Update on carbon nanotube toxicity

Abstract

NanomedicineVol. 4, No. 4 EditorialFree AccessUpdate on carbon nanotube toxicityPetia P SimeonovaPetia P SimeonovaToxicology & Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety & Health, Centers for Disease Control & Prevention, Morgantown, WV 26505, USA. Search for more papers by this authorEmail the corresponding author at phs9@cdc.govPublished Online:8 Jun 2009https://doi.org/10.2217/nnm.09.25AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail In the last several years, significant attention has been paid to the potential toxicity of tiny, but nonetheless interesting, carbon nanotubes (CNTs). These are graphite sheets rolled to form either a seamless cylinder, called single-walled CNTs (SWCNTs), or many cylinders stacked one inside the other, known as multiwalled CNTs (MWCNTs). Their lengths can range from several hundred nanometers to several micrometers, but their diameters can only be less than 100 nm. The organized structure of CNTs along with their high-aspect ratio, large surface area, ultra-light weight, metallic or semi-metallic behavior, high mechanical strength and high electrical conductivity make them extremely attractive for diverse manufacturing purposes. In the biomedical field, for example, CNTs provide novel opportunities for imaging and therapy with high performance and efficacy. However, the unique characteristics of CNTs also raise alarms about their possibly damaging health effects, as both the small size and large surface area of inhaled particles are important determinants of potential pulmonary toxicity.Concerns over potential CNT occupational exposure have been increased after adverse effects related to lung CNT deposition have been found in animal studies [1]. These studies demonstrated acute pulmonary inflammation and chronic pulmonary responses, manifested by biopersistence, granuloma formation around larger agglomerates and fibrotic responses associated with both granulomas and more dispersed materials. Recently, these reports were extended by findings of potential carcinogenic effects. MWCNT respiratory exposure was associated with clastogenicity and aneugenicity in rats as well as in vitro[2] and SWCNT inhalation exposure was associated with induction of K-ras lung mutations in mice [3]. Furthermore, exposing the mesothelial lining of the body cavity of mice, as a surrogate for the mesothelial lining of the human chest cavity, to long MWCNTs resulted in length-dependent, pathogenic inflammatory responses, similar to these induced by asbestos fibers known to play a role in development of pleural mesothelioma [4]. Long-term studies, using various animal models and human-relevant exposure paradigms, are necessary to determine whether CNTs may be a pathogenic factor for progressive diseases such as chronic obstructive pulmonary disease, lung cancer and pleural mesothelioma.The toxicological data on CNT respiratory exposure also suggested the need for complex evaluation of systemic effects, such as cardiovascular, neurologic and immunologic toxicity. The lung insult by multiple mechanisms including inflammatory and neuroreflex reactions, altered pulmonary function or particle distribution through the body, can trigger systemic adverse outcomes. In this respect, our laboratory demonstrated that SWCNT-related pulmonary response was associated with adverse cardiovascular effects including distressed aortic mitochondrial homeostasis, a prerequisite of vascular dysfunction in wild-type mice, and accelerated atherogenesis in ApoE-/- mice, a model of atherosclerosis [5]. Furthermore, following MWCNT-induced lung inflammation, an acute systemic prothrombotic response occurs which may well contribute to an adverse cardiovascular outcome [6]. The nanoparticle toxicology hypothesis emphasizes the likelihood for CNTs to translocate from the lung into the systemic circulation or CNS and induce direct effects. Although there has been extensive attempts to evaluate the biodistribution of CNTs after respiratory exposure using different labeling techniques, there are no published results as yet to support this paradigm.Toxicology studies further suggested that, in addition to the nano-dimensions of CNTs, many other factors may play a role in their toxicity. CNTs are mainly synthesized by catalytic arc discharge, chemical vapor deposition or laser ablation. Therefore, raw nanotubes usually contain significant impurities, such as metal catalysts, which have been shown to contribute to increased toxicity through induction of oxidative stress (reviwed in [1]). Alternatively, purification procedures, such as oxidation, will eliminate the impurities but can result in some imperfections of the carbon framework. Surface defects have been shown to govern some CNT toxic effects [7]. Nanotubes also have a strong tendency for aggregation and the toxicity of the CNT is dependent on the aggregation state. Contrarily, functionalization of CNT by covalent or noncovalent methods helps to disperse and water-solubilize the tubes and appears to reduce their toxicity [8].While potential occupational or environmental human exposure may include exposure to nonfunctionalized CNTs with different degrees of purification, dispersion and characterization, biomedical applications will be associated with the use of well-functionalized and standardized materials. Before any clinical use, these materials will have extensive preclinical evaluation of their pharmacological and toxicological behavior. The first animal studies on chemically functionalized CNTs (f-CNTs) demonstrated that these f-CNTs injected intravenously into animals are cleared rapidly, mainly through the renal route without obvious tissue deposition and damage (reviewed in [9]). SWCNTs covered noncovalently by phospholipids bearing long and more branched polyethylene glycol result in longer blood circulation times and lower uptake by the reticuloedothelial system, desired features for targeted imaging or therapeutic applications [10]. Instead of labeling techniques which carry the risk of gradual dissociation from the materials, the authors used Raman spectroscopy and Raman imaging to probe the biodistribution of SWCNTs in various organs of mice ex vivo over a period of several months. The tubes were cleared mainly by the biliary excretion pathway with a minor contribution by the renal excretion pathway and, incidentally, did not cause obvious side effects in mice. Histology and Raman microscopic mapping demonstrated that polyethylene glycol–f-CNTs persisted within the liver and spleen macrophages for 4 months [11]. Further tests with a larger number of animals and various methods for evaluation of toxicity will provide a more detailed assessment of the safety of the f-CNT biomedical applications.In parallel with standard toxicological approaches, the use of novel methods such as gene-expression profiling, global to identify multiple gene signatures or focused to identify specific pathophysiology-relevant molecular pathways, can be very informative. In addition to many disease evaluations, gene-expression studies in blood have been applied in environmental and drug exposure assessments to identify ‘exposure-induced gene-expression profiles’. Using the specific hypothesis-driven approach of gene expression in whole blood cells together with multiple protein profiling from blood, our laboratory indicated blood gene/protein patterns which closely reflect the CNT-induced lung and systemic toxicity related to cardiovascular outcomes [12]. The combination of gene expression and protein profiling from blood provides insight into the mechanisms of CNT toxicity and advances the characterization of biomarkers with potential applications in human clinical and epidemiological screenings.The crossover of knowledge and methodological approaches between the toxicological, pharmacological and chemical sciences will contribute to the evaluation of the risks, benefits and opportunities for the production of safe carbon nanomaterials. Accordingly, it has been demonstrated in pharmacological studies that imaging techniques based on the intrinsic properties of materials, such as Raman imaging [10] or near-infrared fluorescence of dispersed CNTs [13], are sensitive and reliable methods for nanotube detection. These methods may also be applied to the tracking of CNTs in the body following inhalation exposure. The hints of potential carcinogenic effects in the lung and systemic effects, such as cardiovascular effects related to atherosclerosis, as a result of CNT respiratory exposure can direct more focused and rigorous assessment of the long-term effects of CNT biomedical applications. Characterizing the role of CNT physicochemical features, such as length, defects and dispersion, during the development of toxicity will provide information for optimization of CNT production towards safe and technologically efficient materials. The current state of CNT toxicology promises a timely development of science-based regulation of carbon nanomaterial production and their applications.DisclaimerThe findings and conclusions in this report are those of the author and do not necessarily represent the views of the National Institute for Occupational Safety and Health.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Donaldson K, Aitken R, Tran L et al.: Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety. Toxicol. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download