Mesothelioma: Do asbestos and carbon nanotubes pose the same health risk?

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1 Mesothelioma: Do asbestos and carbon nanotubes pose the same health risk? Marie-Claude Jaurand, Annie Renier, Julien Daubriac To cite this version: Marie-Claude Jaurand, Annie Renier, Julien Daubriac. Mesothelioma: Do asbestos and carbon nanotubes pose the same health risk?. Part Fibre Toxicol, 2009, 6 (1), pp.16. < / >. <inserm > HAL Id: inserm Submitted on 16 May 2014 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

2 Mesothelioma: pose Do asbestos and carbon nanotubes Marie-Claude same health risk? 1INSERM, 2 F Jaurand,1, 2 Annie Renier,1, 2 Julien Daubriac1, 2 Corresponding U674, Fondation Jean Dausset CEPH, Paris, F-75010, France Université addresses: Paris author 7, Paris, F-75013, France INSERM, France MFJ: U674, Fondation Jean Dausset-CEPH, IFR 105, Paris, F-75010, - 1 -

3 Abstract Carbon range their health. nanotubes (CNTs), the product of new technology, may be used in a wide responses of applications. Because they present similarities to asbestos fibres in terms of shape and size, it is legitimate to raise the question of their safety for human action Recent animal and cellular studies suggest that CNTs elicit tissue and cell about similar to those observed with asbestos fibres, which increases concern summarize adverse biological effects of CNTs. While asbestos fibres mechanisms of will are not fully understood, sufficient results are available to develop hypotheses the the significant factors underlying their damaging effects. This review will address characteristics discuss the possible the to what current of extent impact asbestos state they of of known CNTs. present knowledge to similarities be associated about the to with those biological toxicity of asbestos effects will fibres. be of analyzed CNTs Finally, and to - 2 -

4 1. Carbon result fields Introduction important nanotubes (CNTs) have unique chemical and physical characteristics as a and of their nanostructure. CNTs may be used in a wide range of applications, in today as diverse as electronics and medicine [1,2]. Due to their widespread use, it is fibre-like to determine the safety of CNTs for the protection ecological systems ratio. human health. Research to investigate the biological effects of CNTs is advancing High in order to foresee and prevent potentially harmful effects. CNTs have fibres, characteristics in terms of their elongated shape, dimensions and aspect health particles with at least one dimension of less than 100 nm, they correspond to increasing Aspect Ratio Nanoparticles (HARN)[3]. In light of the health impact of mineral toxicity especially the fibrogenic and carcinogenic potency of fibres, and In and socio-economical tragedies caused by unregulated asbestos utilization, the have development and uses of CNTs have triggered concern about their potential especially [4-8]. important recent years, several publications have reported the effects of CNTs. Most studies relevant concerned animal and cell responses, focusing primarily on respiratory diseases, has the inflammatory effects the lung. However, while inhalation one studies probable route of contamination, it must be kept in mind that there are other risk routes of exposure. A severe primary cancer, malignant mesothelioma (MM), incidence been of have MM of closely shown MM development. in linked that populations asbestos asbestos Epidemiological exposed fibres exposure are not the [9,10]. only fibres Epidemiological associated and animal with a - to 3 - asbestiform studies have and non-asbestos demonstrated fibres a higher [11-

5 14]. question further already Some manmade vitreous fibres have caused MM animal experiments [15]. The with of whether CNTs might potentially be linked to MM development justifies genetically-modified research in this area. Moreover, on the basis of the literature, CNTs have exposed shown effects in animals and in cell systems that are similar to those observed These asbestos fibres [1,2,5,7]. Two recent studies showed the occurrence of MM in knowledge cancer-sensitized mice and conventional Fischer 344 rats MM CNTs by intraperitoneal or intrascrotal administration respectively [16,17]. mesothelial initial results underline the urgent need for information to further our pleura, about CNTs potential to cause MM. is a primary tumour of the serosas caused by the neoplastic transformation of cases cells. In populations exposed asbestos fibres, MM mainly occurs in the asbestos and to a lesser extent in the peritoneum and pericardium. MM is considered to (95% highly specific to asbestos exposure, and is found in from 60% over 80% of and [18-23]. In France, the calculated risk of MM attributable to occupational hypotheses exposure was estimated at 83.2% (95% CI 76.8 to 89.6) in men, and 38.4% cell CI 26.8 to 50.0) in women [24]. Many studies carried out to investigate pleural The mesothelial cell response to asbestos fibres have made it possible to reach sound of about the mechanism of action of asbestos fibres in neoplastic mesothelial predict transformation. evaluate aim of the present review to explore whether our knowledge of the mechanism three action of asbestos fibres could offer a useful paradigm to provide a warning or mesothelial points: the their risk cells (i) potential of the and CNTs, fate the health biological of to asbestos interpret effects. mechanism For fibres data the on purposes animal and of our cellular discussion, responses, we consider and to following associated exposure; with the (ii) cell their response; effects (iii)

6 the with toxicology carcinogenic nature of the fibre parameters involved in the harmful effects, and their similarities asbestos CNT of characteristics. effects CNTs, at then look We pleural begin at asbestos level. with Finally, fibres a summary we mechanisms address of current the of similarities action, knowledge focusing between on the on and CNTs Toxicology of CNTs Various heterogeneous Context of toxicological studies on CNT Both single-walled kinds of terms CNTS (SWCNTs) of have their structure, been and the multi-walled impurities focus of toxicological and (MWCNTs) physico-chemical studies. CNTs have properties. CNTs been are studies examined toxicological studies, including commercial and laboratory made CNTs, inflammatory whether purified or used as produced. The effects of have been investigated intraperitoneal following concerned vivo exposure pulmonary of toxicity rodents, [1,2,5]. and on Animal several experiments types of cells mainly culture. focused Most on have responses after exposure by intratracheal instillation or aspiration, or neurons injection. In vitro cell systems with several types of mammalian cells genotoxicity. vitro been studies [2]. used Here Toxicity were to study our related focus inflammatory test will systems dermal be on responses toxicity, respiratory procaryotes and and some genotoxicity. were in vitro also studies A used few in focused to vivo assess and on effects.

7 2.2 Biodistribution Biological effects of CNTs poorly Translocation by of CNTs after deposition in the lung or via other routes has been system investigated. A translocation of SWCNTs in various organs has been reported instillation several authors [25-29]. In a recent study, MWCNTs deposited by intratracheal demonstrated rats revealed clearance due to macrophage uptake and the lymphatic et without evidence of crossing the pulmonary barrier, six months after the [29]. It can be noted that macrophage and lymphatic clearance was also circulating following administration or exposure asbestos fibres [30-33]. Erdely asbestos al. [30] suggest that the release of soluble inflammatory factors could circulate to for vascular blood compartment after lung deposition of CNTs. The release of [35,36]. factors must be taken into consideration account for fibre effects. While Regarding fibres have been detected the pleura, soluble molecules could also account and the physico-chemical pleural Additional the numerous response studies properties, varieties [34], are and needed fundamental of genotoxicity CNTs determine associated studies may the with will be pharmacokinetics due be a broad necessary to clastogenic scale to of of establish physical factors CNTs. Six the parameters leading the translocation process. reported Biological effects mesothelial cells animal In vivo effects on mesothelial cells pathological recently-published experiment findings changes from concerned after studies animal intra-peritoneal concerned experiments the mesothelial CNTs effects on mesothelial cells. Three and injection three cell from inflammatory [37]. cell The system authors response studies. exposed One and

8 C57Bl/6 There 14.8 Mitsui mice to four samples of of different sizes and aggregation states. of was one sample of short MWCNTs (from NanoLab, Inc; mean diameter: length: ± 0.5 nm; length: 1-5 µm); two samples of long MWCNTs (Long1, from MWCNTs & Co.; mean diameter: 84.9 ± 1.9 nm; length: µm [24% > 15 µm 20 length]; Long2 from Univ. Manchester; mean diameter: 165 ± 4.7 nm; mean were µm [84% > 15 µm of length]); and one more tangled > 15 µm), µm tested; as of (from well these length) as were NanoLab, carbon known short black. Inc.; fibres to be At mean (4.5% the differently diameter: same > 15 µm time, pathogenic of 10.4 two length) ± samples 0.3 and nm; in long rodents. of mean amosite fibres length: In (50.4% fibres prior 5- injection experiments, inhalation and intraperitoneal exposure rats to long amosite fibres quantification revealed greater pathogenicity than short fibres in terms of fibrosis and cancer long [38,39]. In the study reported by Poland et al. [37], inflammation was assessed after Histological of 50 µg of MWCNTs/mouse, after 24h and seven days. The end points were macrophages. inflammation in peritoneal lavage and histology of diaphragm. Only responses samples of MWCNTs and of amosite produced inflammation and granulomas. asbestos were to analyses the also These long found results forms revealed with of CNTs. thus amosite the demonstrated There occurrence and were MWCNTs. higher of some frustrated inflammatory similarities Several phagocytosis of responses the between effects with the by of (MWCNTs-7 samples of long fibres. Only the samples that contained long fibres caused granulomas cavity and A long-term frustrated of C57Bl/6 study from phagocytosis. p53+/- was Mitsui; performed mice. diameter: Because by 100 Takagi these et al. [17] who inoculated MWCNTs - 7 nm; - mice length: have 27% a mutation > 5µm) one the allele peritoneal of the

9 Trp53 positive crocidolite. the gene, they are prone to develop cancer. Crocidolite fibres were inoculated as underestimation control. Mesotheliomas were found after exposure to both MWCNTs and histology This study has been discussed on several points, including concern about authors type of mice, inappropriate exposure methods, high exposure dose, prone of the number of particles of MWCNTs and poorly-illustrated route [40,41]. Details can be found in the different papers but some of the spontaneous replies can be summarized here. It is recognized that Trp53+/- mice are more the develop cancers, and that response using high doses by the intraperitoneal absence of exposure provides different information regarding hazard potency. However, experiments excess of mesotheliomas has not been reported in this type of mice, and recently, injection method is applicable to the hazard approach for mesothelial cells in 344 of human data. Concerning the dose, the authors mentioned that other Dimensions using lower doses are progress, giving similar responses [40]. More 72.5% MWCNTs-7 were administered by a single intrascrotal injection in Fischer crocidolite-treated rats (240 µg/rat) maintained for an observation period of 52 weeks [16]. mesotheliomas were 82% of the MWCNTs with a diameter between nm, and in between 1-4 µm length. Five vehicle-treated controls and 7 UICC not rats (470 µg/rat) were also studied. The overall incidence of scrotal was 86% in MWCNT-treated rats while no mesothelioma was found peritoneal vehicle- or crocidolite-treated rats. This method of exposure of mesothelial cells is knowledge usually mesothelium of used to effects assess is used of [42,43]. a these carcinogenic as MWCNTs a Further method data potency to investigate are of clearly fibres. the needed However, repair to mechanism improve injury at our the of on mesothelial cells in vivo.

10 To mesothelial and Effects on mesothelial cells in vitro AP-1, best of our knowledge, four studies have reported in vitro effects on viability cells. DNA breakage and DNA repair were found in both human normal SWCNTs malignant mesothelial cells exposed to SWCNTs, as well cell activation via cells, NF-κB and Akt [44]. Another study concluded that there was alteration of cell and decreased cell proliferation in human mesothelioma cells exposed to different [45]. Three studies reported cytotoxicity on human normal mesothelioma (Met-5A) malignant degrees cell [44,46,47]. mesothelioma line of [47]. dispersion It In cell this noteworthy line, study, exerted and the on toxicity that different large the T of same SV40-transformed CNT-bundles cytotoxicity raw CNT (well-dispersed on material mesothelial a human with been material with a bundle diameter of around 20 nm) was less than that of CNTagglomerates (densely roped aggregates with a rope diameter in the micron-range). controversial. discussed CNTs appear to be taken up by different cell types and diverse in vitro effects have and associated with CNTs uptake [2,45]. However, the cellular uptake of CNTs is functions Both absence and significant uptake have been reported, as recently reactive [1]. Uptake is likely dependent on interactions between cellular receptors used cell surface functions, and CNTs surface reactivity. A variety of cell surface interactions may be found, depending on the cell type. CNTs may also carry diverse be groups. Different sorts of chemicals and biological molecules are currently responses to disperse CNTs that may modify the CNTs surface. Hence cell-cnt (MARCO) recalled [48-52]. are seems that dependent modification In to macrophages, play on an a of number important the the surface of scavenger intrinsic and extrinsic parameters. It should - 9 role - of in asbestos receptor pulmonary with fibres collagenous damage modulates induced structure the by

11 inorganic plasma reported was particles [53] and may be involved in interaction between MWCNTs and MWCNTs, membrane of macrophages [54]. In cells, integrin receptors were controversial to interact with asbestos fibres [50,55]. Recently, no particle internalisation adverse evidenced large T SV40-transformed mesothelial cells (MeT-5A) exposed to interactions cellular of despite results, CNT effects cytotoxicity with as fibre of mesothelial particles, internalisation [46]. cells. Further and more is an studies important data are are necessary process needed accounting to to determine clarify for these Several exposure, Biological effects in other systems inhalation. Inflammation data studies have investigated the inflammatory response provoked by CNT Regarding conducted on mice or rats exposed via intratracheal instillation or particulate Several reviews may be consulted for more details [1,2,4-8]. Some recent systems are summarized in Table 1 [30,56-59]. SWCNTs the large applications of CNTs and the known adverse effects fine cardiovascular other and matter, than system MWCNTs respiratory the [30]. potential produce [1,2]. effects A a recent systemic of CNTs study response, have suggests also which that been deposition may investigated affect of both the on to inflammation Both inflammatory Genotoxicity vivo and is considered responses in vitro effects to and increase production of CNTs the suggest a possible genotoxic effect, related - 10 carcinogenic of - reactive risk oxygen [60]. species, as persistent

12 have In vivo, a mutation of the K-ras oncogene was observed in mice exposed to SWCNTs [44,46,54,57,61-70]. by inhalation, and chromosomal aberrations were detected in type II pneumocytes adenine after intratracheal deposition of MWCNTs in mice [58,61]. Several in vitro studies [69]. reported a genotoxic potency using different cell types (Table 2) Activation of DNA repair processes and mutagenesis of the in phosphoribosyl transferase gene was found mouse embryonic stem cells probe Genotoxicity as assessed by the cytokinesis-block micronucleus test, was found DNA rat lung exposed to MWCNTs [57]. Micronuclei formation occurred CNT-treated human epithelial cells (MCF-7) with MWCNTs, and a pancentrometric breakage analysis demonstrated both chromosome breakage and chromosome loss [61]. to damage was also reported in SWCNT-treated mouse embryo fibroblasts and in Investigations bronchial epithelial BEAS 2B cells [63,67]. No mutation or DNA not was found a FE1-Mutatrade markmouse lung epithelial cell line exposed to SWCNTs but purine oxidation was detected with the Comet assay [71]. generally evaluate reveal mutagenic genotoxicity of the mutagenic activity of [72,73]. particles. potency These of Previous MWCNTs bacterial results assays using with bacterial may bacterial not be test fully systems cells relevant were did not or only moderately positive with asbestos fibres [74] Numerous Asbestos fibres of action emphasized level. The They asbestos make publications several it responses clear legacy that two the associated aspects mechanism - with 11 must - the be of mechanism considered: action of of the asbestos toxicity biological at fibres the response serosal have

13 and asbestos know biological the particle status. The first depends on several factors that include the fate of on fibres following inhalation, i.e., their ability reach the pleura. It is well internalised that deposition, clearance and translocation of fibres are dependent on frustrated mechanisms and partners (mucociliary transport, phagocytic cells), but also dimensions fibre parameters, by macrophages especially than fibre long dimensions. fibres, and Short long fibres possibly are more involve easily 3.2. phagocytosis. The biopersistence of fibres is linked to both their Regarding and stability in the biological milieu. risk Fate of asbestos fibres depends of industrial uses and commercial applications of asbestos fibres, the main asbestos of contamination is linked to the inhalation route. In general, particle deposition pleura. aerodynamic considerations. Several authors have studied the mechanism deposition fibre deposition and retention the lungs [75-78]. Once deposited the lung, compartments fibres may be translocated into different organs and tissues, including the pathways This was demonstrated in animals following inhalation or intratracheal trans-cell [79], and humans by investigation of fibre retention in different body deposited including the pleura [80-82]. A recent paper discusses the translocation gradient of asbestos fibres to the pleura [83]. Translocation appears to be due to epithelial migration and lymphatic circulation. These authors propose that fibres different in the alveolar space can be translocated to the interstitium, down and enter organs. of the layer physiological capillaries is Fibres damaged. can as water inflammation be Once cleared absorption. from the interstitium, This transfer fibres is can facilitated be distributed when the to - 12 increases - the interstitium the interstitial via the pressure, lymphatic allowing system

14 the can The pleural fibres to migrate and be distributed throughout the whole body. Therefore, fibres concentrated. reach the via the capillary system and transfer through the visceral pleura. Translocation parietal pleural has pores of relatively large diameter (about nm), and the only fluid drainage goes through stomatas where particles are found to be of anthracotic of CNTs to the pleura can be assumed, asbestos fibres are not the pleura particles to be translocated to this site. Migration was observed after inhalation determine refractory ceramic fibres and NMVF10a fibreglass in hamsters and rats, and that areas ( black spots ) containing particulate matter are present human experiments [81,84-87]. One important point for the study of CNT toxicity is therefore to concluded their ability to be distributed the body and to reach the pleura. It is likely and the CNT aggregation state will modulate the rate of translocation. Recent treatments aggregation that used comparing the for state different particle of the inhalation effects dispersion CNTs were [58,59]. and will likely tracheal also It can related influence or also pharyngeal to be a assumed the difference biodistribution deposition that in the dispersion CNT of of CNTs these pre- mesothelial particles. Moreover, it must be kept in mind that CNT exposure takes place via routes other than inhalation, which ought to be investigated. Many Biological cells and genomic effects of asbestos fibres on conditions. Inflammation and mesothelial cell activation inflammatory authors have described the inflammatory processes occurring in the lung and in RNS pleura, (reactive and Fibre cells, nitrogen shown deposition which species), that produce fibres in clastogenic several can interact with mesothelial cells in culture - lung 13 - factors: is followed and ROS cytokines (reactive by that oxygen recruitment may stimulate species), of

15 and/or Moreover, process In damage neighbouring mesothelial cells. Fibres also may produce ROS. stress, mesothelial cells respond by fibre internalisation according to a phagocytic At associated with oxidative reactions [34,88-93]. (MAPKs) this situation, mesothelial cells adapt to the oxidative environment by oxidative control increasing oxidant defences and decreasing natural ROS and RNS production. reactions the same time, several regulatory pathways are activated: signalling pathways cells/mesothelial associated with cell proliferation and apoptosis, and DNA repair and linked of cycle progression in response to DNA damage [94,95]. These different genotoxic are consequence of 2 types of interactions: between cells (inflammatory develop genetic cells) damage and and between requires cells proliferation and fibres. As steps, neoplastic comparison transformation between the is Many effects of asbestos and CNTs might provide clues making it possible to mesothelial hypotheses about the potential effects of CNTs. (DNA Genotoxicity showing investigations have focused on DNA damage provoked by asbestos fibres in breaks) cells. Several studies have demonstrated different types of DNA damage due breakage, base oxidation), and perturbation of the mitotic process [94,95], asbestos that base oxidation and DNA breakage (single strand and double strand found were detected in asbestos-treated cells [95-100]. These may be described. ROS / RNS production and the mesothelial cells ability to phagocytise Asbestos fibres. Fibre uptake does not abolish mitotic process as some fibres are of aneuploid in dividing fibres A list cells, produce of mesothelial chromosome abnormal structural cells. anaphases abnormalities chromosome Moreover, has extensive been reported chromosome by different damage authors. was - 14 and - telophases alterations; [ ]. significant enhancement Induction of

16 micronuclei has been reported by all by types Poser of et asbestos al. [106]. in Other primary studies cultures have of shown human genomic mesothelial alterations cells amplification asbestos-treated human mesothelial cells. Loss of heterozygosity was detected as periods asbestos-induced mutations in a human mesothelioma cell line [107]. Using 3D concerning reconstruction, and Cortez aneuploid et al. cell recently formation reported lung mitotic carcinoma abnormalities, cells, even centrosome with long A of recovery post-treatment [108]. These findings are similar to earlier reports using rat pleural mesothelial cells and using less powerful methods. studies Gene expression in asbestos-treated mesothelial cells processes few studies have investigated gene expression in asbestos-treated mesothelial cells DNA microarray analysis (Table 3) [ ]. They confirmed results obtained in to focusing given types of damages. Modulation of several biological order repair were and observed. cell adhesion They pathways. were associated Further studies with inflammatory, comparing the proliferation, cell response Epidemiological CNTs and to the different types of asbestos fibres are likely be informative in in to approach the possible effects of CNTs. MM Gene alterations in mesothelioma changes studies have shown that MM is a consequence of asbestos exposure mesothelial a majority of cases [18-24]. This led us assume that genomic alterations found in found could be linked to the effect of asbestos fibres. The identification of these frequently at can inactivated cells. INK4 provide MM locus, insight tumour cells and exhibit into often suppressor the the frequent molecular type alterations mechanism in tumour of action suppressor of asbestos genes on - 15 gene - of in MM cells. deletions. Germinal NF2 mutations is another in

17 To effect NF2 are responsible for type 2 neurofibromatosis, but NF2 patients are not prone to develop develop mesothelioma. TP53 is mutated less often in MM cells. asbestos investigate whether genetic alterations mesothelioma might be relevant to and of asbestos fibres, animal models of human MM developed. Mesotheliomas Histologically, following exposure, by intraperitoneal injection, of hemizygous NF2 mice to tumour fibres [112,113]. This made it possible to compare characteristics of mouse MM. human mesotheliomas. Regarding very similar tumours were observed, and the genomic alterations in the consequences These suppressor gene are genes involved investigated the were control very of close cell cycle to those and observed junction stability. human 4. the function of the gene, it might be of interest to determine the If of CNT exposure on cell cycle progression and cell architecture. asbestos Asbestos fibre characteristics related to disease should chemistry one looks at fibre parameters, several features appear shared by CNTs and fibres. focus fibres. on To the compare asbestos CNTs characteristics and asbestos modulating fibres in asbestos relation toxicity. potential, Shape, size, we 4.1 CNTs and surface reactivity are all related to cell and tissue responses to asbestos fibre greater Shape clumps, have a thin and elongated shape compatible with a fibre, according to the WHO well-organized definition than a feature three. of structures. that a It particle is seems not The with fully that length parallel similar CNTs of edges and an aspect ratio (length/diameter) - 16 to are CNTs - asbestos, prone may to which vary, form forms reaching aggregates, bundles up ropes to of several rather and

18 micrometers in cells engulfing or longer CNTs [7,114]. [37]. Accordingly, frustrated phagocytosis was observed cell 4.2 Size for The diameters of asbestos fibres fall in the nanosize range. If one refers to the micrometers. dimensions of the UICC samples, which have been used in a number of animal and of studies, crocidolite. the diameter Length depended of chrysotile on fibres the sample, was less but than generally about 100 averaged nm, and 200 several nm 4.3 Metals However, there was a significant range in length and a small percentage content, fibres longer than 10 µm were generally present. and Chemistry contaminants; are considered to be important elements to account for fibre toxicity. Iron Data either structural or as contaminant, may be linked to the formation of ROS RNS. Depending on method of production, CNTs may contain metals as importance the literature moreover, show they a can wide be qualitative functionalized and quantitative to acquire specific diversity properties. of metal 4.4 Surface the chemical composition of CNT samples, emphasizing the production of using well-defined samples for toxicological analyses [7]. studies Surface reactivity generating reactivity is an important parameter in asbestos-related effects. The unless of ROS and RNS was mentioned above. It is interesting note that some dispersing indicate that, in contrast to asbestos, CNTs quench ROS an acellular system medium. functionalized, agents hydroxyl prior radicals are to exposing hydrophobic. [115]. cells While asbestos fibres are hydrophilic, CNTs, - 17 As or - animals a result, to CNTs are suspended often treated in aqueous with

19 Asbestos take consequences observed fibres ability to adsorb biological molecules is another fibre parameter to [ ]. into consideration. Asbestos adsorbs proteins and phospholipids, which has Asbestos cell-fibre interactions. An enhancement of biological effects can be consist (particle internalisation, cytotoxicity), as well a reduction of toxicity and (hemosiderin, bodies are structures found in the lung of asbestos-exposed subjects. They than of an asbestos fibre core surrounded by a complex coat produced by the cell other tissue reaction; they made of apatite mineralization and protein aggregation structures on chrysotile. ferritin). They These are not structures specific are to more asbestos, likely as formed they have on amphiboles been reported rather in 4.5 While fibrous and non-fibrous particles. It would of interest to know whether these the could be formed CNTs [ ]. [123,124]. behaviour biopersistence is not an intrinsic particle parameter, it has received attention for scavenger evaluation of the carcinogenic potency of manmade vitreous fibres (MMVFs) eliminated Biopersistence the lung is result of a clearance mechanism and the The of fibres in biological medium. Clearance depends on particle uptake by mechanism cells; it is then modulated by the fibre and toxicity (short particles are structure following uptake by macrophages; cytotoxic particles impair the process). biological behaviour of the fibres is also size-dependent (fibre dimensions govern breaking and site of deposition in the lung), as well as dependent on the fibre amount of and the medium). fibre chemistry fibres retained Some into (these in smaller the chemical parameters lung fragments. and elements the modulate may dissolve the stability and reduce of the particles fibre strength, in - 18 time - Finally, it remains biopersistence in the lung. To modulates date, CNTs the

20 have relevance 5. been considered biopersistent, but further studies are needed to determine the CNTs of this parameter in the context of human exposure to CNTs [57]. nanotechnologies, human Discussion linked are valuable industrial products with multiple applications in the field of CNTs, yet legitimate concerns about their potential adverse effects on exposed health need to be addressed. The risk of MM, a primary pleural carcinoma providing to asbestos exposure, must be examined in light of the physical nature of compared which are elongated and ultrafine, and the fact that human beings involved to CNTs through inhalation. While not yet definitive, data are now available similarities. information the pulmonary and cellular effects of CNTs, which may be common to those of asbestos fibres. Moreover, the asbestos fibre characteristics CNTs in the toxic processes may be compared to those of CNTs to determine their A These comparisons make it possible to develop hypotheses about industrial and different mechanisms of action. A summary of comparisons between knowledge and asbestos is provided in Tables 4 and 5. community paradigm for the health effects of HARN has emerged from toxicology studies and fibres, including asbestos. A recent report reviewed state-of-the-art other the toxicity of and HARN [3]. This clearly suggest a determine composition. HARN the of potential (nanowires, toxicological The reader toxicity nanorods) features will of find HARN. and in and this concern the quoted proposal between review for HARN additional a research of different information strategy origin on to

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