Since the 2018 valsartan recall, the genotoxic impurity N-nitrosodimethylamine (NDMA) has been frequently detected in various pharmaceuticals. Matrix variability often complicates routine testing, requiring customized analyses. We developed a universal LC-MS/MS method enabling consistent NDMA detection across diverse pharmaceuticals. Separation utilized a C30 column (150 mm × 4.6 mm I.D., 5 µm), offering superior retention and shape selectivity for polar nitrosamines compared to conventional reversed phases. Unlike C18 or pentafluorophenyl phases, which often exhibit limited retention for NDMA, the C30 phase provides exceptional shape selectivity and enhanced hydrophobic interactions. This structural advantage, supplemented by its resistance to phase dewetting under highly aqueous conditions further ensures robust resolution between NDMA and complex drug matrices. The mobile phase consisted of 0.1% v/v formic acid in water and methanol under gradient elution at 1.0 mL/min. Detection used atmospheric pressure chemical ionization in positive ion mode. The method demonstrated a linear range of 2.0-100.0 ng/mL (r2 > 0.999), with a limit of detection of 1.0 ng/mL and a limit of quantification of 2.0 ng/mL. Validation per International Council for Harmonisation (ICH) guidelines confirmed accuracy (87.7%-115.5%) and precision (coefficient of variation, CV ≤ 10.7%). Application to 30 diverse pharmaceutical products, including sartans and ranitidine, showed robust resolution (> 2.0) between the analyte and active pharmaceutical ingredients (APIs). Notably, NDMA was quantified in historical batches of ranitidine (164.83 ± 5.68 ng/mL), nizatidine (10.25 ± 0.52 ng/mL), and amitriptyline (2.28 ± 0.19 ng/mL). While the histamine type 2 receptor antagonists significantly exceeded the acceptable daily intake limit, the remaining 27 products showed no detectable NDMA. These findings highlight the method's effectiveness for real-world surveillance and the critical risk of post-manufacturing NDMA generation during prolonged storage. This universal C30-based method provides a practical, reliable tool for routine screening, facilitating regulatory compliance and improved patient safety without drugspecific method development.
As the global use of light-emitting diodes (LEDs) expands, their waste management has become an increasingly important environmental issue. In the current study, potential health impacts associated with the inhalation of non-recycled LED components, particularly phosphor-dispersion encapsulation materials separated from waste LEDs, were identified. Si content was in the order of cool-white LED (CWL), natural white LED (NWL), and warm-white LED particles (WWL), and notable differences in rare-earth and alkaline-earth metals were observed between groups. When aspirated via the pharynx for 28 days (10 and 50 mu g/mL), NWL and WWL significantly reduced triglyceride levels, and the three types of LED particles accumulated in lung tissue, affecting the distribution of elements in the heart, brain, and kidneys. Compared to the control group, the three types of LED particles increased the total number of pulmonary cells. They (50 & micro;g/lung) also significantly increased pulmonary CXCL-1 and interferon-gamma levels, whereas the pulmonary macrophage chemoattractant protein-1 alpha level decreased significantly. Interestingly, the formation of lamellar bodies and tubular myelin was prominent in the lung tissues of CWL-treated mice, whereas collagen and collagen fibers were abundantly formed in the lungs of WWL-treated mice. Moreover, the lamellar body structures fused to damaged mitochondria or surrounding lamellar bodies, along with the loss of membrane integrity. Collectively, more intensive and effective recycling strategies for LED waste should be established to prevent potential adverse environmental and human health effects. Given that lamellar bodies and tubular myelin, which are potential initiators of pulmonary fibrosis, were found notably in CWL with the highest lithium content, and that lithium is a major raw material for secondary batteries, in-depth research on the relationship between inhaled lithium ions and pulmonary diseases should be conducted.
Cigarette smoke (CS) is a major risk factor for both acute and chronic diseases, predominantly impacting the lungs and cardiovascular system. Increasing evidence indicates that CS also has substantial but underappreciated effects on liver health, including accelerating the progression of alcoholic liver disease (ALD). Because smoking and alcohol consumption often co-occur in clinical populations, understanding their combined effects is important for translational research. This study aimed to elucidate the mechanisms by which CS intensifies ALD through a comprehensive assessment of histopathological changes, biochemical indices, and molecular alterations in the liver. Six-week-old male C57BL/6 mice were initially exposed to three concentrations of CS (150, 300, and 600 μg/L) or filtered air for 2 h per day, 5 days each week, and then administered ethanol to induce ALD. Exposure to CS markedly worsened alcohol-induced liver injury, as evidenced by higher serum alanine aminotransferase and aspartate transaminase activities, increased hepatic lipid accumulation, enhanced oxidative stress, and elevated inflammation. Mice subjected to both CS and ethanol displayed more pronounced hepatic injury than those exposed to either stimulus alone, suggesting an additive deleterious effect that accelerates ALD progression. Importantly, CS strongly induced hepatic cytochrome P450 enzymes, particularly CYP1A2 and CYP2E1, thereby enhancing ethanol metabolism and worsening ALD progression. This mechanistic effect provides an insight that contributes a notable element of novelty to the study. Confirmatory results were observed in ex vivo studies, where primary hepatocytes treated with various concentrations of CS extract and 100 mM ethanol showed comparable injury patterns and CYP induction. Overall, these results indicate that CS exposure exacerbates ALD development, partially through the modulation of hepatic cytochrome P450 enzyme activity.
Toll-like receptor 3 (TLR3) is classically known for mediating inflammatory pathways in Parkinson’s disease (PD). However, the role of TLR3 in nigrostriatal degeneration in PD remains unclear. Here, we observed that TLR3 is predominantly expressed on astrocytes in the substantia nigra in both human PD brain and in rat PD models induced by intra-MFB injection of 1-methyl-4-phenylpyridinium (MPP+). Interestingly, Poly I: C, an activator of TLR3, significantly induced TLR3 expression on astrocytes. Treatment with Poly I: C markedly attenuated nigral dopamine neuron death in the PD rat models. The survival of dopamine neurons was accompanied by the production of ciliary neurotrophic factor and vascular endothelial growth factor-B on astrocytes in Poly I: C-treated PD rats. The attenuation of dopamine neuron death was also observed in the Poly I: C-treated AAV2-hα-syn-A53T-induced rat PD model. Our findings suggest that activating TLR3 in astrocytes could be a potential therapeutic strategy for attenuating PD progression.
Sodium hypochlorite (NaOCl) is a biocidal substance widely used in household bleaching products and industrial applications. However, repeated, or long-term dermal exposure poses risks to human health. To address these concerns, the present study evaluated the potential dermal toxicity of sodium dodecanoyloxybenzenesulfonate (LOBS), which was developed as an alternative to NaOCl as a disinfectant and bleaching agent. This 13-week repeated dermal toxicity study was conducted in compliance with Organisation for Economic Co-operation and Development (OECD) Test Guideline 411. LOBS was administered dermally for 13 weeks and no treatment-related mortality or systemic toxicity was observed. No toxicologically meaningful changes were detected in body weight, food consumption, hematological or clinical chemistry parameters. Furthermore, no alterations were observed in organ weights, or gross and histopathological examinations of major organs. Local reactions observed at the injection site and on the skin were mild and reversible, and were not considered adverse effects related to the test substance. Based on these findings, the no observed adverse effect level for LOBS was determined to be 1000 mg/kg/day for both males and female SD rats. The results indicate that LOBS has an acceptable toxicological profile following repeated dermal exposure. Additionally, this study provides safety data supporting its use as a disinfectant and bleaching agent.
