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L'agénésie de la valve pulmonaire est une cardiopathie congénitale rare (6/3000 cardiopathies congénitales). La tolérance clinique et le pronostic de la forme avec communication inter ventriculaire dépendent de la compression des voies respiratoires par l'artère pulmonaire dilatée. Nous rapportons un cas chez une sénégalaise de 24 ans.

L’arachide est cultivée par plus de 100 pays dans le monde. Les principaux producteurs sont la Chine et l’Inde qui fournissent plus de 60 % de la production mondiale. L’Afrique assure 25 % de la production avec le Nigéria, le Sénégal et le Soudan principalement. Au Sénégal, dans les années 1960, la culture de l’arachide s’était développée comme culture de rente (production d’huile et de tourteau) destinée à l’exportation avec une ouverture croissante sur le marché mondial. Cette culture fut le moteur du développement de l’économie sénégalaise et a assuré jusqu’à 80 % des exportations et fourni la majeure partie des revenus monétaires en milieu rural. Mais à partir de 1970 et notamment depuis les années 1990, on a assisté à une véritable crise de la filière arachidière et les différentes politiques agricoles n’ont pas toujours permis la relance de la filière. Ce travail est une synthèse des informations recueillies sur l’arachide au Sénégal. Il revient sur l’importance de la culture, fait un état des lieux sur la production et la commercialisation, ressort les différentes contraintes de la production et propose des pistes pour la relance de la filière.

INTRODUCTION: La fibrillation atriale est le trouble du rythme cardiaque soutenu le plus fréquent. Les objectifs de ce travail étaient d’étudier la fréquence, les facteurs étiologiques, l’évolution et le traitement de la fibrillation atriale dans un service de cardiologie de Dakar au Sénégal. METHODES: Il s’agit d’une étude rétrospective réalisée sur cinq ans et portant sur l’analyse de 150 dossiers de patients hospitalisés pour une fibrillation atriale. RESULTATS: La fréquence de la fibrillation atriale était de 5,35 % et représentait 66% des troubles du rythme cardiaque avec une prédominance féminine (sex-ratio H/F = 0,45) et un âge moyen de 57,06 ± 18,64 ans. L’origine de la fibrillation était valvulaire dans 36,7% des cas. Les complications thromboemboliques étaient plus fréquentes dans la fibrillation atriale non valvulaire (p=0,006), chez les sujets d’âge > 50 ans (p=0,01) et en cas de dilatation de l’oreillette gauche (p=0,05). Une anticoagulation par anti-vitamine K était instaurée dans 62% des cas et un traitement de contrôle de la fréquence cardiaque dans 87,33%. CONCLUSION: La fibrillation atriale est fréquente en milieu hospitalier africain et concerne des sujets relativement jeunes. L’hypertension artérielle et les valvulopathies rhumatismales sont les principaux facteurs étiologiques. Le traitement reste essentiellement médicamenteux par contrôle de la fréquence cardiaque.

The development and production of engineered 2D nanomaterials are expanding exponentially, increasing the risk of their release into the aquatic environment. A recent study showed 2D MnO 2 nanosheets, under development for energy and biomedical applications, dissolve upon interaction with biological reducing agents, resulting in depletion of intracellular glutathione levels within fish gill cells. However, little is known concerning their toxicity and interactions with subcellular organelles. To address this gap, we examined cellular uptake, cytotoxicity and mitochondrial effects of 2D MnO 2 nanosheets using an in vitro fish gill cell line to represent a target tissue of rainbow trout, a freshwater indicator species. The data demonstrate cellular uptake of MnO 2 nanosheets into lysosomes and potential mechanisms of dissolution within the lysosomal compartment. MnO 2 nanosheets induced severe mitochondrial dysfunction at sub-cytotoxic doses. Quantitative, single cell fluorescent imaging revealed mitochondrial fission and impaired mitochondrial membrane potential following MnO 2 nanosheet exposure. Seahorse analyses for cellular respiration revealed that MnO 2 nanosheets inhibited basal respiration, maximal respiration and the spare respiratory capacity of gill cells, indicating mitochondrial dysfunction and reduced cellular respiratory activity. MnO 2 nanosheet exposure also inhibited ATP production, further supporting the suppression of mitochondrial function and cellular respiration. Together, these observations indicate that 2D MnO 2 nanosheets impair the ability of gill cells to respond to energy demands or prolonged stress. Finally, our data demonstrate significant differences in the toxicity of the 2D MnO 2 nanosheets and their microparticle counterparts. This exemplifies the importance of considering the unique physical characteristics of 2D nanomaterials when conducting safety assessments.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention. See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention.", (©2020 American Association for Cancer Research.)

Many layered crystal phases can be exfoliated or assembled into ultrathin 2D nanosheets with novel properties not achievable by particulate or fibrous nanoforms. Among these 2D materials are manganese dioxide (MnO 2 ) nanosheets, which have applications in batteries, catalysts, and biomedical probes. A novel feature of MnO 2 is its sensitivity to chemical reduction leading to dissolution and Mn 2+ release. Biodissolution is critical for nanosafety assessment of 2D materials, but the timing and location of MnO 2 biodissolution in environmental or occupational exposure scenarios are poorly understood. This work investigates the chemical and colloidal dynamics of MnO 2 nanosheets in biological media for environmental and human health risk assessment. MnO 2 nanosheets are insoluble in most aqueous phases, but react with strong and weak reducing agents in biological fluid environments. In vitro, reductive dissolution can be slow enough in cell culture media for MnO 2 internalization by cells in the form of intact nanosheets, which localize in vacuoles, react to deplete intracellular glutathione, and induce cytotoxicity that is likely mediated by intracellular Mn 2+ release. The results are used to classify MnO 2 nanosheets within a new hazard screening framework for 2D materials, and the implications of MnO 2 transformations for nanotoxicity testing and nanosafety assessment are discussed., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Multi-walled carbon nanotubes (MWCNT) have been shown to elicit the release of inflammatory and pro-fibrotic mediators, as well as histopathological changes in lungs of exposed animals. Current standards for testing MWCNTs and other nanoparticles (NPs) rely on low-throughput in vivo studies to assess acute and chronic toxicity and potential hazard to humans. Several alternative testing approaches utilizing two-dimensional (2D) in vitro assays to screen engineered NPs have reported conflicting results between in vitro and in vivo assays. Compared to conventional 2D in vitro or in vivo animal model systems, three-dimensional (3D) in vitro platforms have been shown to more closely recapitulate human physiology, providing a relevant, more efficient strategy for evaluating acute toxicity and chronic outcomes in a tiered nanomaterial toxicity testing paradigm., Results: As inhalation is an important route of nanomaterial exposure, human lung fibroblasts and epithelial cells were co-cultured with macrophages to form scaffold-free 3D lung microtissues. Microtissues were exposed to multi-walled carbon nanotubes, M120 carbon black nanoparticles or crocidolite asbestos fibers for 4 or 7 days, then collected for characterization of microtissue viability, tissue morphology, and expression of genes and selected proteins associated with inflammation and extracellular matrix remodeling. Our data demonstrate the utility of 3D microtissues in predicting chronic pulmonary endpoints following exposure to MWCNTs or asbestos fibers. These test nanomaterials were incorporated into 3D human lung microtissues as visualized using light microscopy. Differential expression of genes involved in acute inflammation and extracellular matrix remodeling was detected using PCR arrays and confirmed using qRT-PCR analysis and Luminex assays of selected genes and proteins., Conclusion: 3D lung microtissues provide an alternative testing platform for assessing nanomaterial-induced cell-matrix alterations and delineation of toxicity pathways, moving towards a more predictive and physiologically relevant approach for in vitro NP toxicity testing.

Nanotechnology is an emerging industry based on commercialization of materials with one or more dimensions of 100 nm or less. Engineered nanomaterials are currently incorporated into thin films, porous materials, liquid suspensions, or filler/matrix nanocomposites with future applications predicted in energy and catalysis, microelectronics, environmental sensing and remediation, and nanomedicine. Carbon nanotubes are one-dimensional fibrous nanomaterials that physically resemble asbestos fibers. Toxicologic studies in rodents demonstrated that some types of carbon nanotubes can induce mesothelioma, and the World Health Organization evaluated long, rigid multiwall carbon nanotubes as possibly carcinogenic for humans in 2014. This review summarizes key physicochemical similarities and differences between asbestos fibers and carbon nanotubes. The "fiber pathogenicity paradigm" has been extended to include carbon nanotubes as well as other high-aspect-ratio fibrous nanomaterials including metallic nanowires. This paradigm identifies width, length, and biopersistence of high-aspect-ratio fibrous nanomaterials as critical determinants of lung disease, including mesothelioma, following inhalation. Based on recent theoretical modeling studies, a fourth factor, mechanical bending stiffness, will be considered as predictive of potential carcinogenicity. Novel three-dimensional lung tissue platforms provide an opportunity for in vitro screening of a wide range of high aspect ratio fibrous nanomaterials for potential lung toxicity prior to commercialization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

With increasing commercialization of high volume, two-dimensional carbon nanomaterials comes a greater likelihood of environmental release. In aquatic environments, black carbon binds contaminants like aromatic hydrocarbons, leading to changes in their uptake, bioavailability, and toxicity. Engineered carbon nanomaterials can also adsorb pollutants onto their carbon surfaces, and nanomaterial physicochemical properties can influence this contaminant interaction. We used 2D graphene nanoplatelets and isometric carbon black nanoparticles to evaluate the influence of particle morphology and surface properties on adsorption and bioavailability of benzo(a)pyrene, a model aromatic hydrocarbon, to brine shrimp (Artemia franciscana) and a fish liver cell line (PLHC-1). Acellular adsorption studies show that while high surface area carbon black (P90) was most effective at a given concentration, 2D graphene nanoplatelets (G550) adsorbed more benzo(a)pyrene than carbon black with comparable surface area (M120). In both biological models, co-exposure to nanomaterials lead to reduced bioavailability, with G550 graphene nanoplatelets cause a greater reduction in bioavailability or response than the M120 carbon black nanoparticles. However, on a mass basis the high surface area P90 carbon black was most effective. The trends in bioavailability and adsorption were consistent across all biological and acellular studies, demonstrating the biological relevance of these results in different models of aquatic organisms. While adsorption is limited by surface area, 2D graphene nanoplatelets adsorb more benzo(a)pyrene than carbon black nanoparticles of similar surface area and charge, demonstrating that both surface area and shape play important roles in the adsorption and bioavailability of benzo(a)pyrene to carbon nanomaterials., Competing Interests: Conflicts of Interest There are no conflicts of interest for the authors to declare.

Two-dimensional (2D) materials are a broad class of synthetic ultra-thin sheet-like solids whose rapid pace of development motivates systematic study of their biological effects and safe design. A challenge for this effort is the large number of new materials and their chemical diversity. Recent work suggests that many 2D materials will be thermodynamically unstable and thus non-persistent in biological environments. Such information could inform and accelerate safety assessment, but experimental data to confirm the thermodynamic predictions is lacking. Here we propose a framework for early hazard screening of nanosheet materials based on biodissolution studies in reactive media, specially chosen for each material to match chemically feasible degradation pathways. Simple dissolution and in vitro tests allow grouping of nanosheet materials into four classes: A, potentially biopersistent; B: slowly degradable (>24-48 hours); C, biosoluble with potentially hazardous degradation products; and D, biosoluble with low-hazard degradation products. The proposed framework is demonstrated through an experimental case study on MoO 3 nanoribbons, which have a dual 2D / 1D morphology and have been reported to be stable in aqueous stock solutions. The nanoribbons are shown to undergo rapid dissolution in biological simulant fluids and in cell culture, where they elicit no adverse responses up to 100μg ml -1 dose. These results place MoO 3 nanoribbons in Class D, and assigns them a low priority for further nanotoxicology testing. We anticipate use of this framework could accelerate the risk assessment for the large set of new powdered 2D nanosheet materials, and promote their safe design and commercialization.

To identify the potential environmental impacts of aquatic pollutants, rapid and sensitive screening tools are needed to assess adaptive and toxic responses. This study characterizes a novel fish liver microtissue model, produced with the cell line PLHC-1, as an in vitro aquatic toxicity testing platform. These 3D microtissues remain viable and stable throughout the 8-day testing period and relative to 2D monolayers, show increased basal expression of the xenobiotic metabolizing enzyme cytochrome P450 1A (Cyp1a). To evaluate pulsed, low-dose exposures at environmentally relevant concentrations, microtissue responsiveness to the model toxicant benzo(a)pyrene was assessed after single and repeated exposures for determination of both immediate and persistent effects. Significant induction of Cyp1a gene and protein expression was detected after a single 24h exposure to as little as 1nM benzo(a)pyrene, and after a 24h recovery period, Cyp1a expression declined in a dose-dependent manner. However, cell death continued to increase during the recovery period and alterations in microtissue architecture occurred at higher concentrations. To evaluate a pulsed or repeated exposure scenario, microtissues were exposed to benzo(a)pyrene, allowed to recover, then exposed a second time for 24h. Following pre-exposure to benzo(a)pyrene, cyp1a expression remained equally inducible and the pattern and level of Cyp1a protein response to a second exposure were comparable. However, pre-exposure to 1μM or 5μM of benzo(a)pyrene resulted in increased cell death, greater disruption of microtissue architecture, and alterations in cell morphology. Together, this study demonstrates the capabilities of this PLHC-1 microtissue model for sensitive assessment of liver toxicants over time and following single and repeated exposures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose-response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

Understanding the behavior of low-dimensional nanomaterials confined in intracellular vesicles has been limited by the resolution of bioimaging techniques and the complex nature of the problem. Recent studies report that long, stiff carbon nanotubes are more cytotoxic than flexible varieties, but the mechanistic link between stiffness and cytotoxicity is not understood. Here we combine analytical modeling, molecular dynamics simulations, and in vitro intracellular imaging methods to reveal 1D carbon nanotube behavior within intracellular vesicles. We show that stiff nanotubes beyond a critical length are compressed by lysosomal membranes causing persistent tip contact with the inner membrane leaflet, leading to lipid extraction, lysosomal permeabilization, release of cathepsin B (a lysosomal protease) into the cytoplasm, and cell death. The precise material parameters needed to activate this unique mechanical pathway of nanomaterials interaction with intracellular vesicles were identified through coupled modeling, simulation, and experimental studies on carbon nanomaterials with wide variation in size, shape, and stiffness, leading to a generalized classification diagram for 1D nanocarbons that distinguishes pathogenic from biocompatible varieties based on a nanomechanical buckling criterion. For a wide variety of other 1D material classes (metal, oxide, polymer), this generalized classification diagram shows a critical threshold in length/width space that represents a transition from biologically soft to stiff, and thus identifies the important subset of all 1D materials with the potential to induce lysosomal permeability by the nanomechanical mechanism under investigation., Competing Interests: The authors declare no conflict of interest.

Material stability and dissolution in aqueous media are key issues to address in the development of a new nanomaterial intended for technological application. Dissolution phenomena affect biological and environmental persistence; fate, transport, and biokinetics; device and product stability; and toxicity pathways and mechanisms. This article shows that MoS2 nanosheets are thermodynamically and kinetically unstable to O2-oxidation under ambient conditions in a variety of aqueous media. The oxidation is accompanied by nanosheet degradation and release of soluble molybdenum and sulfur species, and generates protons that can colloidally destabilize the remaining sheets. The oxidation kinetics are pH-dependent, and a kinetic law is developed for use in biokinetic and environmental fate modeling. MoS2 nanosheets fabricated by chemical exfoliation with n-butyl-lithium are a mixture of 1T (primary) and 2H (secondary) phases and oxidize rapidly with a typical half-life of 1-30 days. Ultrasonically exfoliated sheets are in pure 2H phase, and oxidize much more slowly. Cytotoxicity experiments on MoS2 nanosheets and molybdate ion controls reveal the relative roles of the nanosheet and soluble fractions in the biological response. These results indicate that MoS2 nanosheets will not show long-term persistence in living systems and oxic natural waters, with important implications for biomedical applications and environmental risk.

Engineered nanomaterials (ENMs) are increasingly entering the environment with uncertain consequences including potential ecological effects. Various research communities view differently whether ecotoxicological testing of ENMs should be conducted using environmentally relevant concentrations-where observing outcomes is difficult-versus higher ENM doses, where responses are observable. What exposure conditions are typically used in assessing ENM hazards to populations? What conditions are used to test ecosystem-scale hazards? What is known regarding actual ENMs in the environment, via measurements or modeling simulations? How should exposure conditions, ENM transformation, dose, and body burden be used in interpreting biological and computational findings for assessing risks? These questions were addressed in the context of this critical review. As a result, three main recommendations emerged. First, researchers should improve ecotoxicology of ENMs by choosing test end points, duration, and study conditions-including ENM test concentrations-that align with realistic exposure scenarios. Second, testing should proceed via tiers with iterative feedback that informs experiments at other levels of biological organization. Finally, environmental realism in ENM hazard assessments should involve greater coordination among ENM quantitative analysts, exposure modelers, and ecotoxicologists, across government, industry, and academia.

For nanotechnology to meet its potential as a game-changing and sustainable technology, it is important to ensure that the engineered nanomaterials and nanoenabled products that gain entry to the marketplace are safe and effective. Tools and methods are needed for regulatory purposes to allow rapid material categorization according to human health and environmental risk potential, so that materials of high concern can be targeted for additional scrutiny, while material categories that pose the least risk can receive expedited review. Using carbon nanotubes as an example, we discuss how data from alternative testing strategies can be used to facilitate engineered nanomaterial categorization according to risk potential and how such an approach could facilitate regulatory decision-making in the future.

Two-dimensional nanomaterials have potential as a new class of antioxidants that combine physical barrier function with ultrahigh surface area for free radical scavenging. This work presents the first measurements of the chemical reactivities of graphene-based materials toward a set of model free radicals and reactive oxygen species using electron paramagnetic resonance spectroscopy (EPR) and sacrificial dye protection assays. Graphene-based materials are shown to protect a variety of molecular targets from oxidation by these species, and to be highly effective as hydroxyl-radical scavengers. When the hydroxyl radical is produced photolytically, the overall antioxidant effect is a combination of preventative antioxidant activity (UV absorption) and ˙OH radical scavenging. Few-layer graphene is more active than monolayer graphene oxide, despite its lower surface area, which indicates that the primary scavenging sites are associated with the sp(2)-carbon network rather than oxygen-containing functional groups. To explain this trend, we propose that GO is a weak hydrogen donor, due to the non-phenolic nature of most OH groups on GO, which reside at basal sp(3)-carbon sites that do not allow for radical resonance stabilization following hydrogen donation. As an example application of graphene antioxidant behavior, we show that encapsulation of TiO2 nanoparticles in graphene nanosacks reduces undesired photo-oxidative damage to nearby organic target molecules, which suggests graphene encapsulation as a new approach to managing adverse environmental or health impacts of redox-active nanomaterials.

Fine particles are under active consideration as alternatives to chemical dispersants for large-scale petroleum spills. Fine carbon particles with engineered surface chemistry have been shown to stabilize oil-in-water emulsions, but the environmental impacts of large-scale particle introduction to the marine environment are unknown. Here we study the impact of surface-engineered carbon-black materials on brine shrimp (Artemia franciscana) as a model marine microcrustacean. Mortality was characterized at 50-1000 mg/L, and levels of heat shock protein 70 (hsp70) were characterized at sublethal particle concentrations (25-50 mg/L). Functionalized carbon black (CB) nanoparticles were found to be nontoxic at all concentrations, while hydrophobic (annealed) and as-produced CB induced adverse effects at high concentrations. CB was also shown to adsorb benzene, a model hydrocarbon representing the more soluble and toxic low-molecular weight aromatic fraction of petroleum, but the extent of adsorption was insufficient to mitigate benzene toxicity to Artemia in coexposure experiments. At lower benzene concentrations (25-75 mg/L), coexposure with annealed and as-produced CB increased hsp70 protein levels. This study suggests that surface functionalization for increased hydrophilicity can not only improve the performance of CB-based dispersants but also reduce their adverse environmental impacts on marine organisms.

Copper-based nanoparticles are an important class of materials with applications as catalysts, conductive inks, and antimicrobial agents. Environmental and safety issues are particularly important for copper-based nanomaterials because of their potential large-scale use and their high redox activity and toxicity reported from in vitro studies. Elemental nanocopper oxidizes readily upon atmospheric exposure during storage and use, so copper oxides are highly relevant phases to consider in studies of environmental and health impacts. Here we show that copper oxide nanoparticles undergo profound chemical transformations under conditions relevant to living systems and the natural environment. Copper oxide nanoparticle (CuO-NP) dissolution occurs at lysosomal pH (4-5), but not at neutral pH in pure water. Despite the near-neutral pH of cell culture medium, CuO-NPs undergo significant dissolution in media over time scales relevant to toxicity testing because of ligand-assisted ion release, in which amino acid complexation is an important contributor. Electron paramagnetic resonance (EPR) spectroscopy shows that dissolved copper in association with CuO-NPs are the primary redox-active species. CuO-NPs also undergo sulfidation by a dissolution-reprecipitation mechanism, and the new sulfide surfaces act as catalysts for sulfide oxidation. Copper sulfide NPs are found to be much less cytotoxic than CuO-NPs, which is consistent with the very low solubility of CuS. Despite this low solubility of CuS, EPR studies show that sulfidated CuO continues to generate some ROS activity due to the release of free copper by H2O2 oxidation during the Fenton-chemistry-based EPR assay. While sulfidation can serve as a natural detoxification process for nanosilver and other chalcophile metals, our results suggest that sulfidation may not fully and permanently detoxify copper in biological or environmental compartments that contain reactive oxygen species.

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis.

Understanding and controlling the interaction of graphene-based materials with cell membranes is key to the development of graphene-enabled biomedical technologies and to the management of graphene health and safety issues. Very little is known about the fundamental behavior of cell membranes exposed to ultrathin 2D synthetic materials. Here we investigate the interactions of graphene and few-layer graphene (FLG) microsheets with three cell types and with model lipid bilayers by combining coarse-grained molecular dynamics (MD), all-atom MD, analytical modeling, confocal fluorescence imaging, and electron microscopic imaging. The imaging experiments show edge-first uptake and complete internalization for a range of FLG samples of 0.5- to 10-μm lateral dimension. In contrast, the simulations show large energy barriers relative to kBT for membrane penetration by model graphene or FLG microsheets of similar size. More detailed simulations resolve this paradox by showing that entry is initiated at corners or asperities that are abundant along the irregular edges of fabricated graphene materials. Local piercing by these sharp protrusions initiates membrane propagation along the extended graphene edge and thus avoids the high energy barrier calculated in simple idealized MD simulations. We propose that this mechanism allows cellular uptake of even large multilayer sheets of micrometer-scale lateral dimension, which is consistent with our multimodal bioimaging results for primary human keratinocytes, human lung epithelial cells, and murine macrophages.

As graphene technologies progress to commercialization and large-scale manufacturing, issues of material and processing safety will need to be more seriously considered. The single word "graphene" actually represents a family of related materials with large variations in number of layers, surface area, lateral dimensions, stiffness, and surface chemistry. Many of these materials have aerodynamic diameters below 5 μm and can potentially be inhaled into the human lung. Graphene materials show several unique modes of interaction with biological molecules, tissues, and cells. The limited literature suggests that graphene materials can be either benign or harmful and that the biological response varies according to a material's physicochemical properties and biologically effective dose. The present article reviews the current literature on the graphene-biological interface with an emphasis on the mechanisms and fundamental biological responses relevant to material safety and also to potential biomedical applications.

The widespread use of silver nanoparticles (Ag-NPs) in consumer and medical products provides strong motivation for a careful assessment of their environmental and human health risks. Recent studies have shown that Ag-NPs released to the natural environment undergo profound chemical transformations that can affect silver bioavailability, toxicity, and risk. Less is known about Ag-NP chemical transformations in biological systems, though the medical literature clearly reports that chronic silver ingestion produces argyrial deposits consisting of silver-, sulfur-, and selenium-containing particulate phases. Here we show that Ag-NPs undergo a rich set of biochemical transformations, including accelerated oxidative dissolution in gastric acid, thiol binding and exchange, photoreduction of thiol- or protein-bound silver to secondary zerovalent Ag-NPs, and rapid reactions between silver surfaces and reduced selenium species. Selenide is also observed to rapidly exchange with sulfide in preformed Ag(2)S solid phases. The combined results allow us to propose a conceptual model for Ag-NP transformation pathways in the human body. In this model, argyrial silver deposits are not translocated engineered Ag-NPs, but rather secondary particles formed by partial dissolution in the GI tract followed by ion uptake, systemic circulation as organo-Ag complexes, and immobilization as zerovalent Ag-NPs by photoreduction in light-affected skin regions. The secondary Ag-NPs then undergo detoxifying transformations into sulfides and further into selenides or Se/S mixed phases through exchange reactions. The formation of secondary particles in biological environments implies that Ag-NPs are not only a product of industrial nanotechnology but also have long been present in the human body following exposure to more traditional chemical forms of silver.

Graphene is a single-atom thick, two-dimensional sheet of hexagonally arranged carbon atoms isolated from its three-dimensional parent material, graphite. Related materials include few-layer-graphene (FLG), ultrathin graphite, graphene oxide (GO), reduced graphene oxide (rGO), and graphene nanosheets (GNS). This review proposes a systematic nomenclature for this set of Graphene-Family Nanomaterials (GFNs) and discusses specific materials properties relevant for biomolecular and cellular interactions. We discuss several unique modes of interaction between GFNs and nucleic acids, lipid bilayers, and conjugated small molecule drugs and dyes. Some GFNs are produced as dry powders using thermal exfoliation, and in these cases, inhalation is a likely route of human exposure. Some GFNs have aerodynamic sizes that can lead to inhalation and substantial deposition in the human respiratory tract, which may impair lung defense and clearance leading to the formation of granulomas and lung fibrosis. The limited literature on in vitro toxicity suggests that GFNs can be either benign or toxic to cells, and it is hypothesized that the biological response will vary across the material family depending on layer number, lateral size, stiffness, hydrophobicity, surface functionalization, and dose. Generation of reactive oxygen species (ROS) in target cells is a potential mechanism for toxicity, although the extremely high hydrophobic surface area of some GFNs may also lead to significant interactions with membrane lipids leading to direct physical toxicity or adsorption of biological molecules leading to indirect toxicity. Limited in vivo studies demonstrate systemic biodistribution and biopersistence of GFNs following intravenous delivery. Similar to other smooth, continuous, biopersistent implants or foreign bodies, GFNs have the potential to induce foreign body tumors. Long-term adverse health impacts must be considered in the design of GFNs for drug delivery, tissue engineering, and fluorescence-based biomolecular sensing. Future research is needed to explore fundamental biological responses to GFNs including systematic assessment of the physical and chemical material properties related to toxicity. Complete materials characterization and mechanistic toxicity studies are essential for safer design and manufacturing of GFNs in order to optimize biological applications with minimal risks for environmental health and safety.

Micron-sized particles of poorly soluble nickel compounds, but not metallic nickel, are established human and rodent carcinogens. In contrast, little is known about the toxic effects of a growing number of Ni-containing materials in the nano-sized range. Here, we performed physicochemical characterization of NiO and metallic Ni nanoparticles and examined their metal ion bioavailability and toxicological properties in human lung epithelial cells. Cellular uptake of metallic Ni and NiO nanoparticles, but not metallic Ni microparticles, was associated with the release of Ni(II) ions after 24-48 h as determined by Newport Green fluorescence. Similar to soluble NiCl₂, NiO nanoparticles induced stabilization and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) transcription factor followed by upregulation of its target NRDG1 (Cap43). In contrast to no response to metallic Ni microparticles, nickel nanoparticles caused a rapid and prolonged activation of the HIF-1α pathway that was stronger than that induced by soluble Ni(II). Soluble NiCl₂ and NiO nanoparticles were equally toxic to H460 human lung epithelial cells and primary human bronchial epithelial cells; metallic Ni nanoparticles showed lower toxicity and Ni microparticles were nontoxic. Cytotoxicity induced by all forms of Ni occurred concomitant with activation of an apoptotic response, as determined by dose- and time-dependent cleavage of caspases and poly (ADP-ribose) polymerase. Our results show that metallic Ni nanoparticles, in contrast to micron-sized Ni particles, activate a toxicity pathway characteristic of carcinogenic Ni compounds. Moderate cytotoxicity and sustained activation of the HIF-1α pathway by metallic Ni nanoparticles could promote cell transformation and tumor progression.

Background: The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathological reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following intraperitoneal injection. This asbestos-like behaviour of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures., Results: Carbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized reference materials and compared with three commercial samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/ml (0.38 μg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphology of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers., Conclusions: Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation.

Exposure to asbestos fibers is associated with non-neoplastic pleural diseases including plaques, fibrosis, and benign effusions, as well as with diffuse malignant pleural mesothelioma. Translocation and retention of fibers are fundamental processes in understanding the interactions between the dose and dimensions of fibers retained at this anatomic site and the subsequent pathological reactions. The initial interaction of fibers with target cells in the pleura has been studied in cellular models in vitro and in experimental studies in vivo. The proposed biological mechanisms responsible for non-neoplastic and neoplastic pleural diseases and the physical and chemical properties of asbestos fibers relevant to these mechanisms are critically reviewed. Understanding mechanisms of asbestos fiber toxicity may help us anticipate the problems from future exposures both to asbestos and to novel fibrous materials such as nanotubes. Gaps in our understanding have been outlined as guides for future research.

Background: Asbestos induces DNA and chromosomal damage, but the DNA repair pathways protecting human cells against its genotoxicity are largely unknown. Polymorphisms in XRCC1 have been associated with altered susceptibility to asbestos-related diseases. However, it is unclear whether oxidative DNA damage repaired by XRCC1 contributes to asbestos-induced chromosomal damage., Objectives: We sought to examine the importance of XRCC1 in protection against genotoxic effects of crocidolite and Libby amphibole asbestos., Methods: We developed a genetic model of XRCC1 deficiency in human lung epithelial H460 cells and evaluated genotoxic responses to carcinogenic fibers (crocidolite asbestos, Libby amphibole) and nongenotoxic materials (wollastonite, titanium dioxide)., Results: XRCC1 knockdown sensitized cells to the clastogenic and cytotoxic effects of oxidants [hydrogen peroxide (H₂O₂), bleomycin] but not to the nonoxidant paclitaxel. XRCC1 knockdown strongly enhanced genotoxicity of amphibole fibers as evidenced by elevated formation of clastogenic micronuclei. Crocidolite induced primarily clastogenic micronuclei, whereas Libby amphibole induced both clastogenic and aneugenic micronuclei. Crocidolite and bleomycin were potent inducers of nuclear buds, which were enhanced by XRCC1 deficiency. Libby amphibole and H₂O₂ did not induce nuclear buds, irrespective of XRCC1 status. Crocidolite and Libby amphibole similarly activated the p53 pathway., Conclusions: Oxidative DNA damage repaired by XRCC1 (oxidized bases, single-strand breaks) is a major cause of chromosomal breaks induced by crocidolite and Libby amphibole. Nuclear buds are a novel biomarker of genetic damage induced by exposure to crocidolite asbestos, which we suggest are associated with clustered DNA damage. These results provide mechanistic evidence for the epidemiological association between XRCC1 polymorphisms and susceptibility to asbestos-related disease.

Unlabelled: Diffuse malignant mesothelioma is an aggressive tumor which displays a median survival of 11.2 months and a 5-year survival of less than 5% emphasizing the need for more effective treatments. This study uses an orthotopic model of malignant mesothelioma established in syngeneic, immunocompetent C57Bl/6 mice which produce malignant ascites and solid tumors that accurately replicate the histopathology of the human disease. Host stromal and immune cell accumulation within malignant ascites and solid tumors was determined using immunofluorescent labeling with confocal microscopy and fluorescence-activated cell sorting. An expression profile of cytokines and chemokines was produced using quantitative real-time PCR arrays. Tumor spheroids and solid tumors show progressive growth and infiltration with host stromal and immune cells including macrophages, endothelial cells, CD4(+) and CD8(+) lymphocytes, and a novel cell type, myeloid derived suppressor cells (MDSCs). The kinetics of host cell accumulation and inflammatory mediator expression within the tumor ascites divides tumor progression into two distinct phases. The first phase is characterized by progressive macrophage and T lymphocyte recruitment, with a cytokine profile consistent with regulatory T lymphocytes differentiation and suppression of T cell function. The second phase is characterized by decreased expression of macrophage chemotactic and T-cell regulating factors, an increase in MDSCs, and increased expression of several cytokines which stimulate differentiation of MDSCs. This cellular and expression profile suggests a mechanism by which host immune cells promote diffuse malignant mesothelioma progression., Electronic Supplementary Material: The online version of this article (doi:10.1007/s12307-010-0048-1) contains supplementary material, which is available to authorized users.

Background/aim: Tumor progression is influenced by the microenvironment. We found stem cells are recruited to malignant mesothelioma spheroids. We aimed to determine if stem cell recruitment depends on the chemokine SDF1, and if inhibition of the cognate receptor CXCR4 affects tumor growth., Materials and Methods: The kinetics of stem cell recruitment was determined using immunofluorescence staining, BrdU incorporation and eGFP transgenic mice. Chemokines were identified using PCR array. Inhibitors of CXCR4 were used to determine the effect on cell migration and tumor progression., Results: The increasing number of stem cells found in tumor spheroids over time is attributed to cell recruitment. Stem cell migration in vitro was enhanced by exogenous SDF1 and abrogated by CXCR4 inhibition and. CXCR4 inhibition reduced tumor burden in vivo., Conclusion: SDF1 is a candidate chemokine for recruitment of stem cells to malignant peritoneal mesothelioma and a potential target for therapy.

Recent research has led to increased concern about the potential adverse human health impacts of carbon nanotubes, and further work is needed to better characterize those risks and develop risk management strategies. One of the most important determinants of the chronic pathogenic potential of a respirable fiber is its biological durability, which affects the long-term dose retained in the lungs, or biopersistence. The present article characterizes the biodurability of single-walled carbon nanotubes using an in vitro assay simulating the phagolysosome. Biodurability is observed to depend on the chemistry of nanotube surface functionalization. Single-walled nanotubes with carboxylated surfaces are unique in their ability to undergo 90-day degradation in a phagolysosomal simulant leading to length reduction and accumulation of ultrafine solid carbonaceous debris. Unmodified, ozone-treated, and aryl-sulfonated tubes do not degrade under these conditions. We attribute the difference to the unique chemistry of acid carboxylation, which not only introduces COOH surface groups, but also causes collateral damage to the tubular graphenic backbone in the form of neighboring active sites that provide points of attack for further oxidative degradation. These results suggest the strategic use of surface carboxylation in nanotube applications where biodegradation may improve safety or add function.

Human diseases associated with exposure to asbestos fibers include pleural fibrosis and plaques, pulmonary fibrosis (asbestosis), lung cancer, and diffuse malignant mesothelioma. The critical determinants of fiber bioactivity and toxicity include not only fiber dimensions, but also shape, surface reactivity, crystallinity, chemical composition, and presence of transition metals. Depending on their size and dimensions, inhaled fibers can penetrate the respiratory tract to the distal airways and into the alveolar spaces. Fibers can be cleared by several mechanisms, including the mucociliary escalator, engulfment, and removal by macrophages, or through splitting and chemical modification. Biopersistence of long asbestos fibers can lead to inflammation, granuloma formation, fibrosis, and cancer. Exposure to synthetic carbon nanomaterials, including carbon nanofibers and carbon nanotubes (CNTs), is considered a potential health hazard because of their physical similarities with asbestos fibers. Respiratory exposure to CNTs can produce an inflammatory response, diffuse interstitial fibrosis, and formation of fibrotic granulomas similar to that observed in asbestos-exposed animals and humans. Given the known cytotoxic and carcinogenic properties of asbestos fibers, toxicity of fibrous nanomaterials is a topic of intense study. The mechanisms of nanomaterial toxicity remain to be fully elucidated, but recent evidence suggests points of similarity with asbestos fibers, including a role for generation of reactive oxygen species, oxidative stress, and genotoxicity. Considering the rapid increase in production and use of fibrous nanomaterials, it is imperative to gain a thorough understanding of their biologic activity to avoid the human health catastrophe that has resulted from widespread use of asbestos fibers., (Copyright (c) 2009 John Wiley & Sons, Inc.)

The human CDKN2A locus encodes 2 distinct proteins, p16(INK4A) and p14(ARF) [mouse p19(Arf)], designated INK4A (inhibitor of cyclin dependent kinase 4) and ARF (alternative reading frame) here, that are translated from alternatively spliced mRNAs. Human ARF is implicated as a tumor suppressor gene, mainly in association with the simultaneous deletion of INK4A. However, questions remain as to whether loss of ARF alone is sufficient to drive tumorigenesis. Here, we report that mice deficient for Arf are susceptible to accelerated asbestos-induced malignant mesothelioma (MM). MMs arising in Arf (+/-) mice consistently exhibit biallelic inactivation of Arf, but, unexpectedly, do not acquire additional recurrent genetic alterations that we previously identified in asbestos-induced MMs arising in Nf2 (+/-) mice. Array CGH analysis was used to detect a recurrent deletion at chromosome 4C6 in MMs from Arf (+/-) mice. A candidate gene in this region, Faf1 (FAS-associated factor 1), was further explored, because it encodes a protein implicated in tumor cell survival and in the pathogenesis of some human tumor types. We confirmed hemizygous loss of Faf1 and down-regulation of Faf1 protein in a series of MMs from Arf (+/-) mice, and we then showed that Faf1 regulates TNF-alpha-mediated NF-kappaB signaling, a pathway previously implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these data indicate that Arf inactivation has a significant role in driving MM pathogenesis, and implicate Faf1 as a key component in the TNF-alpha/NF-kappaB signaling node that has now been independently implicated in asbestos-induced oncogenesis.

Tumors are a mixture of neoplastic and host stromal cells, which establish a microenvironment that contributes to tumor progression. In this study, the contribution of tumor-associated macrophages (TAMs) to tumor growth and metastasis was examined using an orthotopic, immunocompetent murine model of diffuse malignant peritoneal mesothelioma. The expression profile of cytokines and chemokines in solid tumors was consistent with a M2-polarized, TAM-mediated immunosuppressive microenvironment. TAMs were targeted using liposome-encapsulated clodronate (CLIP). Exposure of tumor spheroids to CM-DiI-labeled CLIP in situ confirms targeting of macrophages and not mesothelioma cells. Intraperitoneal (i.p.) delivery of CLIP produced apoptosis in tumor spheroids and solid tumors in contrast to delivery of liposome-encapsulated PBS or PBS. Mice received an i.p. injection of mesothelioma cells with CLIP delivered i.p. every 5 days. This treatment protocol produces a 4-fold reduction in the number of tumors, a 17-fold reduction in the relative tumor burden, and a 5-fold reduction in invasion and metastasis when compared with mice exposed to liposome-encapsulated PBS or PBS. Following transplantation of tumor spheroids and treatment with CLIP, mice showed a 4-fold reduction in the number of tumors and a 15-fold reduction in relative tumor burden. Mice bearing established tumors showed a 2-fold reduction in the number of tumors and relative tumor burden when exposed to half the previous dose of CLIP delivered by repeated i.p. injection. These reductions in tumor burden are statistically significant and identify TAMs as an important host-derived cell that contributes to growth, invasion, and metastasis in diffuse malignant peritoneal mesothelioma.

There is substantial evidence for toxicity and/or carcinogenicity upon inhalation of pure transition metals in fine particulate form. Carbon nanotube catalyst residues may trigger similar metal-mediated toxicity, but only if the metal is bioavailable and not fully encapsulated within fluid-protective carbon shells. Recent studies have documented the presence of bioavailable iron and nickel in a variety of commercial as-produced and vendor "purified" nanotubes, and the present article examines techniques to avoid or remove this bioavailable metal. First, data are presented on the mechanisms potentially responsible for free metal in "purified" samples, including kinetic limitations during metal dissolution, the re-deposition or adsorption of metal on nanotube outer surfaces, and carbon shell damage during last-step oxidation or one-pot purification. Optimized acid treatment protocols are presented for targeting the free metal, considering the effects of acid strength, composition, time, and conditions for post-treatment water washing. Finally, after optimized acid treatment, it is shown that the remaining, non-bioavailable (encapsulated) metal persists in a stable and biologically unavailable form up to two months in an in vitro biopersistence assay, suggesting that simple removal of bioavailable (free) metal is a promising strategy for reducing nanotube health risks.

This work investigates the physical interactions between carbon nanomaterials and tocopheryl polyethylene glycol succinate (TPGS). TPGS is a synthetic amphiphile that undergoes enzymatic cleavage to deliver the lipophilic antioxidant, alpha-tocopherol (vitamin E) to cell membranes, and is FDA approved as a water-soluble vitamin E nutritional supplement and drug delivery vehicle. Here we show that TPGS 1000 is capable of dispersing multi-wall and single-wall carbon nanotubes in aqueous media, and for multiwall tubes is more effective than the commonly used non-ionic surfactant Triton X-100. TPGS is also capable of solubilizing C(60) in aqueous phases by dissolving fullerene in the core of its spherical micelles. Drying of these solutions leads to fullerene/TPGS phase separation and the self-assembly of highly ordered asymmetric nanoparticles, with fullerene nanocrystals attached to the hydrophobic end of crystalline TPGS nanobrushes. The article discusses surface charge, colloidal stability, and the potential applications of TPGS as a safe surfactant for "green" processing of carbon nanomaterials.

SV40 virus has emerged as a potential cofactor with asbestos in the development of diffuse malignant mesothelioma, but its precise role in the pathogenesis of this tumor is unclear. SV40 large T antigen is known to inactivate cellular proteins involved in DNA damage and senescence, including p53 and pRb. We hypothesize that SV40 oncoproteins will sensitize mesothelial cells to DNA damage induced by asbestos or chemotherapeutic agents. SV40 oncoprotein expression in murine mesothelial cell lines enhanced spontaneous and asbestos-induced double-strand breaks, indicated by gamma-H2AX foci, and potentiated micronucleus formation. Mesothelial cells exposed to asbestos or bleomycin for 96 h acquired senescent-like morphology and displayed elevated senescence-associated beta-galactosidase activity, reduced bromodeoxyuridine (BrdUrd) incorporation, and reduced colony formation. SV40 oncoprotein expression abrogated the senescent phenotype, and transfected cell lines showed an increase in both BrdUrd incorporation and colony formation after prolonged DNA damage. Murine mesothelial cell lines lacking wild-type p53 due to a point mutation or gene rearrangement also failed to senesce in response to asbestos or chemotherapeutic agents. In addition, stress-induced senescence in human mesothelial cell lines was impaired by SV40 oncoprotein expression (MeT-5A), p53 small interfering RNA, or spontaneous p53 mutation (REN). These studies suggest that exposure to DNA-damaging agents can induce senescence in both murine and human mesothelioma cell lines and suggest a major, although not exclusive, role for p53 in this response. SV40 virus may contribute to mesothelioma progression by impairing stress-induced senescence, in part through p53 inactivation, thereby favoring survival and proliferation of mesothelial cells that have sustained DNA damage.

Animal models of diffuse malignant mesothelioma have historically been used to assess carcinogenicity of various fiber types and to study the pathogenesis of this unusual neoplasm. Pleural and peritoneal mesotheliomas have been induced in rodents following exposure to erionite or asbestos fibers, radionuclides, particulate nickel compounds, and chemicals such as 3-methylcholanthrene. The role of SV40 virus as a cofactor with asbestos fibers in the development of diffuse malignant mesotheliomas in humans has been explored in animal models. SV40 virus alone induces mesotheliomas in hamsters. Generation of new transgenic mouse strains with targeted expression of SV40 large T and small t antigens in the mesothelium would be very useful for mechanistic studies. Human malignant mesotheliomas frequently show hypermethylation or deletions at the Cdkn2a/Arf and Cdkn2b gene loci and deletions or mutations at the NF2 gene locus. Heterozygous Nf2 (+/-) mice exposed to crocidolite asbestos fibers exhibited accelerated development of malignant mesotheliomas compared to wild-type littermates. Loss of the wild-type Nf2 allele, leading to biallelic inactivation, was observed in nine mesothelioma cell lines derived from Nf2 (+/-) mice. Similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homozygous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene. As in the human disease, murine mesotheliomas also showed constitutive activation of Akt. This murine model of asbestos carcinogenesis recapitulates the molecular and histopathological features of the human disease and has significant implications for preclinical testing of novel preventive or therapeutic modalities.