
<p><strong>Scientific, Technical, Research, </strong><br><strong>Engineering and Modeling Support </strong><br><strong>Final Report </strong></p><p><strong>State of the Science </strong><br><strong>Literature Review: </strong><br><strong>Everything Nanosilver and More </strong></p><p>R E S E A R C H A N D D E V E L O P M E N T </p><p>EPA/600/R-10/084 <br>August 2010 <a href="/goto?url=http:www.epa.gov" target="_blank">www.epa.gov </a></p><p><strong>Scientific, Technical, Research, Engineering and Modeling Support </strong><br><strong>Final Report </strong></p><p><strong>Contract No. EP-C-05-057 </strong><br><strong>Task Order No. 95 </strong></p><p><strong>State of the Science </strong><br><strong>Literature Review: </strong><br><strong>Everything Nanosilver and More </strong></p><p>Prepared for </p><p>Katrina Varner, Task Order Manager </p><p>U.S. Environmental Protection Agency National Exposure Research Laboratory <br>Environmental Sciences Division <br>Las Vegas, NV </p><p>Submitted by </p><p>Jessica Sanford, Task Order Leader, Battelle <br>Raghuraman Venkatapathy, Project Manager, Pegasus </p><p>Prepared by </p><p>Amro El-Badawy David Feldhake <br>Raghuraman Venkatapathy </p><p>Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy. Mention of trade names and commercial products does not constitute endorsement or recommendation for use. </p><p>U.S. Environmental Protection Agency Office of Research and Development <br>Washington, DC 20460 </p><p><strong>TABLE OF CONTENTS </strong>ꢀ <br><strong>List of Figures............................................................................................................................... iii</strong>ꢀꢀ <strong>List of Tables................................................................................................................................. v</strong>ꢀꢀ <strong>List of Abbreviations ................................................................................................................... vi</strong>ꢀꢀ <strong>Executive Summary.................................................................................................................... xii</strong>ꢀꢀ <strong>1. Introduction............................................................................................................................... 1</strong>ꢀꢀ <strong>2. Historical and Current Applications of Silver and Silver Nanomaterials........................... 5</strong>ꢀꢀ </p><p>2.1 Elemental Silver Characteristics and Sources....................................................................... 5 ꢀ 2.2 Chemistry of elemental silver............................................................................................... 5ꢀꢀ 2.3 Historical and Current Applications of Elemental Silver and Silver compounds ................ 7 ꢀ 2.4 Nanosilver: History and Applications................................................................................. 10 ꢀ 2.5 Silver Regulations in the US............................................................................................... 11 ꢀ </p><p><strong>3. Uses of Silver Nanomaterials ................................................................................................. 14 </strong>ꢀ ꢀ </p><p>3.1 Properties of nanosilver ...................................................................................................... 14 ꢀ <br>3.1.1 Antibacterial properties................................................................................................ 14 ꢀ <br>3.1.1.1 Antibacterial mode of action................................................................................. 15 ꢀ <br>3.1.2 Antifungal properties ................................................................................................... 16 ꢀ 3.1.3 Antiviral properties...................................................................................................... 17 ꢀ 3.1.4 Anti-inflammatory properties ...................................................................................... 17 ꢀ 3.1.5 Anti-glycoprotein film properties ................................................................................ 17 ꢀ 3.1.6 Anti-biofilm properties ................................................................................................ 18ꢀꢀ 3.1.7 Surface plasmon resonance properties......................................................................... 18 ꢀ 3.1.8 Plasmonic heating properties....................................................................................... 18 ꢀ 3.1.9 Metal-enhanced fluorescence properties...................................................................... 19 ꢀ 3.1.10 Properties of silver nanomaterials that promote its biosynthesis............................... 19 ꢀ <br>3.2 Scientific Applications........................................................................................................ 20 ꢀ 3.3 Industrial Applications........................................................................................................ 21 ꢀ <br>3.3.1 Catalysis....................................................................................................................... 21 ꢀ 3.3.2 Electronics.................................................................................................................... 22 ꢀ 3.3.3 Other Industrial Applications....................................................................................... 22 ꢀ <br>3.4 Applications in Consumer Products.................................................................................... 22 ꢀ 3.5 Medical Applications.......................................................................................................... 23 ꢀ 3.6 Proposed and Projected Applications ................................................................................. 24 ꢀ </p><p><strong>4. Synthesis and Properties of Silver Nanomaterials............................................................... 27</strong>ꢀꢀ </p><p>4.1 Methods of Synthesis.......................................................................................................... 27 ꢀ <br>4.1.1 Synthesis Categories.................................................................................................... 27 ꢀ <br>4.1.1.1 Top-Down versus Bottom-Up............................................................................... 28 ꢀ 4.1.1.2 Synthesis Reactants in Bottom-Up Techniques.................................................... 30 ꢀ <br>4.1.2 General Discussion on Nanosilver Synthesis .............................................................. 32 ꢀ <br>4.2 Silver Nanocomposites and Bimetallic Nanoparticles........................................................ 35 ꢀ </p><p>Final Report dated 07/15/2010 </p><p><em>State of the Science – Everything Nanosilver and More </em></p><p>iꢀꢀ </p><p>4.3 Environmental Perspective ................................................................................................. 35 ꢀ 4.4 Characteristics of the Silver Nanomaterials Products......................................................... 37 ꢀ 4.5 Characterization Methods, Detection and Speciation......................................................... 54 ꢀ <br>4.5.1 Methods for Measuring Ionic Silver in Nanosilver Suspensions................................. 56 ꢀ 4.5.2 Methods for Isolating Ionic Silver from Nanosilver Suspensions............................... 56 ꢀ 4.5.3 Novel Detection and Characterization Techniques for Environmental Samples......... 57 ꢀ </p><p><strong>5. Potential Magnitude of Silver Nanomaterial Utilization and Environmental Exposure . 67</strong>ꢀꢀ </p><p>5.1 Inventory of Silver Nanomaterials: Industrial and consumer products .............................. 68 ꢀ 5.2 Routes of Release and Exposure, Ecological...................................................................... 72 ꢀ 5.3 Routes of Exposure, Human ............................................................................................... 77 ꢀ <br>5.3.1 Exposure via food ........................................................................................................ 80 ꢀ 5.3.2 Exposure via consumer products ................................................................................. 83 ꢀ 5.3.3 Exposure via Medical Applications............................................................................. 88 ꢀ 5.3.4 Exposure via occupation.............................................................................................. 92 ꢀ <br>5.4 Projected Quantities, Geographic and Demographic Distribution in the US ..................... 94 ꢀ </p><p><strong>6. Toxicity and Health Effects.................................................................................................... 98</strong>ꢀꢀ </p><p>6.1 Silver Toxicity .................................................................................................................... 98 ꢀ 6.2 Nanosilver Toxicity .......................................................................................................... 100 ꢀ <br>6.2.1 Toxicity of Nanosilver to Organisms......................................................................... 102 ꢀ 6.2.2 Ecological or Multispecies Studies of Nanosilver Toxicity ...................................... 105 ꢀ 6.2.3 Studies Concerning Human Health Including Mammalian Models.......................... 109 ꢀ <br>6.2.3.1 Respiratory Tract Toxicity.................................................................................. 113 ꢀ 6.2.3.2 Neuronal Uptake................................................................................................. 118 ꢀ 6.2.3.3 Dermal Toxicity.................................................................................................. 118 ꢀ 6.2.3.4 Gastrointestinal Tract Toxicity ........................................................................... 120 ꢀ 6.2.3.5 Other Organ Toxicity.......................................................................................... 121 ꢀ <br>6.2.3.5.1 Kidney Toxicity ........................................................................................... 122 ꢀ 6.2.3.5.2 Liver Toxicity .............................................................................................. 123 ꢀ 6.2.3.5.3 Immune system Toxicity.............................................................................. 123 ꢀ 6.2.3.5.4 Other blood effects....................................................................................... 124 ꢀ 6.2.3.5.5 Reproductive system Toxicity ..................................................................... 125 ꢀ 6.2.3.5.6 Genotoxicity, carcinogenicity...................................................................... 125 ꢀ <br>6.2.4 Cell Culture Nanosilver Toxicity............................................................................... 125 ꢀ <br>6.3 Conclusions on Nanosilver Toxicity................................................................................. 131 ꢀ </p><p><strong>7. Life Cycle Analysis for Comprehensive Environmental Assessment .............................. 134</strong>ꢀꢀ </p><p>7.1 Nanosilver life cycle assessment ...................................................................................... 136 ꢀ 7.2 Nanosilver comprehensive environmental assessment..................................................... 145 ꢀ </p><p><strong>8. Data Gaps .............................................................................................................................. 147</strong>ꢀꢀ <strong>9. Bibliography.......................................................................................................................... 150</strong>ꢀꢀ <strong>Appendix A – List of US Companies Producing Nanosilver Containing Compounds....... 198 </strong>ꢀ <strong>Appendix B – Woodrow Wilson Database Containing Nanosilver Products...................... 207 </strong>ꢀ <strong>Appendix C – List of Companies Producing Raw Nanosilver in the US............................. 355 </strong>ꢀ </p><p>Final Report dated 07/15/2010 </p><p><em>State of the Science – Everything Nanosilver and More </em></p><p>ii </p><p><strong>List of Figures </strong></p><p><strong>Figure 2.1</strong>: Nanomaterials dimensions on the metric scale (in nm)............................................. 11ꢀꢀ <strong>Figure 2.2</strong>: Analysis of FIFRA registered products containing nanosilver for the period 1950- 2010............................................................................................................................................... 12ꢀꢀ <strong>Figure 4.1</strong>: Top-down and Bottom-up synthesis approaches....................................................... 30ꢀꢀ <strong>Figure 4.2</strong>: Schematic for an organometallic approach of synthesis of silver nanoparticles....... 34ꢀꢀ <strong>Figure 4.3</strong>: Schematic of a spinning disc processor for synthesis of silver nanoparticles........... 36ꢀꢀ <strong>Figure 4.4</strong>: Characterization of silver nanoparticle size and morphology with scanning electron ꢀ microscopy (SEM)........................................................................................................................ 38ꢀꢀ <strong>Figure 4.5</strong>: Schematic diagram of the Electrospray-Scanning Mobility Particle Sizer (ES-SMPS) ꢀ system ........................................................................................................................................... 58ꢀꢀ <strong>Figure 4.6</strong>: Cross section of a small part of the FlFFF channel................................................... 59ꢀꢀ <strong>Figure 5.1</strong>: Forms of nanosilver incorporated in consumer products. ......................................... 69ꢀꢀ <strong>Figure 5.2</strong>: Categories of nanosilver-containing products........................................................... 70ꢀꢀ <strong>Figure 5.3</strong>: Overview of silver flows triggered by biocidal plastics and textiles......................... 75ꢀꢀ <strong>Figure 5.4</strong>: Process simulated in the model developed by Blaser et al. (2008) ........................... 76ꢀꢀ <strong>Figure 5.5</strong>: Routes of exposure, uptake, distribution, and degradation of nanomaterials in the ꢀ environment .................................................................................................................................. 78ꢀꢀ <strong>Figure 5.6</strong>: Fresh Box, manufactured by FinePolymer, Inc. (South Korea), is a nanosilver ꢀ antimicrobial food container......................................................................................................... 81ꢀꢀ <strong>Figure 5.7</strong>: The Nano Tea Pot – Aroma manufactured by Top Nano Technology Co., Ltd ꢀ (Taiwan)........................................................................................................................................ 81ꢀꢀ <strong>Figure 5.8</strong>: Samsung’s Silver Wash washing machine................................................................ 85ꢀꢀ <strong>Figure 5.9</strong>: Illustration showing production flow process and measurement locations in the ꢀ Korean silver nanoparticle manufacturing facility ....................................................................... 88ꢀꢀ <strong>Figure 5.10</strong>: Anti-microbial burn dressing manufactured by Anson Nano-Biotechnology ꢀ (Zhuhai) Co., Ltd., China.............................................................................................................. 91ꢀꢀ <strong>Figure 5.11</strong>: Conjuctival-corneal argyrosis in the craftsman occupationally exposed to silver .. 93ꢀꢀ <strong>Figure 5.12</strong>: Number of companies, universities, laboratories and/or organization working in ꢀ nanotechnology across the US...................................................................................................... 95ꢀꢀ <strong>Figure 5.13</strong>: Nanosilver flows during high emission scenarios................................................... 96ꢀꢀ <strong>Figure 6.1</strong>: Systemic argyria of the skin from ingestion of colloidal silver................................. 99ꢀꢀ <strong>Figure 6.2</strong>: HAADF image of an HIV-1 virus........................................................................... 104ꢀꢀ <strong>Figure 6.3</strong>: A schematic of the human body with pathways of exposure to nanoparticles........ 110ꢀꢀ <strong>Figure 6.4</strong>: Deposition of particles in the respiratory tract as a function of their size............... 114ꢀꢀ <strong>Figure 6.5</strong>: A simplified depiction of potential factors that may influence the effects of ꢀ engineered nanoparticles on the respiratory system ................................................................... 115ꢀꢀ <strong>Figure 6.6</strong>: The proposed mechanism of nanosilver toxicity based on the experimental data .. 131ꢀꢀ <strong>Figure 7.1</strong>: Comprehensive environmental assessment (CEA) ................................................. 136ꢀꢀ <strong>Figure 7.2</strong>: Choices associated with a nanotechnology throughout its life cycle as proposed by ꢀ Meyer et al. (2009)...................................................................................................................... 137ꢀꢀ <strong>Figure 7.3</strong>: Choices associated with a nanotechnology throughout its life cycle as proposed by ꢀ Gill (2007)................................................................................................................................... 138ꢀꢀ <strong>Figure 7.4</strong>: The Nanomaterial Database maintained by Nanowerk........................................... 142ꢀꢀ </p><p>Final Report dated 07/15/2010 </p><p><em>State of the Science – Everything Nanosilver and More </em></p><p>iii <br><strong>Figure 7.5</strong>: Quantified mass flows of silver triggered by the use of biocidal products and by other silver uses........................................................................................................................... 144 <strong>Figure 7.6</strong>: Nanosilver flows from the nanomaterial containing products to various environmental compartments...................................................................................................... 145 </p><p>Final Report dated 07/15/2010 </p><p><em>State of the Science – Everything Nanosilver and More </em></p><p>iv </p><p><strong>List of Tables </strong></p><p><strong>Table 3.1</strong>: Emerging applications of nanosilver in medical products.......................................... 26 ꢀ <strong>Table 4.1</strong>: Description of Evidence for Silver Nanoparticle Synthesis for General Applications39 ꢀ <strong>Table 4.2</strong>: Description of Evidence for Silver Nanoparticles Synthesis for Specific Applicationsꢀꢀ ....................................................................................................................................................... 45 ꢀ <strong>Table 4.3</strong>: Description of Evidence for Silver Nanocomposites.................................................. 49 ꢀ <strong>Table 4.4</strong>: Description of Evidence for Bimetallic Silver Nanoparticles..................................... 51 ꢀ <strong>Table 4.5</strong>: List of Acronyms used in Tables 4.1 to 4.4 ................................................................ 52 ꢀ <strong>Table 4.6</strong>: Possible Conventional Characterization and Detection Techniques for Nanosilver .. 62 ꢀ <strong>Table 5.1</strong>: Main characteristics for human exposure to nanomaterials from food, consumer and ꢀ medical products........................................................................................................................... 78 ꢀ <strong>Table 5.2</strong>: Ranking of potential human exposures to nanosilver................................................. 79 ꢀ <strong>Table 5.3</strong>: Summary of applications of nanotechnology in the food production chain .............. 82 ꢀ <strong>Table 5.4</strong>: Product categories with examples of products containing nanosilver........................ 86 ꢀ <strong>Table 5.5</strong>: Medical devices containing nanosilver....................................................................... 90 ꢀ <strong>Table 5.6</strong>: Emerging applications of nanosilver in medical products.......................................... 91 ꢀ <strong>Table 5.7</strong>: Predicted environmental concentrations in Rhine River............................................. 96 ꢀ <strong>Table 7.1</strong>: Companies selling nanosilver as listed in the Nanowerk database........................... 139 ꢀ </p><p>Final Report dated 07/15/2010 </p><p><em>State of the Science – Everything Nanosilver and More </em></p><p>v</p><p><strong>List of Abbreviations </strong>ꢀ </p><p></p><ul style="display: flex;"><li style="flex:1">-CN </li><li style="flex:1">Cyano group </li></ul><p>-COOH -NH<sub style="top: 0.125em;">2 </sub><br>Carboxyl Group Amine Group </p><ul style="display: flex;"><li style="flex:1">-SH </li><li style="flex:1">Thiol Group </li></ul><p></p><ul style="display: flex;"><li style="flex:1">AAS </li><li style="flex:1">Atomic Absorption Spectroscopy </li></ul><p>American Conference of Governmental Industrial Hygienists Atomic Force Microscopy Silver Isotopes <br>ACGIH AFM <sup style="top: -0.46em;">107</sup>Ag, <sup style="top: -0.46em;">109</sup>Ag </p><ul style="display: flex;"><li style="flex:1">Ag </li><li style="flex:1">Elemental Silver </li></ul><p>Ag<sup style="top: -0.46em;">+</sup>, Ag<sup style="top: -0.46em;">2+</sup>, Ag<sup style="top: -0.46em;">3+ </sup>Ag<sub style="top: 0.125em;">2</sub>O AgBr <br>Ionic Silver Silver Oxide Silver Bromide </p><ul style="display: flex;"><li style="flex:1">AgCl </li><li style="flex:1">Silver Chloride </li></ul><p></p><ul style="display: flex;"><li style="flex:1">AgF </li><li style="flex:1">Silver Fluoride </li></ul><p></p><ul style="display: flex;"><li style="flex:1">AgI </li><li style="flex:1">Silver Iodide </li></ul><p>AgNO<sub style="top: 0.125em;">3 </sub>AgCN AgN<sub style="top: 0.125em;">3 </sub>AgNP AgOH AgONC AgS <br>Silver Nitrate Silver Cyanide Complex Silver Azide Silver nanoparticle Silver Hydroxide Silver Fulminate Silver Sulfide </p><ul style="display: flex;"><li style="flex:1">ALP </li><li style="flex:1">Alkaline Phosphatase </li></ul><p>American Society for Testing and Materials Adenosine Triphosphate Agency for Toxic Substances and Disease Registry Gold <br>ASTM ATP ATSDR Au </p><ul style="display: flex;"><li style="flex:1">BBB </li><li style="flex:1">Blood Brain Barrier </li></ul><p></p><ul style="display: flex;"><li style="flex:1">Before Christ </li><li style="flex:1">B.C. </li></ul><p></p><ul style="display: flex;"><li style="flex:1">BET </li><li style="flex:1">Brunauer-Emmett-Teller Analysis </li></ul><p>vi </p><p>Final Report dated 07/15/2010 </p><p><em>State of the Science – Everything Nanosilver and More </em></p><p>BPEI BSA <br>Branched Polyethyleneimine Bovine Serum Albumin </p><ul style="display: flex;"><li style="flex:1">Ethyl Alcohol </li><li style="flex:1">C<sub style="top: 0.125em;">2</sub>H<sub style="top: 0.125em;">5</sub>OH </li></ul><p></p><ul style="display: flex;"><li style="flex:1">Ca </li><li style="flex:1">Calcium </li></ul><p></p><ul style="display: flex;"><li style="flex:1">CA </li><li style="flex:1">California </li></ul><p>Cal/EPA CE <br>California Environmental Protection Agency Capillary Electrophoresis Comprehensive Environmental Assessment Chloride Ion <br>CEA Cl<sup style="top: -0.46em;">- </sup></p><ul style="display: flex;"><li style="flex:1">cm </li><li style="flex:1">Centimeter </li></ul><p>CNT CO <br>Carbon Nanotube Carbon Monoxide <br>CTAB Cu <br>Cetyltrimethylammonium Bromide Copper <br>Cu(NO<sub style="top: 0.125em;">3</sub>)<sub style="top: 0.125em;">2 </sub>DI <br>Cupric Nitrate Deionized </p><ul style="display: flex;"><li style="flex:1">DLS </li><li style="flex:1">Dynamic Light Scattering </li></ul><p>Differential Mobility Analyzer N,N-Dimethyl Formamide Deoxyribonucleic Acid <br>DMA DMF DNA DOC DPR <br>Dissolved Organic Carbon Department of Pesticide Registration California Department of Toxic Substances Control </p>
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