Review of carbon nanotubes toxicity and exposure—Appraisal of human health risk assessment based on open literature

Carbon nanotubes (CNTs) possess many unique electronic and mechanical properties and are thus interesting for numerous novel industrial and biomedical applications. As the level of production and use of these materials increases, so too does the potential risk to human health. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for carbon nanotubes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Results indicate that the main risks for humans arise from chronic occupational inhalation, especially during activities involving high CNT release and uncontrolled exposure. It is not yet possible to draw definitive conclusions with regards the potential risk for long, straight multi-walled carbon nanotubes to pose a similar risk as asbestos by inducing mesothelioma. The genotoxic potential of CNTs is currently inconclusive and could be either primary or secondary. Possible systemic effects of CNTs would be either dependent on absorption and distribution of CNTs to sensitive organs or could be induced through the release of inflammatory mediators. In conclusion, gaps in the data set in relation to both exposure and hazard do not allow any definite conclusions suitable for regulatory decision-making. In order to enable a full human health risk assessment, future work should focus on the generation of reliable occupational, environmental and consumer exposure data. Data on toxicokinetics and studies investigating effects of chronic exposure under conditions relevant for human exposure should also be prioritised.     

Carbon nanotubes for biomedical imaging: The recent advances

This article reviews the latest progresses regarding the applications of carbon nanotubes (CNTs), including single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs), as multifunctional nano-probes for biomedical imaging. Utilizing the intrinsic band-gap fluorescence of semi-conducting single-walled carbon nanotubes (SWNTs), fluorescence imaging in the near infrared II (NIR-II) region with enhanced tissue penetration and spatial resolution has shown great promise in recent years. Raman imaging based on the resonance Raman scattering of SWNTs has also been explored by a number of groups for in vitro and in vivo imaging of biological samples. The strong absorbance of CNTs in the NIR region can be used for photoacoustic imaging, and their photoacoustic signals can be dramatically enhanced by adding organic dyes, or coating with gold shells. Taking advantages of metal nanoparticle impurities attached to nanotubes, CNTs can also serve as a T2-contrast agent in magnetic resonance (MR) imaging. In addition, when labeled with radioactive isotopes, many groups have developed nuclear imaging with functionalized CNTs. Therefore CNTs are unique imaging probes with great potential in biomedical multimodal imaging.     

A review of exposure and toxicological aspects of carbon nanotubes,and as additives to fire retardants in polymers

Carbon nanotubes (CNTs) have attracted considerable interest due to their unique physical, chemical, optical and electrical properties opening avenues for a large number of industrial applications. They have shown potential as fire retardant additives in polymers, reducing heat release rate and increasing time to ignition in a number of polymers. Relevant work on the types, properties and applications has been reviewed particularly considering their application in fire situations. There are concerns over the health risks associated with CNTs and many papers have likened CNTs to the health problems associated with asbestos. There are contradictions relating to the toxicity of CNTs with some papers reporting that they are toxic while others state the opposite. Directly comparing various studies is difficult because CNTs come in many combinations of size, type, purity levels and source. CNTs can potentially be released from polymers during the combustion process where human exposure may occur. While this review has shed some light regarding issues relating to toxicity under different fire scenarios much more thorough work is needed to investigate toxicity of CNTs and their evolution from CNT–polymer nanocomposites in order to reach firm conclusions.     

Challenges in the use of carbon nanotubes for biomedical applications

Carbon nanotubes (CNTs) are considered for use in numerous technological applications, including as biocompatible modules for the delivery of bioactives. However, there are unique properties of CNTs that limit their use as vehicles for various purposes. This review highlights the various challenges to a pharmaceutical scientist while exploring CNTs as bioactive delivery vehicles. The lack of solubility, nonbiodegradability, circulation half-life of 3-3.5 hours, biocompatibility, and immunogenicity limitations of CNTs are discussed in this review. These limitations indicate the need for modifications in order to explore the feasibility of CNTs as delivery vehicles.     

Mitigation of the impact of single-walled carbon nanotubes on a freshwater green algae: Pseudokirchneriella subcapitata

This study investigates the biological response of Pseudokirchneriella subcapitata to single-walled carbon nanotubes (SWNTs) suspended in gum Arabic (GA), using typical 96-hour algal bioassays and long-term growth studies. Changes in algal biomass and cell morphology associated with specific SWNT-treatments were monitored and the mechanisms of observed biological responses investigated through a combination of biochemical and spectroscopic methods. Results from short-term bioassays showed a growth inhibition in culture media containing >0.5 mg SWNT/L and a final GA concentration of 0.023% (v/v). Interestingly, the observed toxicity disappears when GA concentrations are brought to levels ≥ 0.046%. Long-term experiments based on toxic combination of SWNTs and GA showed that P. subcapitata would easily recover from an initial growth inhibition effect. Overall, these findings point to the possibility of GA to mitigate the toxicity of SWNTs, making it an ideal surfactant if SWNT suspension in GA does not alter the performance sought from these nanotubes.     

Endowing carbon nanotubes with biological and biomedical properties by chemical modifications

The scope of nanotechnology is gaining importance in biology and medicine. Carbon nanotubes (CNTs) have emerged as a promising tool due to their unique properties, high specific surface area, and capacity to cross biological barriers. These properties offer a variety of opportunities for applications in nanomedicine, such as diagnosis, disease treatment, imaging, and tissue engineering. Nevertheless, pristine CNTs are insoluble in water and in most organic solvents; thereby functionalization of their surface is necessary to increase biocompatibility. Derivatization of CNTs also gives the possibility to conjugate different biological and bioactive molecules including drugs, proteins, and targeting ligands. This review focuses on the chemical modifications of CNTs that have been developed to impart specific properties for biological and medical purposes. Biomolecules can be covalently grafted or non-covalently adsorbed on the nanotube surface. In addition, the inner core of CNTs can be exploited to encapsulate drugs, nanoparticles, or radioactive elements.     

Influence of carboxylic acid functionalization on the cytotoxic effects induced by single wall carbon nanotubes on human endothelial cells (HUVEC)

A vast variety of nanomaterials have been developed in the recent years, being carbon nanotubes (CNTs) the ones that have attracted more attention, due to its unique properties which make them suitable for numerous applications. Consequently, it is predicted that tons of CNTs will be produced worldwide every year, being its exposure of toxicological concern. Nanomaterials, once into the body, can translocate from the uptake sites to the blood circulation or the lymphatic system, resulting in distribution throughout the body. Thus, the vascular endothelium can be in contact with them and can suffer from their toxic effects. In this regard, the aim of this work was to investigate the cytotoxicity of single-walled carbon nanotubes (SWCNTs) on human endothelial cells evaluating the influence of acid carboxylic functionalization and also the exposure time (24 and 48 h). Biomarkers assessed were neutral red uptake, protein content, a tetrazolium salt metabolization and cell viability by means of the Trypan blue exclusion test. Cells were exposed to concentrations between 0 and 800 μg/mL SWCNTs for 24 and 48 h. Results have shown that both SWCNTs and carboxylic acid functionalized single-walled carbon nanotubes (COOH-SWCNTs) induce toxic effects in HUVEC cells in a concentration- and time-dependent way. Moreover, the carboxylic acid functionalization results in a higher toxicity compared to the SWCNTs.     

Mechanisms of toxicity by carbon nanotubes

Abstract

Carbon nanotubes (CNTs) consist of a family of carbon built nanoparticles, whose biological effects depend on their physical characteristics and other constitutive chemicals (impurities and functions attached). CNTs are considered the twenty first century material due to their unique physicochemical characteristics and applicability to industrial product. The use of these materials steadily increases worldwide and toxic outcomes need to be studied for each nanomaterial in depth to prevent adverse effects to humans and the environment. Entrance into the body is physical, and usually few nanoparticles enter the body; however, once there, they are persistent due to their limited metabolisms, so their removal is slow, and chronic cumulative health effects are studied. Oxidative stress is the main mechanism of toxicity but size, agglomeration, chirality as well as impurities and functionalization are some of the structural and chemical characteristic contributing to the CNTs toxicity outcomes. Among the many toxicity pathways, interference with cytoskeleton and fibrous mechanisms, cell signaling, membrane perturbations and the production of cytokines, chemokines and inflammation are some of the effects resulting from exposure to CNTs. The aim of this review is to offer an up-to-date scope of the effects of CNTs on biological systems with attention to mechanisms of toxicity.     

A critical review of the biological mechanisms underlying the in vivo and in vitro toxicity of carbon nanotubes: The contribution of physico-chemical characteristics

Abstract

This critical review of the available human health safety data, relating to carbon nanotubes (CNTs), was conducted in order to assess the risks associated with CNT exposure. Determining the toxicity related to CNT exploitation is of great relevance and importance due to the increased potential for human exposure to CNTs within occupational, environmental and consumer settings. When this information is combined with knowledge on the likely exposure levels of humans to CNTs, it will enable risk assessments to be conducted to assess the risks posed to human health. CNTs are a diverse group of materials and vary with regards to their wall number (single and multi-walled CNTs are evident), length, composition, and surface chemistry. The attributes of CNTs that were identified as being most likely to drive the observed toxicity have been considered, and include CNT length, metal content, tendency to aggregate/agglomerate and surface chemistry. Of particular importance, is the contribution of the fibre paradigm to CNT toxicity, whereby the length of CNTs appears to be critical to their toxic potential. Mechanistic processes that are critical to CNT toxicity will also be discussed, with the findings insinuating that CNTs can exert an oxidative response that stimulates inflammatory, genotoxic and cytotoxic consequences. Consequently, it may transpire that a common mechanism is responsible for driving CNT toxicity, despite the fact that CNTs are a diverse population of materials. The similarity of the structure of CNTs to that of asbestos has prompted concern surrounding the exposure of humans, and so the applicability of the fibre paradigm to CNTs will be evaluated. It is also necessary to determine the systemic availability of CNTs following exposure, to determine where potential targets of toxicity are, and to thereby direct in vitro investigations within the most appropriate target cells. CNTs are therefore a group of materials whose useful exploitable properties prompts their increased production and utilization within diverse applications, so that ensuring their safety is of vital importance.     

Carbon nanotubes as optical biomedical sensors

Biosensors are important tools in biomedical research. Moreover, they are becoming an essential part of modern healthcare. In the future, biosensor development will become even more crucial due to the demand for personalized-medicine, point-of care devices and cheaper diagnostic tools. Substantial advances in sensor technology are often fueled by the advent of new materials. Therefore, nanomaterials have motivated a large body of research and such materials have been implemented into biosensor devices. Among these new materials carbon nanotubes (CNTs) are especially promising building blocks for biosensors due to their unique electronic and optical properties. Carbon nanotubes are rolled-up cylinders of carbon monolayers (graphene). They can be chemically modified in such a way that biologically relevant molecules can be detected with high sensitivity and selectivity. In this review article we will discuss how carbon nanotubes can be used to create biosensors. We review the latest advancements of optical carbon nanotube based biosensors with a special focus on near-infrared (NIR)-fluorescence, Raman-scattering and fluorescence quenching.     

Recent advances in bioactive 1D and 2D carbon nanomaterials for biomedical applications

One-dimensional (1D) carbon nanotubes (CNTs) and the two-dimensional (2D) graphene represent the most widely studied allotropes of carbon. Due to their unique structural, electrical, mechanical and optical properties, 1D and 2D carbon nanostructures are considered to be leading candidates for numerous applications in biomedical fields, including tissue engineering, drug delivery, bioimaging and biosensors. The biocompatibility and toxicity issues associated with these nanostructures have been a critical impediment for their use in biomedical applications. In this review, we present an overview of the various materials types, properties, functionalization strategies and characterization methods of 1D and 2D carbon nanomaterials and their derivatives in terms of their biomedical applications. In addition, we discuss various factors and mechanisms affecting their toxicity and biocompatibility.     

Advancement in carbon nanotubes: basics, biomedical applications and toxicity

Objectives Carbon nanotubes (CNTs) have attracted much attention by researchers worldwide in recent years for their small dimensions and unique architecture, and for having immense potential in nanomedicine as biocompatible and supportive substrates, as a novel tool for the delivery of therapeutic molecules including peptides, RNA and DNA, and also as sensors, actuators and composites. Key findings CNTs have been employed in the development of molecular electronic, composite materials and others due to their unique atomic structure, high surface area‐to‐volume ratio and excellent electronic, mechanical and thermal properties. Recently they have been exploited as novel nanocarriers in drug delivery systems and biomedical applications. Their larger inner volume as compared with the dimensions of the tube and easy immobilization of their outer surface with biocompatible materials make CNTs a superior nanomaterial for drug delivery. Literature reveals that CNTs are versatile carriers for controlled and targeted drug delivery, especially for cancer cells, because of their cell membrane penetrability. Summary This review enlightens the biomedical application of CNTs with special emphasis on utilization in controlled and targeted drug delivery, as a diagnostics tool and other possible uses in therapeutic systems. The review also focuses on the toxicity aspects of CNTs, and revealed that genotoxic potential, mutagenic and carcinogenic effects of different types of CNTs must be explored and overcome by formulating safe biomaterial for drug delivery. The review also describes the regulatory aspects and clinical and market status of CNTs.     

Usage of nanoparticles with their potential toxicity assessment and regulatory guidelines

In recent times engineered nanoparticles have been receiving much attention from researchers due to their extensive use in a variety of chemical, biological, and industrial areas. Their physiochemical properties have led to a number of uses in commercial products. Considering their broad applications, with increasing human contact the risks of exposure are also increasing. In vivo toxicity experiments involving administering nanoparticles to living organisms have shown their adverse effects on organ development and reproduction. Nanoparticles can be considerably more toxic than the large-sized particles since they can move relatively freely compared to bulkier molecules. Henceforth, it is our duty to assess the harmful health consequences associated with human exposure to nanoparticles in order to improve safe production and use. We will review the current applications of nanoparticles, and issues related to their toxicity. We will focus on safety regulations, risk assessment and regulatory guidelines of nanoparticles. The validation and standardization of nanotoxicity tests will further promote safe applications of nanotechnology in our daily lives.     

Raman spectroscopy analysis and mapping the biodistribution of inhaled carbon nanotubes in the lungs and blood of mice

Because of their small size, robust structure and unique characteristics, carbon nanotubes (CNTs) are increasingly being used in a variety of biomedical applications, materials and products. As their use increases, so does the probability of their unintended release and human exposure. Therefore, it is important to establish their potential biodistribution and biopersistence to better understand the potential effects of their exposure to humans. This study examines the distribution of CNTs in CD‐1 mice after exposure by inhalation of single‐walled carbon nanotubes (SWCNTs) and investigates the possibility that inhaled nanoparticles could enter the circulatory system via the lungs. Raman spectroscopy was employed for the detection of CNTs in lung tissue and blood based on their unique spectroscopic signatures. These studies have important implications concerning the potential effects of exposure to SWCNTs and their use as potential transport vehicles in nanomedicine. Copyright © 2012 John Wiley & Sons, Ltd.     

Pulmonary toxicity and fibrogenic response of carbon nanotubes

Abstract

Carbon nanotubes (CNTs) have been a subject of intensive research for a wide range of applications. However, because of their extremely small size and light weight, CNTs are readily inhaled into human lungs resulting in increased rates of pulmonary disorders, most notably fibrosis. Several studies have demonstrated the fibrogenic effects of CNTs given their ability to translocate into the surrounding areas in the lung causing granulomatous lesions and interstitial and sub-pleural fibrosis. However, the mechanisms underlying the disease process remain obscure due to the lack of understanding of the cellular interactions and molecular targets involved. Interestingly, certain physicochemical properties of CNTs have been shown to affect their respiratory toxicity, thereby becoming significant determinants of fibrogenesis. CNT-induced fibrosis involves a multitude of cell types and is characterized by the early onset of inflammation, oxidative stress and accumulation of extracellular matrix. Increased reactive oxygen species activate various cytokine/growth factor signaling cascades resulting in increased expression of inflammatory and fibrotic genes. Profibrotic growth factors and cytokines contribute directly to fibroblast proliferation and collagen production. Given the role of multiple players during the pathogenesis of CNT-induced fibrosis, the objective of this review is to summarize the key findings and discuss major cellular and molecular events governing pulmonary fibrosis. We also discuss the physicochemical properties of CNTs and their effects on pulmonary toxicities as well as various biological factors contributing to the development of fibrosis.     

Multifunctional hybrid-carbon nanotubes: new horizon in drug delivery and targeting

Carbon nanotubes (CNTs) have emerged as an intriguing nanotechnological tool for numerous biomedical applications including biocompatible modules for the bioactives delivery ascribed to their unique properties, such as greater loading efficiency, biocompatibility, non-immunogenicity, high surface area and photoluminescence, that make them ideal candidate in pharmaceutical and biomedical science. The design of multifunctional hybrid-CNTs for drug delivery and targeting may differ from the conventional drug delivery system. The conventional nanocarriers have few limitations, such as inappropriate availability of surface-chemical functional groups for conjugation, low entrapment/loading efficiency as well as stability as per ICH guidelines with generally regarded as safe (GRAS) prominences. The multifunctional hybrid-CNTs will sparked and open a new door for researchers, scientist of the pharmaceutical and biomedical arena. This review summarizes the vivid aspects of CNTs like characterization, supramolecular chemistry of CNTs–dendrimer, CNTs–nanoparticles, CNTs–quantum dots conjugate for delivery of bioactives, not discussed so far.     

碳纳米管在生物医药领域的应用及其安全性

碳纳米管包括单壁碳纳米管和多壁碳纳米管,是目前最有应用前景的纳米材料之一.作为载体,其具有的独特中空结构和纳米管径,可运送生物活性分子及药物进入细胞或组织.作为一种新型生物材料,能促进骨组织修复生长、神经再生,减少神经组织瘢痕产生.然而,碳纳米管对人体也有一定的毒性作用,目前研究主要集中在肺脏毒性和细胞毒性,表现为可引起肺脏炎症、内芽肿和细胞凋亡、活力下降、细胞周期改变等.其毒力大小与碳纳米管的特性有关,如结构、长度、表面积、制备方法、浓度、剂量等,毒性作用机制可能与氧化应激有关.     

When carbon nanotubes encounter the immune system: Desirable and undesirable effects

The role of our immune system is to bring efficient protection against invasion by foreign elements, not only pathogens but also any material it may be in contact with. Nanoparticles may enter the body and encounter the immune system either intentionally (e.g. administration for biomedical application) or not (e.g. respiratory occupational exposure). Therefore, it is of fundamental importance to get a thorough knowledge of the way they interact with immune cells and all related consequences. Among nanomaterials, carbon nanotubes (CNTs) are of special interest because of their tremendous field of applications. Consequently, their increasing production, processing and eventual incorporation into new types of composites and/or into biological systems have raised fundamental issues regarding their potential impact on health. This review aims at giving an overview of the known desirable and undesirable effects of CNTs on the immune system, i.e. beneficial modulation of immune cells by CNTs engineered for biomedical applications versus toxicity, inflammation and unwanted immune reactions triggered by CNTs themselves.