148. Carbon Nanotubes

Carbon nanotubes (CNTs) can be seen as graphene sheets rolled to form cylinders. CNTs may be categorised as single- (SWCNT) or multi-walled (MWCNT). Due to the small size, the number of particles as well as the surface area per mass unit is extremely high. CNTs are highly diverse, differing with respect to e.g., diameter, length, chiral angles, chemical functionalisation, purity, stiffness and bulk density. Today, CNTs are utilised primarily for the reinforcement of composite polymers, but there is considerable potential for other applications. The rapidly growing production and use of CNTs increases the risk for occupational exposure. Since CNTs in bulk form are of very low density and much dust is produced during their handling, exposure by inhalation appears to represent the greatest potential risk in the work place. However, most work place measurements involved sampling periods that are too short, varying sampling techniques and non-specific analytical methods. CNTs may be absorbed via inhalation and ingestion. Systemic uptake via the skin has not been demonstrated. Human toxicity data on CNTs are lacking and interpretation of animal studies is often problematic since the physical properties and chemical composition are diverse, impurities may be present and data are sometimes omitted. Because of the physical similarities between asbestos and CNTs, it can be suspected that the latter may also cause lung fibrosis, mesothelioma and lung cancer following inhalation. Intraperitoneal and intrascrotal administration of CNTs causes mesothelioma in animals, but no inhalation carcinogenicity studies have been conducted. Thus, it is too early conclude whether CNTs cause mesothelioma and lung cancer in humans. Both SWCNTs and MWCNTs cause inflammation and fibrosis in the lungs of relevant animal types and for MWCNTs these effects are also seen in the pleura. For instance, minimal histiocytosis and mild granulomatous inflammation in the lungs and lung-draining lymph nodes have been observed in rats exposed for 13 weeks to 0.1 mg/m3 MWCNTs (lowest observed adverse effect level, LOAEL), with more pronounced inflammation in both mice and rats at higher doses. Thus, inflammatory responses in the lungs may be considered as the critical effect. However, the LOAEL of CNTs should be interpreted cautiously, since their toxicity is likely to vary widely, depending on the structure and physicochemical properties, as well as the contribution from non-carbon components. It is also uncertain which dose metric (e.g., mass, number or surface area per air volume unit) is most appropriate. Some studies indicate that longer straight CNTs evoke more pronounced biological effects than shorter or tangled fibres

Searching for early breast cancer biomarkers by serum protein profiling of pre-diagnostic serum; a nested case-control study

<p>Abstract</p> <p>Background</p> <p>Serum protein profiles have been investigated frequently to discover early biomarkers for breast cancer. So far, these studies used biological samples collected <it>at </it>or <it>after </it>diagnosis. This may limit these studies' value in the search for cancer biomarkers because of the often advanced tumor stage, and consequently risk of reverse causality. We present for the first time pre-diagnostic serum protein profiles in relation to breast cancer, using the Prospect-EPIC (European Prospective Investigation into Cancer and nutrition) cohort.</p> <p>Methods</p> <p>In a nested case-control design we compared 68 women diagnosed with breast cancer within three years after enrollment, with 68 matched controls for differences in serum protein profiles. All samples were analyzed with SELDI-TOF MS (surface enhanced laser desorption/ionization time-of-flight mass spectrometry). In a subset of 20 case-control pairs, the serum proteome was identified and relatively quantified using isobaric Tags for Relative and Absolute Quantification (iTRAQ) and online two-dimensional nano-liquid chromatography coupled with tandem MS (2D-nanoLC-MS/MS).</p> <p>Results</p> <p>Two SELDI-TOF MS peaks with m/z 3323 and 8939, which probably represent doubly charged apolipoprotein C-I and C3a des-arginine anaphylatoxin (C3a_desArg), were higher in pre-diagnostic breast cancer serum (p = 0.02 and p = 0.06, respectively). With 2D-nanoLC-MS/MS, afamin, apolipoprotein E and isoform 1 of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4) were found to be higher in pre-diagnostic breast cancer (p < 0.05), while alpha-2-macroglobulin and ceruloplasmin were lower (p < 0.05). C3a_desArgand ITIH4 have previously been related to the presence of symptomatic and/or mammographically detectable breast cancer.</p> <p>Conclusions</p> <p>We show that serum protein profiles are already altered up to three years before breast cancer detection.</p

Protein adducts of hexahydrophthalic anhydride- chemical structures and biomarkers

Organic acid anhydrides (OAAs) are low molecular weight chemicals used in the industry for manufacturing of plastics such as epoxy resins. Exposure to these chemicals may lead to symptoms from the eyes and the respiratory tract in form of conjunctivitis, rhinitis and asthma. In many workers production of specific IgE antibodies are induced suggesting that a type-1 allergy mediated mechanism is involved. The OAAs act as haptens and the binding to endogenous proteins is probably an important part of the pathophysiological mechanism. The aim of this thesis was to identify potentially allergenic chemical structures using hexahydrophthalic anhydride (HHPA), a highly sensitising OAA, as a model substance. The aim was also to develop a new method for biological monitoring of HHPA. The binding of HHPA to several nucleophilic amino acids and a model peptide was initially studied. Stable adducts to lysine and the N-terminal amino group were found. Unstable adducts to cysteine, histidine, tyrosine and tryptophan were also identified. The cysteine adduct could be transferred to lysine residues. Studies of potential allergenic structures were performed on hapten-protein conjugates between HHPA and hemoglobin (Hb) and human serum albumin (HSA), respectively, synthesised in vitro. Enzyme digestions of the conjugates were performed and the binding sites of HHPA were identified through analysis of the peptides using liquid chromatography coupled to tandem mass spectrometry. HHPA adducts were found with several lysine residues and the N-terminal amino group both in Hb and HSA. Further studies must be performed to determine the allergenic potential of these identified adducts. Based on the identifications of the binding sites of HHPA to HSA a method was developed to measure HHPA-adducted tryptic peptides of HSA in nasal lavage samples. The nasal lavages were obtained from five volunteers exposed to HHPA at different air concentrations of HHPA. The major binding sites of HHPA found in the in vitro studies were detected in the in vivo samples as well. The levels of these adducted peptides were highly correlated with the air levels of HHPA on an individual basis but there were large inter-individual differences. Thus, it should be investigated whether these peptides may be used as biomarkers of effective dose, which then would better reflect the risk than more traditional biomarkers

148. Carbon nanotubes

Carbon nanotubes (CNTs) can be seen as graphene sheets rolled to form cylinders. CNTs may be categorised as single- (SWCNT) or multi-walled (MWCNT). Due to the small size, the number of particles as well as the surface area per mass unit is extremely high. CNTs are highly diverse, differing with respect to e.g., diameter, length, chiral angles, chemical functionalisation, purity, stiffness and bulk density. Today, CNTs are utilised primarily for the reinforcement of composite polymers, but there is considerable potential for other applications. The rapidly growing production and use of CNTs increases the risk for occupational exposure. Since CNTs in bulk form are of very low density and much dust is produced during their handling, exposure by inhalation appears to represent the greatest potential risk in the work place. However, most work place measurements involved sampling periods that are too short, varying sampling techniques and non-specific analytical methods. CNTs may be absorbed via inhalation and ingestion. Systemic uptake via the skin has not been demonstrated. Human toxicity data on CNTs are lacking and interpretation of animal studies is often problematic since the physical properties and chemical composition are diverse, impurities may be present and data are sometimes omitted. Because of the physical similarities between asbestos and CNTs, it can be suspected that the latter may also cause lung fibrosis, mesothelioma and lung cancer following inhalation. Intraperitoneal and intrascrotal administration of CNTs causes mesothelioma in animals, but no inhalation carcinogenicity studies have been conducted. Thus, it is too early conclude whether CNTs cause mesothelioma and lung cancer in humans. Both SWCNTs and MWCNTs cause inflammation and fibrosis in the lungs of relevant animal types and for MWCNTs these effects are also seen in the pleura. For instance, minimal histiocytosis and mild granulomatous inflammation in the lungs and lung-draining lymph nodes have been observed in rats exposed for 13 weeks to 0.1 mg/m3 MWCNTs (lowest observed adverse effect level, LOAEL), with more pronounced inflammation in both mice and rats at higher doses. Thus, inflammatory responses in the lungs may be considered as the critical effect. However, the LOAEL of CNTs should be interpreted cautiously, since their toxicity is likely to vary widely, depending on the structure and physicochemical properties, as well as the contribution from non-carbon components. It is also uncertain which dose metric (e.g., mass, number or surface area per air volume unit) is most appropriate. Some studies indicate that longer straight CNTs evoke more pronounced biological effects than shorter or tangled fibres