Modeling of continuous dynamic recrystallization in commercial-purity aluminum

A constitutive model for polycrystalline metals is established within a micromechanical framework. The inelastic deformation is defined by the formation and annihilation of dislocations together with grain refinement due to continuous dynamic recrystallization. The recrystallization studied here occurs due to plastic deformation without the aid of elevated temperatures. The grain refinement also influences the evolution of the dislocation density since the recrystallization introduces a dynamic recovery as well as additional grain and subgrain boundaries, hindering the movement of dislocations through the material microstructure. In addition, motivated by experimental evidence, the rate dependence of the material is allowed to depend on the grain size. Introducing a varying grain size into the evolution of the dislocation density and in the rate dependence of the plastic deformation are believed to be important and novel features of the present model. The proposed constitutive model is implemented in a numerical scheme allowing calibration against experimental results, which is shown using commercial-purity aluminum as example material. The model is also employed in macroscale simulations of grain refinement in this material during extensive inelastic deformation. (C) 2009 Elsevier B.V. All rights reserved

Simulation of discontinuous dynamic recrystallization in pure Cu using a probabilistic cellular automaton

A cellular automaton algorithm with probabilistic cell switches is employed in the simulation of dynamic discontinuous recrystallization. Recrystallization kinetics are formulated on a microlevel where, once nucleated, new grains grow under the driving pressure available from the competing processes of stored energy minimization and boundary energy reduction. Simulations of the microstructural changes in pure Cu under hot compression are performed where the influence of different thermal conditions are studied. The model is shown to capture both the microstructural evolution in terms of grain size and grain shape changes and also the macroscopic flow stress behavior of the material. The latter gives the expected transition from single- to multiple-peak serrated flow with increasing temperature. Further, the effects on macroscopic flow stress by varying the initial grain size is analyzed and the model is found to replicate the shift towards more serrated flow as the initial grain size is reduced. Conversely, the flow stress is stabilized by larger initial grain sizes. The extent of recrystallization as obtained from simulations are compared to classical JMAK theory and proper agreement with theory is established. In addition, by tracing the strain state during the simulations, a post-processing step is devised to obtain the macroscopic deformation of the cellular automaton domain, giving the expected deformation of the equiaxed recrystallized grains due to the macroscopic compression

Kupffer cells are central in the removal of nanoparticles from the organism

<p>Abstract</p> <p>Background</p> <p>The study aims at revealing the fate of nanoparticles administered intravenously and intraperitoneally to adult female mice, some of which were pregnant. Gold nanoparticles were chosen as a model because these particles have been found to be chemically inert and at the same time are easily traced by autometallography (AMG) at both ultrastructural and light microscopic levels.</p> <p>Results</p> <p>Gold nanoparticles were injected intravenously (IV) or intraperitoneally (IP) and traced after 1, 4 or 24 hours. For IV injections 2 and 40 nm particles were used; for IP injections 40 nm particles only. The injected nanoparticles were found in macrophages only, and at moderate exposure primarily in the Kupffer cells in the liver. IV injections resulted in a rapid accumulation/clustering of nanoparticles in these liver macrophages, while the uptake in spleen macrophages was moderate. IP injections were followed by a delayed uptake in the liver and included a moderate uptake in macrophages located in mesenteric lymph nodes, spleen and small intestine. Ultrastructurally, the AMG silver enhanced nanocrystals were found in lysosome-like organelles of the Kupffer cells and other macrophages wherever located.</p> <p>Accumulations of gold nanoparticles were not found in any other organs analysed, i.e. kidneys, brain, lungs, adrenals, ovaries, placenta, and fetal liver, and the control animals were all void of AMG staining.</p> <p>Conclusion</p> <p>Our results suggest that: (1) inert gold nanoparticles do not penetrate cell membranes by non-endocytotic mechanisms, but are rather taken up by endocytosis; (2) gold nanoparticles, independent of size, are taken up primarily by Kupffer cells in the liver and secondarily by macrophages in other places; (3) gold nanoparticles do not seem to penetrate the placenta barrier; (4) the blood-brain barrier seems to protect the central nervous system from gold nanoparticles; (5) 2 nanometer gold particles seem to be removed not only by endocytosis by macrophages, and we hypothesize that part of these tiny nanoparticles are released into the urine as a result of simple filtration in the renal glomeruli.</p

Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes

BACKGROUND: A diverse class of engineered nanomaterials (ENMs) exhibiting a wide array of physical-chemical properties that are associated with toxicological effects in experimental animals is in commercial use. However, an integrated framework for human health risk assessment (HHRA) of ENMs has yet to be established. Rodent 2-year cancer bioassays, clinical chemistry, and histopathological endpoints are still considered the ‘gold standard’ for detecting substance-induced toxicity in animal models. However, the use of data derived from alternative toxicological tools, such as genome-wide expression profiling and in vitro high-throughput assays, are gaining acceptance by the regulatory community for hazard identification and for understanding the underlying mode-of-action. Here, we conducted a case study to evaluate the application of global gene expression data in deriving pathway-based points of departure (PODs) for multi-walled carbon nanotube (MWCNT)-induced lung fibrosis, a non-cancer endpoint of regulatory importance. METHODS: Gene expression profiles from the lungs of mice exposed to three individual MWCNTs with different physical-chemical properties were used within the framework of an adverse outcome pathway (AOP) for lung fibrosis to identify key biological events linking MWCNT exposure to lung fibrosis. Significantly perturbed pathways were categorized along the key events described in the AOP. Benchmark doses (BMDs) were calculated for each perturbed pathway and were used to derive transcriptional BMDs for each MWCNT. RESULTS: Similar biological pathways were perturbed by the different MWCNT types across the doses and post-exposure time points studied. The pathway BMD values showed a time-dependent trend, with lower BMDs for pathways perturbed at the earlier post-exposure time points (24 h, 3d). The transcriptional BMDs were compared to the apical BMDs derived by the National Institute for Occupational Safety and Health (NIOSH) using alveolar septal thickness and fibrotic lesions endpoints. We found that regardless of the type of MWCNT, the BMD values for pathways associated with fibrosis were 14.0–30.4 μg/mouse, which are comparable to the BMDs derived by NIOSH for MWCNT-induced lung fibrotic lesions (21.0–27.1 μg/mouse). CONCLUSIONS: The results demonstrate that transcriptomic data can be used to as an effective mechanism-based method to derive acceptable levels of exposure to nanomaterials in product development when epidemiological data are unavailable. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12989-016-0125-9) contains supplementary material, which is available to authorized users

Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

<p>Abstract</p> <p>Background</p> <p>The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE^-/-). We studied the effects instillation or inhalation Printex 90 of carbon black (CB) and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL) fluid.</p> <p>Results</p> <p>Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE^-/-mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE^-/-mice. Thirdly, we compared effects of instillation in ApoE^-/-mice of three carbonaceous particles; CB, fullerenes C₆₀(C₆₀) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in <it>Il-6, Mip-2 </it>and <it>Mcp-1 </it>mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C₆₀particles caused much weaker inflammatory responses.</p> <p>Conclusion</p> <p>Our data suggest that ApoE^-/-model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C₆₀and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles.</p

Pulmonary exposure to carbon black nanoparticles and vascular effects

<p>Abstract</p> <p>Background</p> <p>Exposure to small size particulates is regarded as a risk factor for cardiovascular diseases.</p> <p>Methods</p> <p>We exposed young and aged apolipoprotein E knockout mice (<it>apoE^-/-</it>) to carbon black (Printex 90, 14 nm) by intratracheal instillation, with different dosing and timing, and measured vasomotor function, progression of atherosclerotic plaques, and VCAM-1, ICAM-1, and 3-nitrotyrosine in blood vessels. The mRNA expression of <it>VCAM-1</it>, <it>ICAM-1</it>, <it>HO-1</it>, and <it>MCP-1 </it>was examined in lung tissue.</p> <p>Results</p> <p>Young <it>apoE^-/-</it>mice exposed to two consecutive 0.5 mg/kg doses of carbon black exhibited lower acetylcholine-induced vasorelaxation in aorta segments mounted in myographs, whereas single doses of 0.05-2.7 mg/kg produced no such effects. The phenylephrine-dependent vasocontraction response was shifted toward a lower responsiveness in the mice exposed once to a low dose for 24 hours. No effects were seen on the progression of atherosclerotic plaques in the aged <it>apoE^-/-</it>mice or on the expression of VCAM-1 and ICAM-1 and the presence of 3-nitrotyrosine in the vascular tissue of either young or aged <it>apoE^-/-</it>mice. The expression of <it>MCP-1 </it>mRNA was increased in the lungs of young <it>apoE^-/-</it>mice exposed to 0.9-2.7 mg/kg carbon black for 24 hours and of aged <it>apoE^-/-</it>mice exposed to two consecutive 0.5 mg/kg doses of carbon black seven and five weeks prior to sacrifice.</p> <p>Conclusion</p> <p>Exposure to nano-sized carbon black particles is associated with modest vasomotor impairment, which is associated neither with nitrosative stress nor with any obvious increases in the expression of cell adhesion proteins on endothelial cells or in plaque progression. Evidence of pulmonary inflammation was observed, but only in animals exposed to higher doses.</p