Abstract
BackgroundA very pure multi-walled carbon nanotube (MWCNT) that was shown to have very low toxicity in vitro, was evaluated for lung and systemic effects and distribution following inhalation exposure.MethodsB6C3F1/N mice were exposed to varying doses (0, 0.06, 0.2, and 0.6 mg/m3) of the (99.1% carbon) MWCNT by inhalation for 30 days (excluding weekends). Ten days following the last exposure, the lungs and spleen were harvested and processed for histology and immune cell population assessment. In addition, lung lavage cells and fluid were analyzed. Stimulated Raman scattering (SRS) was used to identify particles in the lungs, spleen, kidneys, liver, mediastinal and brachial lymph nodes, and olfactory bulb. Splenic tissue sections were stained with hematoxylin and eosin (H&E) for light microscopic histopathology assessment. Blood plasma was analyzed for cytokines and cathepsins. A section of the spleen was processed for RNA isolation and relative gene expression for 84 inflammation-related cytokines/chemokines.ResultsFollowing MWCNT exposure, particles were clearly evident in the lungs, spleens, lymph nodes and olfactory bulbs, (but not livers or kidneys) of exposed mice in a dose-dependent manner. Examination of the lavaged lung cells was unremarkable with no significant inflammation indicated at all particle doses. In contrast, histological examination of the spleen indicated the presence of apoptotic bodies within T cells regions of the white pulp area. Isolated splenic leukocytes had significant changes in various cells including an increased number of proinflammatory CD11b+Ly6C+ splenic cells. The gene expression studies confirmed this observation as several inflammation-related genes were upregulated particularly in the high dose exposure (0.6 mg/m3). Blood plasma evaluations showed a systemic down-regulation of inflammatory cytokines and a dose-dependent up-regulation of lysosomal cathepsins.ConclusionsThe findings in the lungs were consistent with our hypothesis that this MWCNT exposure would result in minimal lung inflammation and injury. However, the low toxicity of the MWCNT to lung macrophages may have contributed to enhanced migration of the MWCNT to the spleen through the lymph nodes, resulting in splenic toxicity and systemic changes in inflammatory mediators.
Highlights
A very pure multi-walled carbon nanotube (MWCNT) that was shown to have very low toxicity in vitro, was evaluated for lung and systemic effects and distribution following inhalation exposure
Lung MWCNT in the lung following exposures Based on previous work and published observations [10], it was expected that prolonged inhalation exposures to MWCNT would lead to detectable particle deposition in the lung that would be retained long-term
Alveolar macrophages (AM) retrieved from the lung lavage fluid (LLF) of the various dose groups were examined for MWCNT particle content using side scatter (SSC) (Fig. 2a)
Summary
A very pure multi-walled carbon nanotube (MWCNT) that was shown to have very low toxicity in vitro, was evaluated for lung and systemic effects and distribution following inhalation exposure. Many of these have been discussed before [3], but a few challenges include but not limited to: 1) selecting from a wide assortment of MWCNT (e.g., length, width, and presence of metal contaminants) in the market; 2) determining what model system to use (in vitro what cells and in vivo what species and strains); 3) choosing what dose(s) to test and what in vivo exposure method to use (instillation or inhalation); 4) MWCNT agglomeration in liquids or air; and 5) selecting what responses/endpoints to evaluate. Models, doses and endpoints, conclusions about the potential health risks from MWCNT exposures could range from benign to severe
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