em In vitro /em studies with particles are a major staple of particle toxicology, generally used to investigate mechanisms and better understand the molecular events underlying cellular effects. particles’ but to a greater degree because of their greater surface area per Phlorizin supplier unit mass. In addition, they may translocate to the blood or brain and cause other effects. Nanoparticles come in an array of compositions, sizes, shapes and with altered surfaces, all of which could alter toxicity. The sheer number of variants that need testing has stimulated a move towards the idea that em in vitro /em testing might provide an answer to the otherwise large scale animal testing, that is both expensive and time consuming. Indeed, Nel et al. [1] have proposed that generation of reactive species and induction of oxidant stress may form the basis for development of in vitro screening methodology. In contrast, Oberdorster et al. [2] summarized the views of a panel of nano scientists which placed in vivo studies as primary to the evaluation of potential health hazard of nanoparticles. We point out here the potential dangers of unique use of an in vitro screening approach in view of experience with other particles, suggesting that particles can cause a rather narrow range of effects on cells in culture which does not reflect the range of different pathogenic effects they cause em in vivo /em . This is likely in large part due to the issue of translocation and toxicokinetics, which is one of the most under-researched areas in nanoparticle toxicology, as well as for conventional particle toxicology. Diverse effects of different particles in causing disease It is an apparent paradox that exposure to different kinds of particles causes a range of different adverse effects whilst, em in vitro /em at the cellular/molecular level, they have been found to influence comparable pathways Phlorizin supplier and mechanisms, mostly based around oxidative stress. The particles under consideration here are asbestos, quartz and PM10 and the different diseases they are associated with are indicated in Table ?Table1.1. As is usually evident from Table ?Table1,1, the different particle types cause different types of pathological effects despite their deposition in the same target tissue, namely the airspaces of the lung. Protracted exposure to the different particle types results in quite different types of pathological response. Table 1 Particle-specific adverse health effects of the 3 particle types under consideration. thead Adverse Rabbit polyclonal to COFILIN.Cofilin is ubiquitously expressed in eukaryotic cells where it binds to Actin, thereby regulatingthe rapid cycling of Actin assembly and disassembly, essential for cellular viability. Cofilin 1, alsoknown as Cofilin, non-muscle isoform, is a low molecular weight protein that binds to filamentousF-Actin by bridging two longitudinally-associated Actin subunits, changing the F-Actin filamenttwist. This process is allowed by the dephosphorylation of Cofilin Ser 3 by factors like opsonizedzymosan. Cofilin 2, also known as Cofilin, muscle isoform, exists as two alternatively splicedisoforms. One isoform is known as CFL2a and is expressed in heart and skeletal muscle. The otherisoform is known as CFL2b and is expressed ubiquitously effects /thead ParticlePulmonaryExtra-pulmonaryAsbestosInterstitial fibrosis, bronchogenic carcinoma, pleural mesothelioma, pleural fibrosis, pleural plaquesPeritoneal mesothelioma, Autoimmune disease hr / QuartzNodular fibrosis, small airways disease, bronchogenic carcinoma, pleural fibrosisAutoimmune disease hr / PM10Increased lung cancer risk Exacerbations of COPD, Development of COPD Exacerbations of asthmaDeaths and hospitalisations for cardiovascular disease, Open in a separate window Similar effects of particles em in vitro /em Numerous Phlorizin supplier in vitro studies indicate that asbestos, quartz and PM10 have comparable activities in cells em in vitro /em C via oxidative stress, activation of NF-B, pro-inflammatory effects and oxidative adduct formation (Table ?(Table2)2) [3-24]. We submit that this paradox, i.e. the mismatch between the similarities in effect seen em in vitro /em and the differences in disease seen em in vivo /em , Phlorizin supplier poses a threat to the power of in vitro nanotoxicology. Table 2 Studies showing significant effects of the different particle types on inflammatory, genotoxic and oxidative stress endpoints in vitro thead Endpoint /thead ParticleOxidative stressNF-B activationAP-1 ActivationChemokine production epithelial cellsTNF production macsGrowth factor productionDirect genotox-icityApoptosis hr / Asbestos[21][4][23][16][8][14] fibroblasts[15][3] hr / Quartz[9][17][18][20][6][24] epithelial cells[35][12] hr / PM10[19][13][22][65][5][7] epithelial cells[11][10] Open in a separate window In addition, there are other examples where em in vitro /em testing has been shown to misclassify health hazard. The first would be glass fibres. Glass fibres have been reported to be positive in cell testing studies: generating reactive oxygen species, causing oxidant stress, causing DNA damage, inducing chromosomal aberrations,.