS challenge. ROS scavenger administration before isoflurane abolished the isoflurane preconditioning effect as well as isoflurane-induced inhibition of phosphorylation of inhibitory κBα, NFκB p65, iNOS activation, and mRNA expression of TNF-α and IL-6 in acute LPS-challenged lungs. CONCLUSIONS: This study suggests a crucial role of upregulated ROS generation by isoflurane for modification of inflammatory pathways by isoflurane preconditioning in acute inflammation of the lung.

Twenty-Eight-Day Repeated Inhalation Toxicity Study of Aluminum Oxide Nanoparticles in Male Sprague-Dawley Rats.

Aluminum oxide nanoparticles (Al2O3 NPs) are among the most widely used nanomaterials; however, relatively little information about their risk identification and assessment is available. In the present study, we aimed to investigate the potential toxicity of Al2O3 NPs following repeated inhalation exposure in male Sprague-Dawley rats. Rats were exposed to Al2O3 NPs for 28 days (5 days/week) at doses of 0, 0.2, 1, and 5 mg/m3 using a nose-only inhalation system. During the experimental period, we evaluated the clinical signs, body weight change, hematological and serum biochemical parameters, necropsy findings, organ weight, and histopathology findings. Additionally, we analyzed the bronchoalveolar lavage fluid (BALF), including differential leukocyte counts, and aluminum contents in the major organs and blood. Aluminum contents were the highest in lung tissues and showed a dose-dependent relationship in the exposure group. Histopathology showed alveolar macrophage accumulation in the lungs of rats in the 5 mg/m3 group during exposure and recovery. These changes tended to increase at the end of the recovery period. In the BALF analysis, total cell and neutrophil counts and lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels significantly increased in the 1 and 5 mg/m3 groups during exposure. Under the present experimental conditions, we suggested that the no-observed-adverse-effect level of Al2O3 NPs in male rats was 1 mg/m3, and the target organ was the lung.