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      Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

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          Abstract

          Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers.

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          Nutritional aspects of manganese homeostasis.

          Judy Aschner, Michael Aschner (2005)
          Manganese (Mn) is an essential mineral. It is present in virtually all diets at low concentrations. The principal route of intake for Mn is via food consumption, but in occupational cohorts, inhalation exposure may also occur (this subject will not be dealt with in this review). Humans maintain stable tissue levels of Mn. This is achieved via tight homeostatic control of both absorption and excretion. Nevertheless, it is well established that exposure to high oral, parenteral or ambient air concentrations of Mn can result in elevations in tissue Mn levels. Excessive Mn accumulation in the central nervous system (CNS) is an established clinical entity, referred to as manganism. It resembles idiopathic Parkinson's disease (IPD) in its clinical features, resulting in adverse neurological effects both in laboratory animals and humans. This review focuses on an area that to date has received little consideration, namely the potential exposure of parenterally fed neonates to exceedingly high Mn concentrations in parenteral nutrition solutions, potentially increasing their risk for Mn-induced adverse health sequelae. The review will consider (1) the essentiality of Mn; (2) the concentration ranges, means and variation of Mn in various foods and infant formulas; (3) the absorption, distribution, and elimination of Mn after oral exposure and (4) the factors that raise a theoretical concern that neonates receiving total parenteral nutrition (TPN) are exposed to excessive dietary Mn.
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            The kinetics of the tissue distribution of silver nanoparticles of different sizes.

            D P K Lankveld, A G Oomen, P Krystek … (2010)
            Blood kinetics and tissue distribution of 20, 80 and 110 nm silver nanoparticles were investigated in rats up to 16 days after intravenous administration once daily for 5 consecutive days. Following both single and repeated injection, silver nanoparticles disappeared rapidly from the blood and distributed to all organs evaluated (liver, lungs, spleen, brain, heart, kidneys and testes) regardless of size. The 20 nm particles distributed mainly to liver, followed by kidneys and spleen, whereas the larger particles distributed mainly to spleen followed by liver and lung. In the other organs evaluated, no major differences between the sizes were observed. Size-dependent tissue distribution suggests size-dependent toxicity and health risks. Repeated administration resulted in accumulation in liver, lung and spleen, indicating that these organs may be potential target organs for toxicity after repeated exposure. A physiologically based pharmacokinetic (PBPK) model for nanoparticles which describes the kinetics of silver nanoparticles was developed. Model parameter values were estimated by fitting to data. No clear relation between parameter values and corresponding particle diameters became apparent. Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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              Inhaled nanoparticles--a current review.

              Richard O. Williams, Philip J Peters, Wei Yang (2008)
              The field of nanotechnology may hold the promise of significant improvements in the health and well being of patients, as well as in manufacturing technologies. The knowledge of this impact of nanomaterials on public health is limited so far. This paper briefly reviews the unique size-controlled properties of nanomaterials, their disposition in the body after inhalation, and the factors influencing the fate of inhaled nanomaterials. The physiology of the lung makes it an ideal target organ for non-invasive local and systemic drug delivery, especially for protein and poorly water-soluble drugs that have low oral bioavailability via oral administration. The potential application of pulmonary drug delivery of nanoparticles to the lungs, specifically in context of published results reported on nanomaterials in environmental epidemiology and toxicology is reviewed in this paper.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Toxicol
                Journal ID (iso-abbrev): J Toxicol
                Journal ID (publisher-id): JT
                Title: Journal of Toxicology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1687-8191
                ISSN (Electronic): 1687-8205
                Publication date (Print): 2012
                Publication date (Electronic): 7 May 2012
                Volume: 2012
                Electronic Location Identifier: 791431
                Affiliations
                1Health, Safety, Environment, and Security, Afton Chemical Corp., Richmond, VA 23219, USA
                2Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA
                3College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA
                Author notes

                Academic Editor: Kannan Krishnan

                Article
                DOI: 10.1155/2012/791431
                PMC ID: 3356703
                PubMed ID: 22645610
                SO-VID: 384ba9e8-a6aa-484a-a9ec-67a41003ed08
                Copyright © Copyright © 2012 Michael D. Taylor et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 22 October 2011
                Date accepted : 25 January 2012
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Toxicology
                Data availability:
                ScienceOpen disciplines: Toxicology

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