Contents lists available at ScienceDirect Toxicology and Applied Pharmacology journal homepage: www.elsevier.com/locate/taap A case study of the translocation, bioprocessing and tissue interactions of EMP following inhalation exposure Uschi M. Graham ⁎ , Günter Oberdörster, Bruce Case, Alan Dozier University of Kentucky, USA ARTICLE INFO Keywords: Human Lung EMP Nanoparticles Ferritin Bioprocessing ABSTRACT Human autopsied lung sections from a resident in the Quebec asbestos region were examined. The study utilized high resolution transmission electron microscopy, scanning transmission electron microscopy (HRTEM/STEM) with the analytical capabilities of electron energy loss spectroscopy (EELS) and energy dispersive spectroscopy (EDS) detectors. We report the first analytical ultrastructural characteristics of EMPs, detailing chemical con- centration gradients inside the iron-protein coatings and lateral elemental gradients in the local tissue regions. It is shown that the EMPs are subjected to bioprocessing which involves physicochemical transformations and also an elemental transport mechanism that alters the inhaled EMP as well as the surrounding cellular matrix. At high resolution imaging the iron-rich coating around the EMP was observed to have a distinct channel-like nanos- tructure with some parallel aligned nanofibrils that are reminiscent of tooth enamel which consists of biomi- neralized nanocomposites with alternating organic/inorganic matrices. 1. Introduction The health hazards of asbestos, one of the most notorious of EMPs, came to light more than half a century ago when studies linked silica- alumina-magnesium-bearing fiber exposure to mesothelioma, a rare cancer of the lining of the chest (Roggli et al., 2010). Reviews on Amphibole forms of asbestos and asbestos-like materials and their biologic properties show that certain fiber characteristics: elemental composition, crystal structure, and fiber length (> 5 μm and aspect ratios of 3:1), are linked to disease (Pooley and Ransome, 1986; Gibbs and Pooley, 1996; Berman and Crump, 2008; Bernstein et al., 2003). The development of mesothelioma also hinges on the ability of the fi- bers to persist in the lungs for decades. The presence of fibers in lung parenchyma, related lymph nodes and pleural tissues of workers ex- posed to asbestos is detailed by Bignon et al. (1977), and a systematic review of the literature on occupational asbestos exposure and lung cancer was provided by Roggli et al. (2010) and recently by Nielsen et al. (2018). The reports also detail that pleural plaques, asbestos bodies and fibers are helpful markers of exposure to asbestos while fiber location is not a reliable measure in differentiating asbestos-related lung cancer. Certain particle sizes of asbestos were discovered to more likely penetrate deep into the lung, causing inflammatory responses followed by free radical damage to DNA and surrounding cellular components. The morphologic features seen in the development of asbestosis at its various stages relate exposure levels to specific tissue reactions. This has allowed detailed guidelines to be developed that provide grading schemes to characterize disease development (Roggli et al., 2010). Hesterberg et al., 1998, discusses the importance of fiber ‘biopersistence’, lung dose, and shows how differences in various as- bestos types effect biological responses after chronic inhalation ex- posure. There is mounting evidence that asbestos is not the only fiber type to be capable of triggering mesothelioma. Elongated mineral particles (EMP) such as erionite (Wagner et al., 1985), fluoro-edenite, a volcanic mineral (Miozzi et al., 2016), or carbon nanotubes, an engineered nano- material Poland et al. (2008), have been shown in the past to cause similar physical reactions like asbestos and have formed mesothelioma. Carbon nanotubes are thin enough to reach past the upper airways and into regions of the lungs where oxygen exchanges into blood. Some carbon nanotubes are long enough to initiate problems through me- chanisms such as frustrated phagocytosis in similar ways like asbestos fibers Poland et al. (2008), causing the lung's defenses to break down when macrophages cannot fully process the long fibers. Multi-walled carbon nanotubes have been shown by Suzui et al., 2016, to induce pleural malignant mesothelioma and lung tumors after intratracheal instillation into rat lung. This indicates that there are reactive processes that stem from the interaction of these EMP types at the cellular and subcellular level (Vlasova et al., 2016). Unfortunately, the underlying https://doi.org/10.1016/j.taap.2018.07.002 Received 21 January 2018; Received in revised form 20 June 2018; Accepted 2 July 2018 ⁎ Corresponding author. E-mail address: graham@topasol.com (U.M. Graham). Toxicology and Applied Pharmacology 361 (2018) 81–88 Available online 03 July 2018 0041-008X/ © 2018 Elsevier Inc. All rights reserved. T