Toxicity Evaluation, Risk Assessment and Management

Nanotoxicology Toxicity Evaluation, Risk Assessment and Management

Nanotoxicology Toxicity Evaluation, Risk Assessment and Management

Edited by

Vineet Kumar Nandita Dasgupta Shivendu Ranjan

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2018 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-4987-9941-6 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Kumar, Vineet (Vineet Kumar Rudra), editor. | Dasgupta, Nandita (Environmental chemist), editor. | Ranjan, Shivendu, editor. Title: Nanotoxicology : toxicity evaluation, risk assessment, and management / [edited by] Vineet Kumar, Nandita Dasgupta & Shivendu Ranjan. Description: Boca Raton : CRC Press, Taylor & Francis Group, 2018. | Includes bibliographical references. Identifiers: LCCN 2017048960 | ISBN 9781498799416 (hardback) Subjects: LCSH: Nanostructured materials--Toxicology. | Nanostructured materials--Health aspects. Classification: LCC RA1270.N36 N37 2018 | DDC 610.28--dc23 LC record available at https://lccn.loc.gov/2017048960 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents Preface.......................................................................................................................ix Editors.......................................................................................................................xi Contributors.......................................................................................................... xiii 1. Critical Evaluation of Toxicity Tests in Context to Engineered Nanomaterials: An Introductory Overview...............................................1 Madan Lal Verma 2. Ethics in Nanotechnology and Society Perception................................. 19 Suleyman Tekmen and Zuhal Alım 3. Impact of Physicochemical Properties and Surface Chemistry of Nanomaterials on Toxicity...................................................................... 35 Akhela Umapathi, Anubhav Kaphle, Pundarikanakallahalli Nagaraju Navya, Sourabh Monnappa Kuppanda Jafri, Nikhath Firdose, Devendra Jain, Sangly Pranesh Srinivas, Harishkumar Madhyastha, Radha Madhyastha, and Hemant Kumar Daima 4. Application of Nanomaterials in Food, Cosmetics, and Other Related Process Industries...........................................................................63 Adhena A. Werkneh, Eldon R. Rene, and Piet N. L. Lens 5. Effect of Route of Exposure on the Toxicity Behavior of Nanomaterials........................................................................................... 81 Praveen Guleria, Shiwani Guleria, and Vineet Kumar 6. Factors Affecting the Toxicity of Engineered Nanomaterials: Interference and Limitations of In Vitro Assays.................................... 97 Sanjay Singh 7. Influence of Test Model Selection on Nanotoxicity Evaluation......... 125 Oluyomi Stephen Adeyemi, David Adeiza Otohinoyi, and Faoziyat Adenike Sulaiman 8. Nanotoxicity In Vitro: Limitations of the Main Cytotoxicity Assays..................................................................................... 171 Montserrat Mitjans, Daniele Rubert Nogueira-Librelotto, and María Pilar Vinardell

v

vi

Contents

9. Genotoxicity and Carcinogenicity of Daily Used Nanoparticles: In Vivo Studies............................................................................................. 193 Hanan Ramadan Hamad Mohamed 10. Influence of Nanomaterials on Human Health..................................... 219 Hadi Ebrahimnejad and Sahel Motaghi 11. Mechanisms of Nanotoxicity to Cells, Animals, and Humans.......... 237 Belinda Wong Shu Ee, Puja Khanna, Ng Cheng Teng, and Baeg Gyeong Hun 12. Methods and Protocols for In Vitro Animal Nanotoxicity Evaluation: A Detailed Review................................................................ 285 Venkatraman Manickam, Leema George, Amiti Tanny, Rajeeva Lochana, Ranjith Kumar Velusamy, M. Mathan Kumar, Bhavapriya Rajendran, and Ramasamy Tamizhselvi 13. Methods and Protocols for In Vivo Animal Nanotoxicity Evaluation: A Detailed Review................................................................ 323 Fátima Torrico Medina, Isabel Andueza, and Alirica I. Suarez 14. Nanotoxicity Evaluation Using Experimental Animals: A Detailed Review...................................................................................... 389 Anita Jemec Kokalj, Damjana Drobne, and Sara Novak 15. Pharmacokinetics Approach for Nanotoxicity Evaluation................. 419 Akhilesh Dubey and Shilpa Sharma 16. Genomic Approach of Nanotoxicity Evaluation................................... 449 Debjani Nath 17. Nano-Genotoxicity Evaluation: A Review.............................................463 Olusegun I. Ogunsuyi, Opeoluwa M. Fadoju, Motunrayo M. Coker, Solomon O. Akinrinade, Ifeoluwa T. Oyeyemi, Okunola A. Alabi, Chibuisi G. Alimba, and Adekunle A. Bakare 18. Nanoinformatics: An Alternative of In Vitro and In Vivo Nanotoxicity Evaluations...........................................................................505 Georgios Leonis, Antreas Afantitis, and Georgia Melagraki 19. In Silico Methods for Nanotoxicity Evaluation: Opportunities and Challenges............................................................................................. 527 Natalia Sizochenko, Alicja Mikolajczyk, Jerzy Leszczynski, and Tomasz Puzyn

Contents

vii

20. Sensors Used to Evaluate Nanotoxicity.................................................. 559 Bambang Kuswandi 21. Nanosensors: The Future of Efficient Sensing Technologies in Nanomedicine.......................................................................................... 593 Arun Prakash Periasamy, Rini Ravindranath, and Prathik Roy 22. Embryonic Stem Cell as a Cellular Model for Testing the Toxicity of Engineered Nanoparticles..................................................... 613 Jyoti Parkash, Arti Sharma, and Ankur Jairath 23. Regulations for Safety Assessment of Nanomaterial.......................... 635 Tiago Severo Peixe, Elizabeth de Souza Nascimento, Rachel Picada Bulcão, Carlos Eduardo Matos dos Santos, and Mariana C. N. Pais 24. Challenges, Recommendations, and Strategies for Nanotoxicology Evaluation and Its Management................................. 649 Bensu Karahalil Index...................................................................................................................... 657

Preface Nanotechnology is considered to be the next revolution in technology. No doubt nanotechnology will impact humans with long lasting beneficial effects. Richard Feyman theoretically defined the unlimited prospective of nanomaterials in 1959. Nanotechnology offers the application of materials with at least one dimension in a nanometer scale. A nanometer is one billionth of a meter or 1/80,000 the width of a human hair or about ten times the diameter of a hydrogen atom. However, in a practical sense, nanotechnology boomed with the discovery of the scanning tunneling microscope and the atomic force microscope in the 1980s. At present, nanotechnology is a multidisciplinary scientific field. It has applications in every discipline of science including agriculture, drug industry, material science, sensors, catalysis, biotechnology, microbiology, electronics, mechanical and electrical engineering, and so on. But like genetic engineering, nanotechnology is another high-end technology that despite its huge commercial potential can also produce serious threats to human health and the environment. Toxicity evaluation of chemicals and macroparticles is considered essential for the safe use of these materials. Unlike the conventional toxicological analysis methods and protocols applied to various toxins and contaminants that are applicable to all, nanoparticles’ toxicity mainly depends upon a number of factors such as size, shape, and surface properties. In this regard, it is really important to develop proper protocols and new toxicological evaluation methods. The unique properties of nanomaterials make them different from their bulk counterparts. In addition to such unique properties, the nanometric size of nanomaterials can invite some detrimental effects on the health and well being of living organisms and the environment. So, the fascinating field of nanotechnology is growing rapidly with some serious concerns about the toxicity behaviors of nanoparticles. The combination of nanotechnology with various fields like biology, chemistry, physics, engineering, and so on, has led to the new generation of nanodevices. Nanomaterials can induce toxicity through direct contact or through food, water, and other consumer nanomaterial-containing products. Humans can be exposed to nanomaterials via products containing nanomaterials without appropriate product labeling and contamination of products with nanomaterials. Thus, it is important to distinguish nanomaterials with such ill effects from nanomaterials with no or minimum toxicity. The commercial viability of nanomaterial-based products in the future depends upon careful toxicity evaluation. The methods used for the toxicity evaluation of macroparticles or bulk counterparts have been currently employed for nanotoxicity evaluation. There are some limitations of these methods that need to be updated in context to nanomaterials. Similarly, the guidelines regulating the toxicity ix

x

Preface

evaluation and safe use of nanomaterials need to be reevaluated considering the unique properties of nanomaterials. This book covers issues like basic principles of nanotoxicity, methods used for nanotoxicity evaluation, risk assessment and its management for nanomaterial toxicity with a focus on current trends, limitations, challenges, and future directions of nanotoxicity evaluation. Various experts from different countries will discuss these issues in detail in this book. This book will be helpful to researchers, educators, and students who are interested in research opportunities for avoiding the environmental and health hazards of nanomaterials. This book will also be useful for industrial practitioners, policy makers, and other professionals in the fields of toxicology, medicine, pharmacology, food, drugs, and other regulatory sciences. Nanotoxicity: Assessing and Managing Nanomaterial’s Risk Vineet Kumar Nanomaterials: Smaller Materials—Bigger Threats! Shivendu Ranjan and Nandita Dasgupta

Editors Vineet Kumar is currently working as Assistant Professor (Biotechnology) in the School of Biotechnology and Biosciences, Lovely Professional University, Phagwara, Jalandhar, Punjab, India. Previously, he was Assistant Professor in the Department of Biotechnology, DAV University, Jalandhar, Punjab, India, and UGC-Dr DSK postdoctoral fellow (2013–2016) at the Department of Chemistry, Panjab University, Chandigarh, UT, India. He has worked in different areas of biotechnology and nanotechnology in various institutes and universities, namely, CSIR-Institute of Microbial Technology, Chandigarh, U.T., India, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P., India, and Himachal Pradesh University, Shimla, H.P., India. His areas of interest include green synthesis of nanoparticles, nanotoxicity testing of nanoparticles, and application of nanoparticles in drug delivery, food technology, sensing, dye degradation, and catalysis. He has published many articles in these areas in peer-reviewed journals. He is also serving as an editorial board member and reviewer for international peer reviewed journals. He has received various awards such as a senior research fellowship, best poster award, postdoctoral fellowship, and so on. Dr. Nandita Dasgupta has vast working experience in micro/nanoscience and is currently working at the Indian Institute of Food Processing Technology, Thanjavur, Tamil Nadu, Ministry of Food Processing Industries, Government of India. She has worked at universities, research institutes and industries, including Vellore Institute of Technology (VIT) University, Vellore, Tamil Nadu, India; Council of Scientific and Industrial Research (CSIR)-Central Food Technological Research Institute (CFTRI), Mysuru, Karnataka, India; and Uttar Pradesh Drugs and Pharmaceutical Co. Ltd., Lucknow, Uttar Pradesh, India. Her areas of interest include micro/nanomaterial fabrication and its applications in various fields—medicine, food, environment, agriculture, and biomedical studies. She has published six edited books and one authored book by Springer, Switzerland and two by CRC Press, Florida, USA. She has completed a contract for a three-volume book for Elsevier, one volume with Wiley, two book xi

xii

Editors

volumes for CRC Press and one volume for Royal Society of Chemistry (RSC) (UK). She has authored many chapters and also published many scientific articles in international peer-reviewed journals. She has received the certificate for “Outstanding Contribution” in reviewing from Elsevier, Netherlands. She has also been nominated for advisory panel for Elsevier Inc., Netherlands. She is the associate editor of Environmental Chemistry Letters—a Springer journal of 3.59 impact factor—and also serving as editorial board member and referee for reputed international peer-reviewed journals. She has received several awards and recognitions from different national and international organizations. Dr. Shivendu Ranjan has extensive expertise in micro/nanotechnology and is currently working at the Indian Institute of Food Processing Technology, Thanjavur, Tamil Nadu, Ministry of Food Processing Industries, Government of India. He has founded and drafted the concept for the first edition of the “VIT Bio Summit” in 2012, and the same has been continued till date by the university. He has worked in the Council of Scientific and Industrial ResearchCentral Food Technological Research Institute, Mysuru, Karnataka, India as well as Uttar Pradesh Drugs and Pharmaceutical Co. Ltd., Lucknow, Uttar Pradesh, India. His research interests are multidisciplinary and include micro/nanobiotechnology, nano-toxicology, environmental nanotechnology, nanomedicine and nanoemulsions. He is the associate editor of Environmental Chemistry Letters—a Springer journal of 3.59 impact factor—and an editorial board member in Biotechnology and Biotechnological Equipment (Taylor & Francis). He is serving as executive editor of a journal in iMed Press, USA, and also serving as editorial board member and referee for reputed international peerreviewed journals. He has published six edited books and one authored book by Springer, Switzerland and two by CRC Press, USA. He has recently completed his contract of three-volume book for Elsevier, two volumes for CRC Press and one with Wiley and Royal Society of Chemistry (RSC) (UK). He has published many scientific articles in international peer-reviewed journals and has authored many book chapters as well as review articles. He has bagged several awards and recognitions from different national as well as international organizations.

Contributors Oluyomi Stephen Adeyemi Department of Biological Sciences Landmark University Omu-Aran, Nigeria Antreas Afantitis Department of Chemoinformatics NovaMechanics Ltd Nicosia, Cyprus Solomon O. Akinrinade Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria Okunola A. Alabi Department of Biology Federal University of Technology Akure, Nigeria Zuhal Alım Department of Chemistry University of Ahi Evran Kırşehir, Turkey Chibuisi G. Alimba Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria Isabel Andueza Pharmaceutical Technology Chief Department School of Pharmacy Universidad Central de Venezuela Caracas, Venezuela

Adekunle A. Bakare Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria Rachel Picada Bulcão Faculdade Educacional Araucária, Paraná Ng Cheng Teng Department of Anatomy National University of Singapore Singapore Motunrayo M. Coker Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria Hemant Kumar Daima Amity Institute of Biotechnology Amity University Rajasthan Jaipur, Rajasthan, India and Department of Biotechnology Siddaganga Institute of Technology Nano-Bio Interfacial Research Laboratory (NBIRL) Tumakuru, Karnataka, India Carlos Eduardo Matos dos Santos Altox Lab Perdizes, São Paulo, Brazil Damjana Drobne Department of Biology University of Ljubljana Ljubljana, Slovenia

xiii

xiv

Akhilesh Dubey Division of Biological Sciences and Engineering Netaji Subhas Institute of Technology Dwarka, New Delhi, India Hadi Ebrahimnejad Department of Food Hygiene and Public Health School of Veterinary Medicine Shahid Bahonar University of Kerman Kerman, Iran Opeoluwa M. Fadoju Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria Nikhath Firdose Department of Biotechnology Siddaganga Institute of Technology Nano-Bio Interfacial Research Laboratory (NBIRL) Tumakuru, Karnataka, India Leema George Department of Biotechnology VIT University Vellore, Tamilnadu, India Praveen Guleria Plant Biotechnology and Genetic Engineering Lab Department of Biotechnology DAV University Jalandhar, Punjab, India

Contributors

Sourabh Monnappa Kuppanda Jafri Department of Biotechnology Siddaganga Institute of Technology Nano-Bio Interfacial Research Laboratory (NBIRL) Tumakuru, Karnataka, India Devendra Jain Department of Molecular Biology and Biotechnology Maharana Pratap University of Agriculture and Technology Udaipur, Rajasthan, India Ankur Jairath Central University of Punjab Bathinda Punjab, India Anubhav Kaphle Goettingen Center for Molecular Biosciences Georg-August-Universität Göttingen Göttingen, Lower Saxony, Germany and Department of Biotechnology Siddaganga Institute of Technology Nano-Bio Interfacial Research Laboratory (NBIRL) Tumakuru, Karnataka, India

Shiwani Guleria Department of Microbiology Lovely Professional University Phagwara, Punjab, India

Bensu Karahalil Faculty of Pharmacy Toxicology Department Gazi University Ankara, Turkey

Baeg Gyeong Hun Department of Anatomy National University of Singapore Singapore

Puja Khanna Department of Anatomy National University of Singapore Singapore

xv

Contributors

Anita Jemec Kokalj Department of Biology University of Ljubljana Ljubljana, Slovenia Vineet Kumar Department of Biotechnology Lovely Professional University Phagwara, Punjab, India M. Mathan Kumar Department of Biotechnology VIT University Vellore, Tamilnadu, India Bambang Kuswandi Faculty of Pharmacy Chemo and Biosensors Group University of Jember East Java, Indonesia Piet N. L. Lens UNESCO-IHE Institute of Water Education Delft, The Netherlands Georgios Leonis Department of Chemoinformatics NovaMechanics Ltd Nicosia, Cyprus Jerzy Leszczynski Interdisciplinary Center for Nanotoxicity Jackson State University Jackson, Mississippi Rajeeva Lochana Department of BioSciences VIT University Vellore, Tamilnadu, India Harishkumar Madhyastha Department of Applied Physiology University of Miyazaki Miyazaki, Japan

Radha Madhyastha Department of Applied Physiology University of Miyazaki Miyazaki, Japan Venkatraman Manickam Department of BioSciences VIT University Vellore, Tamilnadu, India Fátima Torrico Medina Department of Biological Sciences School of Pharmacy Universidad Central de Venezuela Caracas, Venezuela Georgia Melagraki Department of Chemoinformatics NovaMechanics Ltd Nicosia, Cyprus Alicja Mikolajczyk Department of Chemistry University of Gdansk Wita Stwosza, Gdansk, Poland Montserrat Mitjans Department Bioquimica i Fisiologia Facultat de Farmàcia i Ciències de l’Alimentació Universitat de Barcelona Barcelona, Spain Hanan Ramadan Hamad Mohamed Zoology Department Cairo University Giza, Egypt Sahel Motaghi Department of Basic Sciences School of Veterinary Medicine Shahid Bahonar University of Kerman Kerman, Iran

xvi

Elizabeth de Souza Nascimento Universidade de São Paulo Cidade Universitária São Paulo, Brazil Debjani Nath Department of Zoology University of Kalyani Nadia, West Bengal, India Pundarikanakallahalli Nagaraju Navya Department of Biotechnology Siddaganga Institute of Technology Nano-Bio Interfacial Research Laboratory (NBIRL) Tumakuru, Karnataka, India

Contributors

Jyoti Parkash Central University of Punjab Bathinda Punjab, India Tiago Severo Peixe Universidade Estadual de Londrina Londrina, Paraná, Brazil Arun Prakash Periasamy Department of Chemistry National Taiwan University Taipei, Taiwan Tomasz Puzyn Department of Chemistry University of Gdansk Wita Stwosza, Gdansk, Poland

Daniele Rubert Nogueira-Librelotto Department de Farmácia Industrial Universidade Federal de Santa Maria Santa Maria, RS, Brazil

Bhavapriya Rajendran Department of BioSciences VIT University Vellore, Tamilnadu, India

Sara Novak Department of Biology University of Ljubljana Ljubljana, Slovenia Olusegun I. Ogunsuyi Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria

Rini Ravindranath Department of Chemistry National Taiwan University and Nanoscience and Technology Program Taiwan International Graduate Program Taipei, Taiwan

David Adeiza Otohinoyi School of Medicine All Saints University Roseau, Dominica

Eldon R. Rene UNESCO-IHE Institute of Water Education Delft, The Netherlands

Ifeoluwa T. Oyeyemi Department of Zoology University of Ibadan Ibadan, Oyo, Nigeria

Prathik Roy Department of Chemistry University of Canterbury Christchurch, New Zealand

Mariana C. N. Pais FERST Consulting Itaim Bibi, São Paulo, Brazil

Arti Sharma Baba Farid Group of Institution Bathinda Punjab, India

xvii

Contributors

Shilpa Sharma Division of Biological Sciences and Engineering Netaji Subhas Institute of Technology Dwarka, New Delhi, India Sanjay Singh Division of Biological and Life Sciences School of Arts and Sciences Ahmedabad University Central Campus Ahmedabad, Gujarat, India Natalia Sizochenko Interdisciplinary Center for Nanotoxicity Jackson State University Jackson, Mississippi and Department of Chemistry University of Gdansk Wita Stwosza, Gdansk, Poland Sangly Pranesh Srinivas School of Optometry Indiana University Bloomington, Indiana Alirica I. Suarez Natural Products Chief Laboratory School of Pharmacy Universidad Central de Venezuela Caracas, Venezuela

Amiti Tanny Department of BioSciences VIT University Vellore, Tamilnadu, India Suleyman Tekmen University of Bayburt Central Research Laboratory Bayburt, Turkey Akhela Umapathi Amity Institute of Biotechnology Amity University Rajasthan Jaipur, Rajasthan, India Ranjith Kumar Velusamy Department of Biotechnology VIT University Vellore, Tamilnadu, India Madan Lal Verma Centre for Chemistry and Biotechnology Deakin University Victoria, Australia María Pilar Vinardell Department Bioquimica i Fisiologia Facultat de Farmàcia i Ciències de l’Alimentació Universitat de Barcelona Barcelona, Spain

Faoziyat Adenike Sulaiman Department of Biochemistry University of Ilorin Ilorin, Nigeria

Adhena A. Werkneh Department of Environmental Health Mekelle University Mekelle, Ethiopia

Ramasamy Tamizhselvi Department of Biotechnology VIT University Vellore, Tamilnadu, India

Belinda Wong Shu Ee Department of Anatomy National University of Singapore Singapore

1 Critical Evaluation of Toxicity Tests in Context to Engineered Nanomaterials: An Introductory Overview Madan Lal Verma CONTENTS 1.1 Introduction.....................................................................................................1 1.2 Methods for Visualizing Cellular Uptake and Biodistribution of Engineered Nanomaterials....................................................................... 3 1.3 Evaluation of Transport and Uptake of Engineered Nanomaterials In Vitro...................................................................................4 1.4 In Vivo Uptake, Transport, and Detection................................................... 4 1.5 In Vitro Cytotoxicity Tests: Cytotoxicity Tests, Genotoxicity Tests..........6 1.6 In Vivo Toxicity Testing: Toxicokinetics, Immunological Response, Chronic Toxicity, and Carcinogenicity.....................................8 1.7 Considerations for Selection of Toxicity Tests for Engineered Nanomaterials—In Vitro versus In Vivo.................................................... 10 1.8 Conclusions.................................................................................................... 11 References................................................................................................................ 12

1.1 Introduction Nanomaterials exist naturally in the environment such as dust storms, volcanic ash, and soot from forest fires or are the incidental byproducts of combustion processes (e.g., diesel engines, welding, etc.). They are usually physicochemical heterogeneous and are often termed ultrafine particles (Donaldson et al. 2005; Ning et al. 2006; Buzea et al. 2007). Thus, human beings are exposed to naturally occurring nanomaterials. However, with the start of the tailor made synthesis of nanomaterials at research and development centers, there are pros and cons associated with these nanomaterials. Top down and bottom up approaches are employed for the production of nanomaterials. The number of nanotechnology products keeps increasing day by day and is becoming a part of our life. The efficiency of many processes

1

2

Nanotoxicology

including bioprocessing, nanosensor technology, and so on is improving multi-fold with the inclusion of nanomaterials. However, excessive exposure of nanomaterials to different consumers, ranging from research personnel to the common man, has become a matter of great concern due to the potential nanotoxic effects (Kermanizadeh et al. 2013; Singh and Ramarao 2013; Guadagnini et al. 2015). Thus, it is pertinent to identify the potential risk factors that are harmful to human health and the environment (Kermanizadeh et al. 2013). Current literature analysis sheds light on the toxicity of engineered nanomaterials revealing that some nanomaterials are relatively safe as compared to other nanomaterials, which are harmful (Magdolenova et al. 2012; Kumar et al. 2014). The toxicity properties of such nanomaterials are directly associated with the physical and chemical properties of the concerned nanomaterials (Figure 1.1). The present chapter provides a concise and critical review of the various parameters of engineered nanomaterials (ENMs) employed for the detection and evaluation of toxicity via in vitro and in vivo assays. Recent considerations for toxicity tests for engineered nanomaterials are also discussed.

Size

Chemical composition

Shape

ENMs toxicity factors

Surface covering

Dose of ENMs administration Route of ENMs administration

FIGURE 1.1 Various factors responsible for the toxicity of engineered nanomaterials (ENMs).

Critical Evaluation of Toxicity Tests in Context to Engineered Nanomaterials

3

1.2 Methods for Visualizing Cellular Uptake and Biodistribution of Engineered Nanomaterials During intended and unintended exposure to nanomaterials, engineered nanomaterials (ENMs) may come in contact with the biological fluids of the human body system through different routes such as inhalation, ingestion, and the skin. Once inside the human body, ENMs will get the opportunity to interact with various biomacromolecules such as proteins, sugars, lipids, and nucleic acids. Immediate crowding of the macromolecules, primarily proteins on the surface of the ENMs occurs; this phenomenon is known as protein corona (Shang et al. 2014). The nature of protein corona is dynamic and depends on the individual components and their affinities toward the macromolecules in the biological fluids. Cellular uptake (internalization) may involve transport across the cell membrane which can be of two types: receptor mediated active transport and passive transport. The cellular uptake of ENMs was determined fluorimetrically using Coumarin 6 as a fluorescent model drug (Panyam et al. 2002). The unique physical and chemical properties of ENMs render the benefits of increased absorption that lead to the enhanced cellular uptake of ENMs (Mundargi et al. 2008; Adair et al. 2010). However, this enhanced cellular uptake can also lead to the increased interaction of ENMs with subcellular organelles which results in the provocation of various signaling pathways. This also evokes a stress response in the cell that includes free radical formation, cellular-organelle damage, and even cell death (Bayles et al. 2010, Wang et al. 2011a,b). The degree of cytotoxicity of the nanomaterials, either low or high, depends on their cellular uptake (Ryman-Rasmussen et al. 2007; Geys et al. 2008). The low toxicity of nanoparticles is demonstrated due to inefficient cellular uptake (Singh and Ramarao 2013). Researchers studied the cellular uptake of a fluorescent drug (Coumarin 6) using polymeric nanoparticles. In vitro release of Coumarin 6 from nanoparticles showed that less than 1% dye leached from nanoparticles in 24 h. The confocal microscopy study revealed that nanoparticles are effectively and quickly internalized in the cells of macrophage cell lines (RAW 264.7). ENMs entered into the cytoplasmic compartment rather than the cell nucleus. Since 2-dimensional imaging cannot exactly trace the location of intracellular versus surface-bound ENMs, the cellular uptake of ENMs was confirmed by using 3-dimensional imaging. However, the punctuate fluorescence shows that the ENMs are localized in cellular organelles such as lysosomes; the diffused cytoplasmic fluorescence confirms the presence of ENMs in the cytoplasm. The ENMs are trafficked to the lysosomal compartment where they may undergo charge reversal resulting in lysosomal escape (Panyam et al. 2002; Cartiera et al. 2009). Thus, in addition to cytoplasm, the ENMs may be present in cell organelles.

4

Nanotoxicology

1.3 Evaluation of Transport and Uptake of Engineered Nanomaterials In Vitro Transport and uptake of the ENMs becomes crucial for evaluation when they enter into specialized tissues, for example, the brain and fetuses. Such investigation required in vitro studies using cell culture techniques with specialized transwell apparatus to provide access to apical as well as basal compartments (Kettiger et al. 2013). The evaluation of transport and uptake of ENMs of different chemical compositions can be systematically done by using cell lines of different origins. Such cell lines represent various compartments of target tissue such as macrophage, hepatocyte, renal epithelial, pulmonary epithelial, and neuronal cells (Singh and Ramarao 2013). A systematic study to determine the high or low concentrations’ effects of ENMs was needed to evaluate the cell viability effects. For example, Singh and Ramarao, (2013) studied the concentration effect of ENMs on cell viability by using a series of different cell lines originated from RAW 264.7 (macrophage), Hep G2 (hepatocyte), A549 (lung epithelial), A498 (kidney epithelial), and Neuro 2A (neuronal). One researcher reported a novel fluorescence recovery after quenching (FRAQ) assay to determine intracellular degradation of ENMs (Singh and Ramarao 2013). ENMs showed toxicity at the highest doses in all cell lines. Moreover, ENMs were efficiently internalized by RAW 264.7 cells and stimulated reactive oxygen species and tumor necrosis factor-alpha production (Figure 1.2). However, the stability of intracellular organelles such as lysosomal and mitochondrial organelles remained unaffected. The intracellular degradation of ENMs was determined by monitoring changes in osmolality of the culture medium and a novel fluorescence recovery after quenching assay (Ryman-Rasmussen et al. 2007; Geys et al. 2008; Singh and Ramarao 2013). Cell death showed a good correlation with osmolality of the culture medium suggesting the role of increased osmolality in cell death. Energy inhibition assay is commonly employed for understanding the transport and uptake of cellular mechanisms. Energy inhibition studies work on diverse metabolic conditions and inhibitors in coupling with imaging tools via confocal or electron microscopy (Kaweeteerawat et al. 2015).

1.4 In Vivo Uptake, Transport, and Detection The primary target of ENMs is the respiratory organs followed by other organs such as the gastrointestinal tract. ENMs enter the gastrointestinal tract through different routes: (i) an indirect route via mucociliary movement and (ii) a direct route via the oral intake of water, food, cosmetics, drugs, and drug delivery systems (Meng et al. 2007). The interactions of the


5

NP

Internalization

Degradation

ROS cytokines

FIGURE 1.2 Mechanism of cytotoxicity of ENMs. Abbreviations: NP, nanoparticle; ROS, reactive oxygen species. (Adapted from Singh, R. P. and P. Ramarao. 2013. Toxicol Lett 136(1):131–143.)

physico-chemical properties (e.g., size, shape, surface chemistry, composition, and aggregation) of ENMs with biological systems inside the body in order to elucidate the relationship for induction of toxic biological responses can be summarized as follows: (a) The main entry for ENMs to the body occurs primarily by six routes: intravenous, dermal, subcutaneous, inhalation, intraperitoneal, and oral; (b) absorption takes place where the ENMs first interact with complex biological components (proteins, cells) to form the biological corona of the nanoparticles; (c) afterward, ENMs spread to various organs of the body and may retain the pristine structure of the nanoparticles or even be modified/metabolized; (d) ENMs enter the cells and reside in the initial organ before moving to other body organs or finally being excreted (Fischer and Chan 2007; Maynard 2006). ENMs’ interaction with biological systems may cause toxic effects such as inflammation, cytotoxicity, fibrosis, allergy, tissue damage, and organ failure (Maynard 2006; Nel et al. 2006; Singh et al. 2009). In vivo uptake and detection of the ENMs becomes complex due to biological interactions, for example, opsonization (Iversen et al. 2011). The biodistribution of ENMs within the tissue relies on various factors associated with nanomaterials such as size and surface chemistry and requires long durations to monitor the full profile of in vivo uptake and transport of cellular mechanisms. Sophisticated instruments such as inductively coupled plasma mass spectrometry (ICP-MS) are used to evaluate tissue levels for a range of targeted nanomaterials (Laborda et al. 2016).

6

Nanotoxicology

1.5 I n Vitro Cytotoxicity Tests: Cytotoxicity Tests, Genotoxicity Tests In vitro tests, either cytotoxicity or genotoxicity are commonly employed to obtain initial information on engineered nanomaterials’ toxicity (Table 1.1). In vitro cytotoxicity tests are performed using cell lines or isolated primary human cells, for example, macrophages. In vitro cytotoxicity studies for evaluation of ENMs have been carried out systematically by using standard methods such as MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and Coomassie blue (CB) assays (Singh et al. 2012; Singh and Ramarao 2012). Cells were incubated with various concentrations of ENMs for 72 h. After incubation, cells were washed extensively with phosphate buffer saline (PBS) solutions to remove ENMs, then cell viability was determined by standard assay methods. In brief, culture supernatants from control or ENMs-containing samples were collected and cells were incubated with MTT. The formazan was dissolved in organic solvents such as dimethyl sulfoxide (DMSO) and absorbance was measured at 550 nm. While in CB assay, the reaction mixture containing culture supernatants and Bradford reagent was incubated and absorbance was determined at 595 nm. The absorbance of control samples was assumed to be 100% and cell viability of treated samples was determined with respect to control samples (Singh and Ramarao 2013). DCFDA (2′,7′-dichlorofluorescin diacetate) assay was done to evaluate the free radicals. Free radical production was determined by monitoring the production of reactive oxygen species and reactive nitrogen species in the macrophage cell lines (Singh and Ramarao 2012). RNS (Reactive Nitrogen Species) production was determined by nitrite assay in culture supernatants using Griess reagent (Tsikas 2005). A reaction mixture containing equal volumes of culture supernatant and the Griess reagent was incubated at room temperature for 30 min and resulted in diazo salt formation. The absorbance was measured at 540 nm. The nitrite concentration was calculated from a standard graph constructed using sodium nitrite (Singh et al. 2012; Singh and Ramarao 2012). Cytokine productions (TNF-α and IL-6 levels) were measured in culture supernatants by colorimetric enzyme linked immunosorbent assay (ELISA). Mitochondrial stability assay was performed to observe changes in mitochondrial membrane potential. This stability assay is done using standard methods such as Rh123 and Safranin O. The Rh123 fluorescence intensity was determined at 530 nm excitation and 590 nm emission. The absorbance of Safranin O was determined at 523 and 555 nm and the ratio of intensities was calculated (Deryabina et al. 2001; Severin et al. 2010). Lysosomal stability was determined by leakage of acridine orange from acridine orange-loaded lysosomes and the accumulation of neutral red in intact lysosomes. Acridine orange, a lysomotropic agent, preferentially accumulates in intracellular organelles such as lysosomes that show a red fluorescence. This dye leaks out into the cytoplasm

Measurement of viable cells after lysosomal uptake of dyes Tetrazolium based colorimetrical assay involves conversion to formazan that enables measurement of functional cells

Neutral red assay

Colorimetrical assay for immune response detection and estimate cytokines concentration

Single cell gel electrophoresis Detects DNA damage either single- and double-strand breaks

Measurement of changes in the frequency of micronucleus formation

Enzyme-linked immunosorbent assays

Comet assay

Micronuclei assay

MTS and MTT assays

LDH assay

Dyes selectively stains non-living cells/dead cells Colorimetrical measurement of LDH

Advantages

Trypan blue assay

In Vitro Assay

DNA and engineered nanomaterials detection; interference with formamidopyrimidine DNA glycosylase, photocatalytic ENMs increase DNA breakage after uv light exposure Cytochalasin B decreases nanomaterial endocytosis

Adsorption of cytokines

Time consuming, LDH adsorption, LDH activity inhibition Dye adsorption and optical intereference Formazan adsorption by ENMs; possibility of reduction, for example, superoxide, optical interference

Time consuming

Disadvantages

Determining the Cytotoxicity of Engineered Nanomaterials via In Vitro Assays

TABLE 1.1

Magdolenova et al. (2012), Hillegass et al. (2010)

Kroll et al. (2012), Wang et al. (2011a,b), Oostingh et al. (2011), Sadik et al. (2009), Casey et al. (2007), Laaksonen et al. (2007), Worle-Knirsch et al. (2006), Monteiro-Riviere and Inman (2006) Guadagnini et al. (2015), Brown et al. (2010), Kocbach et al. (2008), Veranth et al. (2007), Monteiro-Riviere and Inman (2006) Ferraro et al. (2016), Karlsson et al. (2015), Kain et al. (2012)

Oh et al. (2014), Kroll et al. (2012), Carlsson et al. (1993) Ong et al. (2014), Repetto et al. (2008)

Hillegass et al. (2010), Altman et al. (1993)

References

Critical Evaluation of Toxicity Tests in Context to Engineered Nanomaterials 7

8

Nanotoxicology

in damaged lysosomes and renders a green fluorescence. The intensity of the green fluorescence is directly proportional to the degree of lysosomal damage. Further, the increment in the intensity of green fluorescence by cytoplasmic acridine orange appears early compared with the decrement in the intensity of red fluorescence by lysosomal acridine orange (Antunes et al. 2001; Castino et al. 2007). The intensity of the degree of fluorescence was measured at 488 nm excitation and 540 nm emission. Neutral red assay is based on the accumulation of the dye in intact lysosomes. A reduction in viable lysosomes leads to a reduction in neutral red uptake by cells and is done by taking absorbance at 540 nm. Genotoxicity of nanoparticles refers to the toxicity against the genetic material of the cell. It affects DNA integrity that ultimately leads to DNA damage. This may cause mutagenicity and carcinogenicity in some cases (Nesslany and Benameur 2015). The genotoxic properties of ENMs render DNA damage due to oxidative stress resulting from the hyper-production of reactive oxygen species and reactive nitrogen species (Kisin et al. 2007; Barnes et al. 2008). Induction of oxidative stress by ENMs is the mechanism most responsible for the cause of potential toxicity (Li et al. 2010; Manke et al. 2013). ENMs-mediated reactive oxygen species and reactive nitrogen species production mechanisms can be divided into three groups: intrinsic production, production by interaction with cell targets, and production mediated by the inflammatory reaction. These three groups share responsibility for most of the primary or secondary genotoxic effects observed so far with ENMs (Nesslany and Benameur 2016). Currently, evaluation of engineered nanomaterials is done by in vitro genotoxicity tests including the Ames, micronucleus, and HPRT (hypoxanthine phosphorybosyl transferase) mutation assays. These tests can do a safe assessment of nanomaterials-induced DNA damage. However, the Organisation for Economic Co-operation and Development (OECD)-based genotoxicity assays for engineered nanomaterials are not universal, for example, the Ames test is not applicable for the assessment of engineered nanomaterials, while in vitro HPRT and micronucleus assays for nanomaterial assessment require specific protocols. Thus, there is a requirement for strategic planning to deal with in vitro genotoxicity testing (Doak et al. 2012).

1.6 I n Vivo Toxicity Testing: Toxicokinetics, Immunological Response, Chronic Toxicity, and Carcinogenicity ENMs behave quite differently in the complex environment of living systems. Thus, ENMs work differently in vitro versus in vivo studies. Evaluation of ENMs using in vivo study provides a more realistic outcome of the potential toxicity (Kumar et al. 2012). Compared to in vitro tests, in vivo analyses are laborious and expensive. Various factors such as route of administration, biodistribution, biodegradability, short- or long-term disposition, induction


9

of developmental defects, and activation of the compliment and/or immune system are all major issues in determining in vivo nanotoxicity, and cannot possibly be done through in vitro assays (Table 1.2; Rizzo et al. 2013; Kettiger et al. 2013). Recently, zebrafish embryo assay has been employed to assess the acute toxic effects as well as the “long-term” developmental defects resulting from exposure to engineered nanomaterials (George et al. 2011). Exposure of metal and metal oxide ENMs such as silver (Ag), gold (Au), silicon dioxide (SiO2), magnesium oxide (MgO), titanium oxide (TiO2), and zinc oxide (ZnO) to a living system induce a low in vivo toxicity (Auffan et al. 2009; Lu et al. 2009; Warheit et al. 2009; Zhu et al. 2009). However, factors such as the chemical stability of the nanoparticles are mainly responsible for causing toxicity at the cellular level. The oxidized/reduced/solubilized properties of ENMs are potentially toxic and need special consideration before use (Auffan et al. 2009). Sung et al. (2009) reported the effects of Ag nanoparticles in Sprague-Dawley rats. A low dose was non-toxic. However, higher doses produced severe effects TABLE 1.2 Showing Possible Engineered Nanomaterials (ENMs) Effects as the Basis for Pathophysiology and Toxicity Experimental NM Effects ROS generation Oxidative stress Mitochondrial perturbation

Inflammation

Uptake by reticulo-endothelial system

Protein denaturation, degradation Nuclear uptake Uptake in neuronal tissue Perturbation of phagocytic function, “particle overload,” mediator release Endothelial dysfunction, effects on blood clotting Generation of neoantigens, breakdown in immune tolerance Altered cell cycle regulation DNA damage

Possible Pathophysiological Outcomes Protein, DNA and membrane injury, oxidative stress Phase II enzyme induction, inflammation, mitochondrial perturbation Inner membrane damage, permeability transition (PT), pore opening, energy failure, apoptosis, apo-necrosis, cytotoxicity Tissue infiltration with inflammatory cells, fibrosis, granulomas, atherogenesis, acute phase protein expression (e.g., C-reactive protein) Asymptomatic sequestration and storage in liver, spleen, lymph nodes, possible organ enlargement and dysfunction Loss of enzyme activity, auto-antigenicity DNA damage, nucleoprotein clumping, autoantigens Brain and peripheral nervous system injury Chronic inflammation, fibrosis, granulomas, interference in clearance of infectious agent Atherogenesis, thrombosis, stroke, myocardial infarction Autoimmunity, adjuvant effects Proliferation, cell cycle arrest, senescence Mutagenesis, metaplasia, carcinogenesis

Source: Adapted from Nel, A. et al. 2006. Science 311:622–627.

10

Nanotoxicology

on organs such as the lungs and liver. Ag nanoparticles also induced inflammatory responses at higher concentrations. This in vivo study with ENMs has shown dose-dependent cytotoxic effects. Cho et al. (2009) investigated the toxicity effects of Au nanoparticles in mice and found the induction of inflammatory immune- and metabolic-process responses in the liver of mice. Huang et al. (2009) reported a minimal cytotoxic effect on the surface of some organs by modified nanoparticles such as carboxymethyl dextran-coated iron oxide in the brain of mice. Kobayashi et al. (2009) studied the effects of variable sizes of TiO2 nanoparticles on rat lungs. Different degrees of agglomeration with variable sizes of ENMs developed different toxicity effects such as higher reversible inflammation. Simberg et al. (2009) investigated the effects of superparamagnetic iron oxide nanoparticles in the mouse model. In vivo studies have shown that high concentrations of superparamagnetic iron oxide nanoparticles in the lumen caused thrombosis in the blood vessels. Further, entrapment of ENMs in the growing intravascular thrombi led to cell death. Therefore, tumor-targeted ENMs inhibited tumor growth. Zhu et al. (2008) reported oxidative stress in the lungs of male Sprague-Dawley rats using intratracheal administration of magnetic nanoparticles. Such ENMs-induced oxidative stress produced a series of lung problems that includes follicular hyperplasia, protein effusion, pulmonary capillary vessel hyperaemia, and alveolar lipoproteinosis. Sayes et al. (2007) demonstrated the effects of ZnO nanoparticles in rats. The in vivo study showed pulmonary toxicity effects in reversible inflammation. Warheit et al. (2009) observed toxicity effects of TiO2 such as acute dermal irritation in rabbits. Liu et al. (2008) investigated the effect of intravenously administered modified single-walled carbon nanotubes in mice. The ENMs were found to be nontoxic and excreted in feces via the biliary and renal pathways. The possible mechanism for non-toxicity was due to the biological inertness provided to the ENMs with the aid of surface modification with polyethylene glycol. Ma-Hock et al. (2009) studied the toxic effects of multi-walled carbon nanotubes in Wistar rats and found them to be safe even with exposure for more than three months. However, the immunological response of neutrophil production was reported at higher levels of ENMs. Thus, the above discussed recent studies of in vivo toxicity effects in different animal models show the response of immunological systems and chronic toxicity of exposure to ENMs at high doses. However, ENMs are found to be quite safe at low concentrations.

1.7 Considerations for Selection of Toxicity Tests for Engineered Nanomaterials—In Vitro versus In Vivo Ideally, every new ENM should be evaluated for potential toxicity; this will require an insight for the particular factors/characteristics responsible for


that particular nanotoxicity (Soenen et al. 2011; Carreira et al. 2015). With this in mind, an important initiative was taken by EU Framework 7 Health program in the form of a NanoTEST project. The main motive behind this project was to develop rapid assessment of the toxicological profiles of nanomaterials using in vitro and in silico methods (Dusinska et al. 2009). NanoTEST was also designed to evaluate the uptake and transport of medical diagnostics-relevant engineered nanomaterials, in particular in reference to checking ENMs’ potential to cross specific cell barriers. The penetrating nature of ENMs will allow further dissemination throughout the body or specific penetration to sensitive areas, for example, the fetus during pregnancy. The probability of invasive ENMs reaching secondary targets is quite high; this will require careful consideration of potential toxicity (Iversen et al. 2012). A recent literature survey reveals that more stringent controls should be undertaken for nanotoxicological studies and guidelines should be provided to reduce the potential for ENM-assay interactions along with linked aberrant results (Ong et al. 2014). Higher doses of ENMs in a concentration of 10 mg/L have a greater probability of interfering with assay function, and the use of such a high dose is not uncommon in toxicological studies. Therefore, ENM concentration should be restricted in the final sample, recognizing that even with multiple washes/centrifugations ENMs could remain within cells or bound to membranes (Davoren et al. 2007; MonteiroRiviere et al. 2009). Furthermore, the use of centrifugation is counterproductive in case the ENMs have tightly bound to the assay components, inadvertently removing dyes and/or proteins essential for accurate readings (Holder et al. 2012). Thus, it is strongly recommended that researchers should carefully consider the final dose of ENM concentration (Ong et al. 2014). Recently, nanomaterial synthesis via biogeneic routes has been based on green chemistry principles that are the most sought-after alternative to chemical and physical methods (Dahl et al. 2007; Iravani 2011; Verma et al. 2013a,b). More efficient biogenic routes for microorganisms (bacteria and fungi) and plants avoid harmful reagents and are even safer for human beings (Ravindran et al. 2003; Albrecht et al. 2006).

1.8 Conclusions Nanotechnology has an impact on the advance of the sciences including major benefits for society. The continuous production of a copious number of engineered nanomaterials has provided promising technical benefits to consumers and medical appliances. Despite the advantageous properties of nanomaterials such as being antimicrobial (antifungal, antiviral, and antibiotic), drug carriers, contrasting agents, and so on, the susceptibility of

12

Nanotoxicology

nanoscale materials to be toxic to human health and the environment is quite high and exposes a major gap in knowledge (Matysiak et al. 2016). ENMs exposure generates harmful effects through interaction with biological systems as revealed in several in vivo studies. The literature survey of the toxicity of engineered nanomaterials concludes that nanoparticles have the potential to be toxic. However, the degree of toxicity can be modulated by various factors of the engineered nanomaterials such as size, shape, surface charge, modifications, and so on. The critical parameters of ENMs play a pivotal role in the degree of toxicity such as dose, route of administration, and exposure. Thus, every nanomaterial needs to pass rigorous testing before being considered safe. Hence, multidisciplinary collaborative research is required to fill the knowledge gaps in the research and development activities under the umbrella of nanotoxicity research. Employing holistic approaches such as biogenic synthesis and omics techniques will show solutions for these c urrent concerns.

References Adair, J. H., M. P. Parette, E. I. Altinoğlu, and M. Kester. 2010. Nanoparticulate alternatives for drug delivery. ACS Nano 4:4967–4970. Albrecht, M. A., C. W. Evans, and C. L. Raston. 2006. Green chemistry and the health implications of nanoparticles. Green Chem 8:417–432. Altman, S., L. Randers, and G. Rao. 1993. Comparison of trypan blue dye exclusion and fluorometric assays for mammalian cell viability determinations. Biotechnol Prog 9:671–674. Antunes, F., E. Cadenas, and U. T. Brunk. 2001. Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture. Biochem J 356:549–555. Auffan, M., J. Rose, M. R. Wiesner, and J. Y. Bottero. 2009. Chemical stability of metallic nanoparticles: A parameter controlling their potential cellular toxicity in vitro. Environ Pollut 157:1127–1133. Barnes, C. A., A. Elsaesser, J. Arkusz et al. 2008. Reproducible comet assay of amorphous silica nanoparticles detects no genotoxicity. Nano Lett 8:3069–3074. Bayles, A. R., H. S. Chahal, D. S. Chahal, C. P. Goldbeck, B. E. Cohen, and B. A. Helms. 2010. Rapid cytosolic delivery of luminescent nanocrystals in live cells with endosome-disrupting polymer colloids. Nano Lett 10:4086–4092. Brown, D. M., C. Dickson, P. Duncan, F. Al-Attili, and V. Stone. 2010. Interaction between nanoparticles and cytokine proteins: Impact on protein and particle functionality. Nanotechnology 21(21):215104. Buzea, C., I. I. Pacheco, and K. Robbie. 2007. Nanomaterials and nanoparticles: Sources and toxicity. Biointerphases 2(4):17–71. Carlsson, H., V. Prachayasittikul, and L. Bulow. 1993. Zinc ions bound to chimeric His4/lactate dehydrogenase facilitate decarboxylation of oxaloacetate. Protein Eng 6(8):907–911.


Carreira, S. C., L. Walker, K. Paul, and M. Saunders. 2015. The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTEST. Nanotoxicology 9(S1):66–78. Cartiera, M. S., K. M. Johnson, V. Rajendran, M. J. Caplan, and W. M. Saltzman. 2009. The uptake and intracellular fate of PLGA nanoparticles in epithelial cells. Biomaterials 30:2790–2798. Casey, A., E. Herzog, M. Davoren, F. M. Lyng, H. J. Byrne, and G. Chambers. 2007. Spectroscopic analysis confirms the interactions between single walled c arbon nanotubes and various dyes commonly used to assess cytotoxicity. Carbon 45(7):1425–1432. Castino, R., N. Bellio, G. Nicotra, C. Follo, N. F. Trincheri, and C. Isidoro. 2007. Cathepsin D-Bax death pathway in oxidative stressed neuroblastoma cells. Free Radic Biol Med 42:1305–1316. Cho, W. S., M. Cho, J. Jeong et al. 2009. Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles. Toxicol Appl Pharmacol 236:16–24. Dahl, J. A., B. L. S. Maddux, and J. E. Hutchinson. 2007. Toward greener nanosynthesis. Chem Rev 107:2228–2269. Davoren, M., E. Herzog, A. Casey, B. Cottineau, G. Chambers, H. J. Byrne, and F. M. Lyng. 2007. In vitro toxicity evaluation of single walled carbon nanotubes on human A549 lung cells. Toxicol In Vitro 21:438–448. Deryabina, Y. I., E. N. Bazhenova, N. E. Saris, and R. A. Zvyagilskaya. 2001. Ca2+ efflux in mitochondria from the yeast Endomyces magnusii. J Biol Chem 276:47801–47806. Doak, S. H., B. Manshian, G. J. S. Jenkins, and N. Singh. 2012. In vitro genotoxicity testing strategy for nanomaterials and the adaptation of current OECD guidelines. Mutat Res Genet Toxicol Environ Mutagen 745:104–111. Donaldson, K., L. Tran, L. A. Jimenez, R. Duffin, D. E. Newby, N. Mills, W. MacNee, and V. Stone. 2005. Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure. Part Fibre Toxicol 2:10. Dusinska, M., M. Dusinska, L. Fjellsbø, Z. Magdolenova, A. Rinna, A. Marcomini, G. Pojana, D. Bilanicova, and D. Vallotto. 2009. Testing strategies for the safety of nanoparticles used in medical applications. Nanomedicine (London, England) 4(6):605–607. Ferraro, D., U. Anselmi-Tamburini, I. G. Tredici, V. Ricci, and P. Sommi. 2016. Overestimation of nanoparticles-induced DNA damage determined by the comet assay. Nanotoxicology 10:861–870. Fischer, H. C. and W. C. N. Chan 2007. Nanotoxicity: The growing need for in vivo study. Curr Opin Biotechnol 18:565–571. George, S., T. Xia, R. Rallo et al. 2011. Use of a high-throughput screening approach coupled with in vivo zebrafish embryo screening to develop hazard ranking for engineered nanomaterials. ACS Nano 5:1805–1817. Geys, J., A. Nemmar, E. Verbeken, E. Smolders, M. Ratoi, M. F. Hoylaerts, B. Nemery, and P. H. Hoet. 2008. Acute toxicity and prothrombotic effects of quantum dots: Impact of surface charge. Environ Health Perspect 116:1607–1613. Guadagnini, R., B. Halamoda Kenzaoui, L. Walker et al. 2015. Toxicity screenings of nanomaterials: Challenges due to interference with assay processes and components of classic in vitro tests. Nanotoxicology 9:13–24. Hillegass, J. M., A. Shukla, S. A. Lathrop, M. B. MacPherson, N. K. Fukagawa, and B. T. Mossman. 2010. Assessing nanotoxicity in cells in vitro. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2(3):219–231.

14

Nanotoxicology

Holder, A. L., R. Goth-Goldstein, D. Lucas, and C. P. Koshland. 2012. Particle-induced artifacts in the MTT and LDH viability assays. Chem Res Toxicol 25:1885–1892. Huang, S., P. J. Chueh, Y. W. Lin, T. S. Shih, and S. M. Chuang. 2009. Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nano-TiO2 long-term exposure. Toxicol Appl Pharmacol 241:182–194. Iravani, S. 2011. Green synthesis of metal nanoparticles using plants. Green Chem 13:2638–2650. Iversen, N. K., S. Frische, K. Thomsen et al. 2012. Superparamagnetic iron oxide polyacrylic acid coated γ-Fe2O3 nanoparticles do not affect kidney function but cause acute effect on the cardiovascular function in healthy mice. Toxicol Appl Pharmacol 266(2):276–288. Iversen, T. G., T. Skotland, and K. Sandvig. 2011. Endocytosis and intracellular transport of nanoparticles: Present knowledge and need for future studies. Nanotoday 6:176–185. Kain, J., H. L. Karlsson, and L. Möller. 2012. DNA damage induced by micro- and nanoparticles-interaction with FPG influences the detection of DNA oxidation in the comet assay. Mutagenesis 27(4):491–500. Karlsson, H. L., S. Di Bucchianico, A. R. Collins, and M. Dusinska. 2015. Can the comet assay be used reliably to detect nanoparticle-induced genotoxicity? Environ Mol Mutagen 56(2):82–96. Kaweeteerawat, C., A. Ivask, R. Liu et al. 2015. Toxicity of metal oxide nanoparticles in Escherichia coli correlates with conduction band and hydration energies. Environ Sci Technol 49(2):1105–1112. Kermanizadeh, A., G. Pojana, B. K. Gaiser et al. 2013. In vitro assessment of e ngineered nanomaterials using a hepatocyte cell line: Cytotoxicity, pro-inflammatory cytokines and functional markers. Nanotoxicology 7:301–313. Kettiger, H., A. Schipanski, P. Wick, and J. Huwyler. 2013. Engineered nanomaterial uptake and tissue distribution: From cell to organism. Int J Nanomedicine 8:3255–3269. Kisin, E. R., A. R. Murray, M. J. Keane et al. 2007. Single-walled carbon nanotubes: Geno- and cytotoxic effects in lung fibroblast V79 cells. J Toxicol Environ Health. A 70:2071–2079. Kobayashi, N., M. Naya, S. Endoh, J. Maru, K. Yamamoto, and J. Nakanishi. 2009. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats: Different short- and long-term post-instillation results. Toxicology 264:110–118. Kocbach, A., A. I. Totlandsdal, M. Låg, M. Refsnes, and P. E. Schwarze. 2008. Differential binding of cytokines to environmentally relevant particles: A possible source for misinterpretation of in vitro results? Toxicol Lett 176(2):131–137. Kroll, A., M. H. Pillukat, D. Hahn, and J. Schnekenburger. 2012. Interference of engineered nanoparticles with in vitro toxicity assays. Arch Toxicol 86(7):1123–1136. Kumar, V., S. K. Kansal, and S. K. Mehta. 2014. Toxicity of nanomaterials: Present scenario and future scope. In: Nanotechnology: Recent Trends, Emerging Issues and Future Directions, Nazrul Islam ed. Nova Science Publishers, New York, USA, chapter 19, pp 461–486. Kumar, V., A. Kumari, P. Guleria, and S. K. Yadav. 2012. Evaluating the toxicity of selected types of nanochemicals. Rev Environ Contam Toxicol 215:39–121.


Laaksonen, T., H. Santos, H. Vihola et al. 2007. Failure of MTT as a toxicity testing agent for mesoporous silicon microparticles. Chem Res Toxicol 20(12):1913–1918. Laborda, F., E. Bolea, and J. Jiménez-Lamana. 2016. Single particle inductively coupled plasma mass spectrometry for the analysis of inorganic engineered nanoparticles in environmental samples. Trends Environ Anal Chem 9:15–23. Li, J. J., S. Muralikrishnan, C. T. Ng, L. Y. L. Yung, and B. H. Bay. 2010. Nanoparticleinduced pulmonary toxicity. Exp Biol Med (Maywood) 235:1025–1033. Liu, Z., C. Davis, W. Cai, L. He, X. Chen, and H. Dai. 2008. Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc Natl Acad Sci USA 105:1410–1415. Lu, S., R. Duffin, C. Poland, P. Daly, F. Murphy, E. Drost, W. MacNee, V. Stone, and K. Donaldson. 2009. Efficacy of simple short-term in vitro assays for predicting the potential of metal oxide nanoparticles to cause pulmonary inflammation. Environ Health Perspect 117:241–247. Magdolenova, Z., Y. Lorenzo, A. Collins, and M. Dusinska. 2012. Can standard genotoxicity tests be applied to nanoparticles? J Toxicol Environ Health A 75(13–15):800–806. Ma-Hock, L., S. Treumann, V. Strauss et al. 2009. Inhalation toxicity of multiwall carbon nanotubes in rats exposed for 3 months. Toxicol Sci 112:468–481. Manke, A., L. Wang, and Y. Rojanasakul. 2013. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int 2013:15. Matysiak, M., L. Kapka-Skrzypczak, K. C. Brzóska, A. Gutleb, and M. Kruszewski. 2016. Proteomic approach to nanotoxicity. J Proteomics 137:35–44. Maynard A. D. 2006. Safe handling of Nanotechnology. Nature 444:267–269. Meng, H., Z. Chen, G. Xing, H. Yuan, C. Chen, F. Zhao, C. Zhang, and Y. Zhao. 2007. Ultrahigh reactivity provokes nanotoxicity: Explanation of oral toxicity of nano-copper particles. Toxicol Lett 175:1–3. Monteiro-Riviere, N. A. and A. O. Inman. 2006. Challenges for assessing carbon nanomaterial toxicity to the skin. Carbon 44(6):1070–1078. Monteiro-Riviere, N. A., A. O. Inman, and L. W. Zhang. 2009. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol Appl Pharm 234:222–235. Mundargi, R. C., V. R. Babu, V. Rangaswamy, P. Patel, and T. M. Aminabhavi. 2008. Nano/micro technologies for delivering macromolecular therapeutics using poly(D, L-lactide-co-glycolide) and its derivatives. J Control Release 125:193–209. Nel, A., T. Xia, L. Madler, and N. Li. 2006. Toxic potential of materials at the n anolevel. Science 311:622–627. Nesslany, F. and L. Benameur. 2015. Genotoxicity of nanoparticles. Encyclopedia of Nanotechnology 1328–1338. Ning, Z., C. S. Cheung, J. Fu, M. A. Liu, and M. A. Schnell. 2006. Experimental study of environmental tobacco smoke particles under actual indoor environment. Sci Total Environ 367(2–3):822–830. Oh, S. J., H. Kim, Y. Liu et al. 2014. Incompatibility of silver nanoparticles with lactate dehydrogenase leakage assay for cellular viability test is attributed to protein binding and reactive oxygen species generation. Toxicol Lett 225(3):422–432. Ong, K. J., T. J. MacCormack, R. J. Clark et al. 2014. Widespread nanoparticle-assay interference: Implications for nanotoxicity testing. PLoS One 9(3): e90650.

16

Nanotoxicology

Oostingh, G. J., E. Casals, P. Italiani et al. 2011. Problems and challenges in the development and validation of human cell-based assays to determine nanoparticle-induced immunomodulatory effects. Part Fibre Toxicol 2011:8. Panyam, J., W. Z. Zhou, S. Prabha, S. K. Sahoo, and V. Labhasetwar. 2002. Rapid endolysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: Implications for drug and gene delivery. FASEB J. 16:1217–1226. Ravindran, P., J. Fu, and S. L. Wallen. 2003. Completely green synthesis and stabilisation of metal nanoparticles. J Am Chem Soc 125:13940–13941. Repetto, G., A. del Peso, and J. L. Zurita. 2008. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc 3(7):1125–1131. Rizzo, L. Y., S. K. Golombek, M. E. Mertens et al. 2013. In vivo nanotoxicity testing using the zebrafish embryo assay. J Mater Chem B Mater Biol Med 1:10. Ryman-Rasmussen, J. P., J. E. Riviere, and N. A. Monteiro-Riviere. 2007. Variables influencing interactions of untargeted quantum dot nanoparticles with skin cells and identification of biochemical modulators. Nano Lett 7:1344–1348. Sadik, O., A. L. Zhou, S. Kikandi, N. Du, Q. Wang, and K. Varner. 2009. Sensors as tools for quantitation, nanotoxicity and nanomonitoring assessment of engineered nanomaterials. J Environ Monit 11(10):1782–1800. Sayes, C. M., K. L. Reed, and D. B. Warheit. 2007. Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 97:163–180. Severin, F. F., I. I. Severina, Y. N. Antonenko et al. 2010. Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci USA 107:663–668. Shang, L., K. Nienhaus, and G. U. Nienhaus. 2014. Engineered nanoparticles interacting with cells: Size matters. J Nanobiotechnology 12:5. Simberg, D., W. M. Zhang, S. Merkulov, K. McCrae, J. H. Park, M. J. Sailor, and E. Ruoslahti. 2009. Contact activation of kallikrein-kinin system by superparamagnetic iron oxide nanoparticles in vitro and in vivo. J Control Release 140:301–305. Singh, N., B. Manshian, G. J. S. Jenkins, S. M. Griffiths, P. M. Williams, T. G. G. Maffeis, C. J. Wright, and S. H. Doak. 2009. Nanogenotoxicology: The DNA damaging potential of engineered nanomaterials. Biomaterials 30:3891–3914. Singh, R. P., M. Das, V. Thakare, and S. Jain. 2012. Functionalization density dependent toxicity of oxidized multiwalled carbon nanotubes in a murine macrophage cell line. Chem Res Toxicol 25:2127–2137. Singh, R. P. and P. Ramarao. 2012. Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles. Toxicol Lett 213:249–259. Singh, R. P. and P. Ramarao. 2013. Accumulated polymer degradation products as effector molecules in cytotoxicity of polymeric nanoparticles. Toxicol Lett 136(1):131–143. Soenen, S. J., P. Rivera-Gil, J.-M. Montenegro, W. J. Parak, S. C. De Smedt, and K. Braeckmans. 2011. Cellular toxicity of inorganic nanoparticles: Common aspects and guidelines for improved nanotoxicity evaluation. Nano Today 6:446–465. Sung, J. H., J. H. Ji, J. D. Park et al. 2009. Subchronic inhalation toxicity of silver nanoparticles. Toxicol Sci 108:452–461. Tsikas, D. 2005. Methods of quantitative analysis of the nitric oxide metabolites nitrite and nitrate in human biological fluids. Free Radic Res 39:797–815.


Veranth, J., E. G. Kaser, M. M. Veranth, M. Koch, and G. S. Yost. 2007. Cytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Part Fibre Toxicol 4(1):2. Verma, M. L., M. Naebe, C. J. Barrow, and M. Puri. 2013a. Enzyme immobilisation on amino-functionalised multi-walled carbon nanotubes: Structural and biocatalytic characterisation. PLoS One 8(9):e73642. Verma, M. L., R. Rajkhowa, X. Wang, C. J. Barrow, and M. Puri. 2013b. Exploring novel ultrafine Eri silk bioscaffold for enzyme stabilisation in cellobiose h ydrolysis. Bioresour Technol 145, 302–306. Wang, L., Y. Liu, W. Li et al. 2011a. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Lett 11:772–780. Wang, S. J., H. Yu, and J. K. Wickliffe. 2011b. Limitation of the MTT and XTT assays for measuring cell viability due to superoxide formation induced by nano-scale TiO2. Toxicol In Vitro 25(8):2147–2151. Warheit, D. B., C. M. Sayes, and K. L. Reed. 2009. Nanoscale and fine zinc oxide particles: Can in vitro assays accurately forecast lung hazards following inhalation exposures? Environ Sci Technol 43:7939–7945. Wörle-Knirsch, J. M., K. Pulskamp, and H. F. Krug. 2006. Carbon nanotubes hoax scientists in viability assays. Nano Lett 6(6):1261–1268. Zhu, M. T., W. Y. Feng, B. Wang, T. C. Wang, Y. Q. Gu, M. Wang, Y. Wang, H. Ouyang, Y. L. Zhao, and Z. F. Chai. 2008. Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats. Toxicology 247:102–111. Zhu, X., J. Wang, X. Zhang, Y. Chang, and Y. Chen. 2009. The impact of ZnO nano particle aggregates on the embryonic development of zebrafish (Danio rerio). Nanotechnology 20:195103.

Critical Evaluation of Toxicity Tests in Context to Engineered Nanomaterials: An Introductory Overview Adair, J. H. , M. P. Parette , E. I. Altinolu , and M. Kester . 2010. Nanoparticulate alternatives for drug delivery. ACS Nano 4:49674970. Albrecht, M. A. , C. W. Evans , and C. L. Raston . 2006. Green chemistry and the health implications of nanoparticles. Green Chem 8:417432. Altman, S. , L. Randers , and G. Rao . 1993. Comparison of trypan blue dye exclusion and fluorometric assays for mammalian cell viability determinations. Biotechnol Prog 9:671674. Antunes, F. , E. Cadenas , and U. T. Brunk . 2001. Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture. Biochem J 356:549555. Auffan, M. , J. Rose , M. R. Wiesner , and J. Y. Bottero . 2009. Chemical stability of metallic nanoparticles: A parameter controlling their potential cellular toxicity in vitro . Environ Pollut 157:11271133. Barnes, C. A. , A. Elsaesser , J. Arkusz 2008. Reproducible comet assay of amorphous silica nanoparticles detects no genotoxicity. Nano Lett 8:30693074. Bayles, A. R. , H. S. Chahal , D. S. Chahal , C. P. Goldbeck , B. E. Cohen , and B. A. Helms . 2010. Rapid cytosolic delivery of luminescent nanocrystals in live cells with endosomedisrupting polymer colloids. Nano Lett 10:40864092. Brown, D. M. , C. Dickson , P. Duncan , F. Al-Attili , and V. Stone . 2010. Interaction between nanoparticles and cytokine proteins: Impact on protein and particle functionality. Nanotechnology 21(21):215104. Buzea, C. , I. I. Pacheco , and K. Robbie . 2007. Nanomaterials and nanoparticles: Sources and toxicity. Biointerphases 2(4):1771. Carlsson, H. , V. Prachayasittikul , and L. Bulow . 1993. Zinc ions bound to chimeric His4/lactate dehydrogenase facilitate decarboxylation of oxaloacetate. Protein Eng 6(8):907911.13 Carreira, S. C. , L. Walker , K. Paul , and M. Saunders . 2015. The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTEST. Nanotoxicology 9(S1):6678. Cartiera, M. S. , K. M. Johnson , V. Rajendran , M. J. Caplan , and W. M. Saltzman . 2009. The uptake and intracellular fate of PLGA nanoparticles in epithelial cells. Biomaterials 30:27902798. Casey, A. , E. Herzog , M. Davoren , F. M. Lyng , H. J. Byrne , and G. Chambers . 2007. Spectroscopic analysis confirms the interactions between single walled carbon nanotubes and various dyes commonly used to assess cytotoxicity. Carbon 45(7):14251432. Castino, R. , N. Bellio , G. Nicotra , C. Follo , N. F. Trincheri , and C. Isidoro . 2007. Cathepsin D-Bax death pathway in oxidative stressed neuroblastoma cells. Free Radic Biol Med 42:13051316. Cho, W. S. , M. Cho , J. Jeong 2009. Acute toxicity and pharmacokinetics of 13 nm-sized PEGcoated gold nanoparticles. Toxicol Appl Pharmacol 236:1624. Dahl, J. A. , B. L. S. Maddux , and J. E. Hutchinson . 2007. Toward greener nanosynthesis. Chem Rev 107:22282269. Davoren, M. , E. Herzog , A. Casey , B. Cottineau , G. Chambers , H. J. Byrne , and F. M. Lyng . 2007. In vitro toxicity evaluation of single walled carbon nanotubes on human A549 lung cells. Toxicol In Vitro 21:438448. Deryabina, Y. I. , E. N. Bazhenova , N. E. Saris , and R. A. Zvyagilskaya . 2001. Ca2+ efflux in mitochondria from the yeast Endomyces magnusii . J Biol Chem 276:4780147806. Doak, S. H. , B. Manshian , G. J. S. Jenkins , and N. Singh . 2012. In vitro genotoxicity testing strategy for nanomaterials and the adaptation of current OECD guidelines. Mutat Res Genet Toxicol Environ Mutagen 745:104111. Donaldson, K. , L. Tran , L. A. Jimenez , R. Duffin , D. E. Newby , N. Mills , W. MacNee , and V. Stone . 2005. Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure. Part Fibre Toxicol 2:10. Dusinska, M. , M. Dusinska , L. Fjellsb , Z. Magdolenova , A. Rinna , A. Marcomini , G. Pojana , D. Bilanicova , and D. Vallotto . 2009. Testing strategies for the safety of nanoparticles used in medical applications. Nanomedicine (London, England) 4(6):605607. Ferraro, D. , U. Anselmi-Tamburini , I. G. Tredici , V. Ricci , and P. Sommi . 2016. Overestimation of nanoparticles-induced DNA damage determined by the comet assay. Nanotoxicology 10:861870. Fischer, H. C. and W. C. N. Chan 2007. Nanotoxicity: The growing need for in vivo study. Curr Opin Biotechnol 18:565571.

George, S. , T. Xia , R. Rallo 2011. Use of a high-throughput screening approach coupled with in vivo zebrafish embryo screening to develop hazard ranking for engineered nanomaterials. ACS Nano 5:18051817. Geys, J. , A. Nemmar , E. Verbeken , E. Smolders , M. Ratoi , M. F. Hoylaerts , B. Nemery , and P. H. Hoet . 2008. Acute toxicity and prothrombotic effects of quantum dots: Impact of surface charge. Environ Health Perspect 116:16071613. Guadagnini, R. , B. Halamoda Kenzaoui , L. Walker 2015. Toxicity screenings of nanomaterials: Challenges due to interference with assay processes and components of classic in vitro tests. Nanotoxicology 9:1324. Hillegass, J. M. , A. Shukla , S. A. Lathrop , M. B. MacPherson , N. K. Fukagawa , and B. T. Mossman . 2010. Assessing nanotoxicity in cells in vitro . Wiley Interdiscip Rev Nanomed Nanobiotechnol 2(3):219231.14 Holder, A. L. , R. Goth-Goldstein , D. Lucas , and C. P. Koshland . 2012. Particle-induced artifacts in the MTT and LDH viability assays. Chem Res Toxicol 25:18851892. Huang, S. , P. J. Chueh , Y. W. Lin , T. S. Shih , and S. M. Chuang . 2009. Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nanoTiO2 long-term exposure. Toxicol Appl Pharmacol 241:182194. Iravani, S. 2011. Green synthesis of metal nanoparticles using plants. Green Chem 13:26382650. Iversen, N. K. , S. Frische , K. Thomsen 2012. Superparamagnetic iron oxide polyacrylic acid coated -Fe2O3 nanoparticles do not affect kidney function but cause acute effect on the cardiovascular function in healthy mice. Toxicol Appl Pharmacol 266(2):276288. Iversen, T. G. , T. Skotland , and K. Sandvig . 2011. Endocytosis and intracellular transport of nanoparticles: Present knowledge and need for future studies. Nanotoday 6:176185. Kain, J. , H. L. Karlsson , and L. Mller . 2012. DNA damage induced by micro- and nanoparticles-interaction with FPG influences the detection of DNA oxidation in the comet assay. Mutagenesis 27(4):491500. Karlsson, H. L. , S. Di Bucchianico , A. R. Collins , and M. Dusinska . 2015. Can the comet assay be used reliably to detect nanoparticle-induced genotoxicity? Environ Mol Mutagen 56(2):8296. Kaweeteerawat, C. , A. Ivask , R. Liu 2015. Toxicity of metal oxide nanoparticles in Escherichia coli correlates with conduction band and hydration energies. Environ Sci Technol 49(2):11051112. Kermanizadeh, A. , G. Pojana , B. K. Gaiser 2013. In vitro assessment of engineered nanomaterials using a hepatocyte cell line: Cytotoxicity, pro-inflammatory cytokines and functional markers. Nanotoxicology 7:301313. Kettiger, H. , A. Schipanski , P. Wick , and J. Huwyler . 2013. Engineered nanomaterial uptake and tissue distribution: From cell to organism. Int J Nanomedicine 8:32553269. Kisin, E. R. , A. R. Murray , M. J. Keane 2007. Single-walled carbon nanotubes: Geno- and cytotoxic effects in lung fibroblast V79 cells. J Toxicol Environ Health. A 70:20712079. Kobayashi, N. , M. Naya , S. Endoh , J. Maru , K. Yamamoto , and J. Nakanishi . 2009. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats: Different short- and long-term post-instillation results. Toxicology 264:110118. Kocbach, A. , A. I. Totlandsdal , M. Lg , M. Refsnes , and P. E. Schwarze . 2008. Differential binding of cytokines to environmentally relevant particles: A possible source for misinterpretation of in vitro results? Toxicol Lett 176(2):131137. Kroll, A. , M. H. Pillukat , D. Hahn , and J. Schnekenburger . 2012. Interference of engineered nanoparticles with in vitro toxicity assays. Arch Toxicol 86(7):11231136. Kumar, V. , S. K. Kansal , and S. K. Mehta . 2014. Toxicity of nanomaterials: Present scenario and future scope. In: Nanotechnology: Recent Trends, Emerging Issues and Future Directions, Nazrul Islam ed. Nova Science Publishers, New York, USA, chapter 19, pp 461486.15 Kumar, V. , A. Kumari , P. Guleria , and S. K. Yadav . 2012. Evaluating the toxicity of selected types of nanochemicals. Rev Environ Contam Toxicol 215:39121. Laaksonen, T. , H. Santos , H. Vihola 2007. Failure of MTT as a toxicity testing agent for mesoporous silicon microparticles. Chem Res Toxicol 20(12):19131918. Laborda, F. , E. Bolea , and J. Jimnez-Lamana . 2016. Single particle inductively coupled plasma mass spectrometry for the analysis of inorganic engineered nanoparticles in environmental samples. Trends Environ Anal Chem 9:1523. Li, J. J. , S. Muralikrishnan , C. T. Ng , L. Y. L. Yung , and B. H. Bay . 2010. Nanoparticleinduced pulmonary toxicity. Exp Biol Med (Maywood) 235:10251033. Liu, Z. , C. Davis , W. Cai , L. He , X. Chen , and H. Dai . 2008. Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc Natl Acad Sci USA 105:14101415.

Lu, S. , R. Duffin , C. Poland , P. Daly , F. Murphy , E. Drost , W. MacNee , V. Stone , and K. Donaldson . 2009. Efficacy of simple short-term in vitro assays for predicting the potential of metal oxide nanoparticles to cause pulmonary inflammation. Environ Health Perspect 117:241247. Magdolenova, Z. , Y. Lorenzo , A. Collins , and M. Dusinska . 2012. Can standard genotoxicity tests be applied to nanoparticles? J Toxicol Environ Health A 75(1315):800806. Ma-Hock, L. , S. Treumann , V. Strauss 2009. Inhalation toxicity of multiwall carbon nanotubes in rats exposed for 3 months. Toxicol Sci 112:468481. Manke, A. , L. Wang , and Y. Rojanasakul . 2013. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int 2013:15. Matysiak, M. , L. Kapka-Skrzypczak , K. C. Brzska , A. Gutleb , and M. Kruszewski . 2016. Proteomic approach to nanotoxicity. J Proteomics 137:3544. Maynard A. D. 2006. Safe handling of Nanotechnology. Nature 444:267269. Meng, H. , Z. Chen , G. Xing , H. Yuan , C. Chen , F. Zhao , C. Zhang , and Y. Zhao . 2007. Ultrahigh reactivity provokes nanotoxicity: Explanation of oral toxicity of nano-copper particles. Toxicol Lett 175:13. Monteiro-Riviere, N. A. and A. O. Inman . 2006. Challenges for assessing carbon nanomaterial toxicity to the skin. Carbon 44(6):10701078. Monteiro-Riviere, N. A. , A. O. Inman , and L. W. Zhang . 2009. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol Appl Pharm 234:222235. Mundargi, R. C. , V. R. Babu , V. Rangaswamy , P. Patel , and T. M. Aminabhavi . 2008. Nano/micro technologies for delivering macromolecular therapeutics using poly(D, L-lactide-coglycolide) and its derivatives. J Control Release 125:193209. Nel, A. , T. Xia , L. Madler , and N. Li . 2006. Toxic potential of materials at the nanolevel. Science 311:622627. Nesslany, F. and L. Benameur . 2015. Genotoxicity of nanoparticles. Encyclopedia of Nanotechnology 13281338. Ning, Z. , C. S. Cheung , J. Fu , M. A. Liu , and M. A. Schnell . 2006. Experimental study of environmental tobacco smoke particles under actual indoor environment. Sci Total Environ 367(23):822830. Oh, S. J. , H. Kim , Y. Liu 2014. Incompatibility of silver nanoparticles with lactate dehydrogenase leakage assay for cellular viability test is attributed to protein binding and reactive oxygen species generation. Toxicol Lett 225(3):422432. Ong, K. J. , T. J. MacCormack , R. J. Clark 2014. Widespread nanoparticle-assay interference: Implications for nanotoxicity testing. PLoS One 9(3): e90650.16 Oostingh, G. J. , E. Casals , P. Italiani 2011. Problems and challenges in the development and validation of human cell-based assays to determine nanoparticle-induced immunomodulatory effects. Part Fibre Toxicol 2011:8. Panyam, J. , W. Z. Zhou , S. Prabha , S. K. Sahoo , and V. Labhasetwar . 2002. Rapid endolysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: Implications for drug and gene delivery. FASEB J. 16:12171226. Ravindran, P. , J. Fu , and S. L. Wallen . 2003. Completely green synthesis and stabilisation of metal nanoparticles. J Am Chem Soc 125:1394013941. Repetto, G. , A. del Peso , and J. L. Zurita . 2008. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc 3(7):11251131. Rizzo, L. Y. , S. K. Golombek , M. E. Mertens 2013. In vivo nanotoxicity testing using the zebrafish embryo assay. J Mater Chem B Mater Biol Med 1:10. Ryman-Rasmussen, J. P. , J. E. Riviere , and N. A. Monteiro-Riviere . 2007. Variables influencing interactions of untargeted quantum dot nanoparticles with skin cells and identification of biochemical modulators. Nano Lett 7:13441348. Sadik O. , A. L. Zhou , S. Kikandi , N. Du , Q. Wang , and K. Varner . 2009. Sensors as tools for quantitation, nanotoxicity and nanomonitoring assessment of engineered nanomaterials. J Environ Monit 11(10):17821800. Sayes, C. M. , K. L. Reed , and D. B. Warheit . 2007. Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 97:163180. Severin, F. F. , I. I. Severina , Y. N. Antonenko 2010. Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci USA 107:663668. Shang, L. , K. Nienhaus , and G. U. Nienhaus . 2014. Engineered nanoparticles interacting with cells: Size matters. J Nanobiotechnology 12:5. Simberg, D. , W. M. Zhang , S. Merkulov , K. McCrae , J. H. Park , M. J. Sailor , and E. Ruoslahti . 2009. Contact activation of kallikrein-kinin system by superparamagnetic iron oxide nanoparticles in vitro and in vivo . J Control Release 140:301305.

Singh, N. , B. Manshian , G. J. S. Jenkins , S. M. Griffiths , P. M. Williams , T. G. G. Maffeis , C. J. Wright , and S. H. Doak . 2009. Nanogenotoxicology: The DNA damaging potential of engineered nanomaterials. Biomaterials 30:38913914. Singh, R. P. , M. Das , V. Thakare , and S. Jain . 2012. Functionalization density dependent toxicity of oxidized multiwalled carbon nanotubes in a murine macrophage cell line. Chem Res Toxicol 25:21272137. Singh, R. P. and P. Ramarao . 2012. Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles. Toxicol Lett 213:249259. Singh, R. P. and P. Ramarao . 2013. Accumulated polymer degradation products as effector molecules in cytotoxicity of polymeric nanoparticles. Toxicol Lett 136(1):131143. Soenen, S. J. , P. Rivera-Gil , J.-M. Montenegro , W. J. Parak , S. C. De Smedt , and K. Braeckmans . 2011. Cellular toxicity of inorganic nanoparticles: Common aspects and guidelines for improved nanotoxicity evaluation. Nano Today 6:446465. Sung, J. H. , J. H. Ji , J. D. Park 2009. Subchronic inhalation toxicity of silver nanoparticles. Toxicol Sci 108:452461. Tsikas, D. 2005. Methods of quantitative analysis of the nitric oxide metabolites nitrite and nitrate in human biological fluids. Free Radic Res 39:797815.17 Veranth, J. , E. G. Kaser , M. M. Veranth , M. Koch , and G. S. Yost . 2007. Cytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Part Fibre Toxicol 4(1):2. Verma, M. L. , M. Naebe , C. J. Barrow , and M. Puri . 2013a. Enzyme immobilisation on aminofunctionalised multi-walled carbon nanotubes: Structural and biocatalytic characterisation. PLoS One 8(9):e73642. Verma, M. L. , R. Rajkhowa , X. Wang , C. J. Barrow , and M. Puri . 2013b. Exploring novel ultrafine Eri silk bioscaffold for enzyme stabilisation in cellobiose hydrolysis. Bioresour Technol 145, 302306. Wang, L. , Y. Liu , W. Li 2011a. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Lett 11:772780. Wang, S. J. , H. Yu , and J. K. Wickliffe . 2011b. Limitation of the MTT and XTT assays for measuring cell viability due to superoxide formation induced by nano-scale TiO2 . Toxicol In Vitro 25(8):21472151. Warheit, D. B. , C. M. Sayes , and K. L. Reed . 2009. Nanoscale and fine zinc oxide particles: Can in vitro assays accurately forecast lung hazards following inhalation exposures? Environ Sci Technol 43:79397945. Wrle-Knirsch, J. M. , K. Pulskamp , and H. F. Krug . 2006. Carbon nanotubes hoax scientists in viability assays. Nano Lett 6(6):12611268. Zhu, M. T. , W. Y. Feng , B. Wang , T. C. Wang , Y. Q. Gu , M. Wang , Y. Wang , H. Ouyang , Y. L. Zhao , and Z. F. Chai . 2008. Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats. Toxicology 247:102111. Zhu, X. , J. Wang , X. Zhang , Y. Chang , and Y. Chen . 2009. The impact of ZnO nanoparticle aggregates on the embryonic development of zebrafish (Danio rerio). Nanotechnology 20:195103.

Ethics in Nanotechnology and Society Perception Balzani, V. , A. Credi , S. Silvi , and M. Venturi . 2016. Artificial nanomachines based on interlocked molecular species: Recent advances. Chem Soc Rev 35:11351149. Binnig, G. , C. F. Quate , and C. Gerber . 1986. Atomic force microscope. Phys Rev Lett 56:930933.31 Binnig, G. and H. Rohrer . 1986. Scanning tunneling microscopy. IBM J Res Dev 30:355369. Choi, B. Y. , S. J. Kahng S. Kim 2006. Conformational molecular switch of the Azobenzene molecule: A scanning tunneling microscopy study. Pyhs Rev Lett 96:156106:14. Drexler, K. E. 1981. Molecular engineering: An approach to the development of general capabilities for molecular manipulation. Proc Natl Acad Sci 78:52755278. Drexler, K. E. 2004. Nanotechnology: From Feynman to funding. Bull Sci Technol Soc 24:2127. Eigler, D. M. and E. K. Shweizer . 1990. Positioning single atoms with a scanning tunneling microscope. Nature 344:524526. Ekinci, K. L. 2005. Electromechanical transducers at the nanoscale: Actuation and sensing of motion in nanoelectromechanical systems (NEMS). Small 1:786797. Feynman, R. P. 1960. There is plenty of room at the bottom, an invitation to enter a new field of physics. Eng Sci 23:2236.

Grunwald, A. 2005. NanotechnologyA new field of ethical inquiry? Sci Eng Ethics 11:187201. Huang, X. and El-Sayed, M. A. 2010. Gold nanoparticles: Optical properties and implementations in cancer diagnosis and photothermal therapy. J Adv Res 1:1328. Hulla, J. E. , S. C. Sahu and A. W. Hayes . 2015. Nanotechnology: History and future. Hum Exp Toxicol 34:13181321. Iijima, S. 1991. Helical microtubules of graphitic carbon. Nature 354:5658. ISO Technical Committee (TC) 229 . 2006. NanotechnologiesThe Ethics and Politics of Nanotechnology. UNESCO, Rice University, USA. Koch, C. C. , K. M. Youssef R. O. Scattergood and K. L. Murty . 2005. Breakthroughs in optimization of mechanical properties of nanostructured metals and alloys. Adv Eng Mater 7:787794. Kolomeisky, A. B. and M. E. Fisher . 2007. Molecular Motors: A Theorist's Perspective. Annu Rev Phys Chem 58:675695. Kroto, H. W. , J. R. Heath S. C. O'Brien R. F. Curl , and R. E. Smalley . 1985. C60: Buckminsterfullerene. Nature 318:162163. Krumeich, F. 2017. Some Milestones in the History of Electron Microscopy. http://www.microscopy.ethz.ch/history.htm. MacDonald, C. 2004. Nanotech is Novel; the Ethical Issues are not. http://www.thescientist.com/?articles.view/articleNo/15436/title/Nanotech-is-Novel--the-Ethical-Issues-Are-Not/ (Published February 16, 2004). Malsch, I. 2004 . Benefits, Risks, Ethical, Legal and Social Aspects of Nanotechnology, 4th nanoforum report. http://www.nanowerk.com/nanotechnology/reports/reportpdf/report3.pdf Martnez, R. V. , F. Garca R. Garca 2007. Nanoscale Deposition of Single-Molecule Magnets onto SiO2 Patterns. Adv Mater 19:291295. Merkle, R. C. 1991. Computational nanotechnology. Nanotechnology 2:134141. Meyer, M. and O. Kuusi . 2004. Nanotechnology: Generalizations in an interdisciplinary field of science and technology. HYLE-Int. J. Philos Chem. 10:153168. Mller, D. J. and Y. F. Dufrene . 2011. Atomic force microscopy: A nanoscopic window on the cell surface. Trends Cell Biol 21:461469.32 National Nanotechnology Initiative Nano.gov, 2017. What is nanophysics? http://www.nano.gov/nanotech-101/what/definition National Science and Technology Council Committee on Technology, Subcommittee on Nanoscale Science, Engineering and Technology . 2000. National Nanotechnology Initiative: The Initiative and its Implementation Plan. http://www.wtec.org/loyola/nano/IWGN.Implementation.Plan/nni.implementation.plan.pdf National Science and Technology Council . 1999. Nanotechnology: Shaping the World Atom by Atom. http://www.wtec.org/loyola/nano/IWGN.Public.Brochure/IWGN.Nanotechnology.Brochure.pdf Oyabu, N. , . Custance I. Yi Y. Sugawara and S. Morita . 2003. Mechanical vertical manipulation of selected single atoms by soft nanoindentation using near contact atomic force microscopy. Phys Rev Lett 90:176102:14. Oyabu, N. , Y. Sugimoto M. Abe O. Custance and S. Morita . 2005. Lateral manipulation of single atoms at semiconductor surfaces using atomic force microscopy. Nanotechnology 16:112117. Ozin, G. A. , Manners, I. , Fournier-Bidoz, S. , and Arsenault, A. 2005. Dream nanomachines. Adv Mater 17:30113018. Pascual, J. I. , J. Gomez-Herrero C. Rogero 2007. Seeing molecular orbitals. Chem Phys Lett 321:7882. Ramsden, J. 2009. Applied nanotechnology. Oxford: Elsevier Inc. Repp, J. and G. Meyer . 2005. Molecules on insulating films: Scanning-tunneling microscopy imaging of individual molecular orbitals. Phys Rev Lett 94:026803:14. Revell, P. A. 2006. The biological effects of nanoparticles. Nanotechnol Percept 2:283298. Robison, W. L. 2004. Nano-Ethics. Amsterdam: IOS Press. Roco, M. C. 2005. International perspective on government nanotechnology funding in 2005. J Nanopart Res 7:707712. Sahoo, S. K. , S. Parveen and J. J. Panda . 2007. The present and future of nanotechnology in human health care. Nanomedicine 3:2031. Schmidt, G. , M. Decker H. Ernst 2003. Small Dimensions and Material Properties: A Definition of Nanotechnology. Bad Neuenahr-Ahrweiler GmbH: Europaische Akademie Graue Reihe. Schmidt, M. , R. Kusche B. Von Issendorff and H. Haberland . 1998. Irregular variations in the melting point of size-selected atomic clusters. Nature 393:238240. Simmons, M. Y. 2012. Single atom devices in silicon and Germanium. Silicon-Germanium Technology and Device Meeting (ISTDM). IEEE Xplore. 1-1, June 46, 2012, Berkeley, CA.

Snow, A. W. and H. Wohltjen . 1998. Size-induced metal to semiconductor transition in a stabilized gold cluster ensemble. Chem Mater 10:947949. Srivastava, D. and S. N. Atluri . 2002. Computational nanotechnology: A current perspective. Comput Model Eng Sci 3:531538. Srivastava, D. , M. Menon and P. M. Ajayan . 2003. Branched carbon nanotube junctions predicted by computational nanotechnology and fabricated through nanowelding. J Nanopart Res 5:395400. Taniguchi, N. 1974. On the basic concept of nano-technology. Proc. Intl. Conf. Prod. Eng. Tokyo, Part II, Japan Society of Precision Engineering, August 2629, Tokyo, Japan. The Royal Society and the Royal Academy of Engineering . 2004. Nanoscience and nanotechnologies: opportunities and uncertainties. https://royalsociety.org//media/Royal_Society_Content/policy/publications/2004/9693.pdf 33 Tiwari, D. K. , J. Behari and P. Sen . 2008. Application of nanoparticles in waste water treatment. World Appl Sci J 3:417433. Tran, C. L. , K. Donaldson V. Stones 2005. A Scoping Study to Identify Hazard Data Needs for Addressing the Risks Presented by Nanoparticles and Nanotubes. London: Institute of Occupational Medicine. Weisenhorn, A. L. , J. E. MacDougall S. A. Gould 1990. Imaging and manipulating molecules on a zeolite surface with an atomic force microscope. Science 247:13301333. Winston, M. E. and R. D. Edelbach . 2014. Society, Ethics and Techology. Belmont: Clark Baxter Wadsworth Publishing Company. Xia, Y. , J. A. Rogers K. E. Paul , and G. M. Whitesides . 1999. Unconventional methods for fabricating and patterning nanostructures. Chem Rev 99:18231848.

Impact of Physicochemical Properties and Surface Chemistry of Nanomaterials on Toxicity Adams, C. P. , K. A. Walker , S. O. Obare , and K. M. Docherty . 2014. Size-dependent antimicrobial effects of novel palladium nanoparticles. PLoS One 9(1):112.54 Andersson, P. O. , C. Lejon , B. Ekstrand-Hammarstrom , C. Akfur , L. Ahlinder , A. Bucht , and L. Osterlund . 2011. Polymorph- and size-dependent uptake and toxicity of TiO(2) nanoparticles in living lung epithelial cells. Small 7(4):514523. doi: 10.1002/smll.201001832 Arvizo, R. R. , O. R. Miranda , M. A. Thompson , C. M. Pabelick , R. Bhattacharya , J. D. Robertson , V. M. Rotello , Y. S. Prakash , and P. Mukherjee . 2010. Effect of nanoparticle surface charge at the plasma membrane and beyond. Nano Letters 10(7):25432548. doi: 10.1021/nl101140t Ashkarran, A. A. , M. Ghavami , H. Aghaverdi , P. Stroeve , and M. Mahmoudi . 2012. Bacterial effects and protein corona evaluations: Crucial ignored factors in the prediction of bio-efficacy of various forms of silver nanoparticles. Chemical Research in Toxicology 25(6):12311242. doi: 10.1021/tx300083s Bermudez, E. , J. B. Mangum , B. A. Wong , B. Asgharian , P. M. Hext , D. B. Warheit , and J. I. Everitt . 2004. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci 77(2):347357. doi: 10.1093/toxsci/kfh019 Bnnemann, H. and R. M. Richards . 2001. Nanoscopic metal particlessynthetic methods and potential applications. European Journal of Inorganic Chemistry 2001(10):24552480. Canelas, D. A. , K. P. Herlihy , and J. M. DeSimone . 2009. Top-down particle fabrication: Control of size and shape for diagnostic imaging and drug delivery. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 1(4):391404. doi: 10.1002/wnan.40 Carlson, C. , S. M. Hussain , A. M. Schrand , L. K. Braydich-Stolle , K. L. Hess , R. L. Jones , and J. J. Schlager . 2008. Unique cellular interaction of silver nanoparticles: Size-dependent generation of reactive oxygen species. The Journal of Physical Chemistry B 112(43):1360813619. doi: 10.1021/jp712087m Carnovale, C. , G. Bryant , R. Shukla , and V. Bansal . 2016. Size, shape and surface chemistry of nano-gold dictate its cellular interactions, uptake and toxicity. Progress in Materials Science 83:152190. doi: http://dx.doi.org/10.1016/j.pmatsci.2016.04.003 Cedervall, T. , I. Lynch , M. Foy , T. Berggrd , S. C. Donnelly , G. Cagney , S. Linse , and K. A. Dawson . 2007. Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angewandte Chemie International Edition 46(30):57545756. doi: 10.1002/anie.200700465 Champion, J. A. and S. Mitragotri . 2006. Role of target geometry in phagocytosis. Proceedings of the National Academy of Sciences of the United States of America 103(13):49304934. doi:

10.1073/pnas.0600997103 Cheng, L. C. , X. Jiang , J. Wang , C. Chen , and R. S. Liu . 2013. Nano-bio effects: Interaction of nanomaterials with cells. Nanoscale 5(9):35473569. doi: 10.1039/c3nr34276j Chrimes, A. F. , K. Khoshmanesh , P. R. Stoddart , A. A. Kayani , A. Mitchell , H. Daima , V. Bansal , and K. Kalantar-zadeh . 2012. Active control of silver nanoparticles spacing using dielectrophoresis for SERS. Analytical Chemistry. doi: 10.1021/ac203381n Clift, M. J. D. , B. Rothen-Rutishauser , D. M. Brown , R. Duffin , K. Donaldson , L. Proudfoot , K. Guy , and V. Stone . 2008. The impact of different nanoparticle surface chemistry and size on uptake and toxicity in a murine macrophage cell line. Toxicology and Applied Pharmacology 232(3):418427. doi: http://dx.doi.org/10.1016/j.taap.2008.06.009 55 Daima, H. K. 2013. Towards fine-tuning the surface corona of inorganic and organic nanomaterials to control their properties at nano-bio interface. PhD, School of Applied Sciences RMIT. Daima, H. K. and V. Bansal . 2015. Chapter 10 - Influence of Physicochemical Properties of Nanomaterials on Their Antibacterial Applications. In Nanotechnology in Diagnosis, Treatment and Prophylaxis of Infectious Diseases, edited by M. R. Kon , 151166. Boston: Academic Press. Daima, H. K. and P. N. Navya . 2016. Rational engineering of physicochemical properties of nanomaterials for biomedical applications with nanotoxicological perspectives. Nano Convergence 3(1):114. Daima, H. K. , P. R. Selvakannan , S. K. Bhargava , S. K. Shastry , and V. Bansal . 2014a. Amino acids-conjugated gold, silver and their alloy nanoparticles: Role of surface chemistry and metal composition on peroxidase like activity. TechConnect World Conference and Expo Washington, USA. Daima, H. K. , P. Selvakannan , Z. Homan , S. K. Bhargava , and V. Bansal . 2011. Tyrosine mediated gold, silver and their alloy nanoparticles synthesis: Antibacterial activity toward gram positive and gram negative bacterial strains. 2011 International Conference on Nanoscience, Technology and Societal Implications, NSTSI11. Daima, H. K. , P. R. Selvakannan , A. E. Kandjani , R. Shukla , S. K. Bhargava , and V. Bansal . 2014b. Synergistic influence of polyoxometalate surface corona towards enhancing the antibacterial performance of tyrosine-capped Ag nanoparticles. Nanoscale 6(2):758765. doi: 10.1039/C3NR03806H Daima, H. K. , P. R. Selvakannan , R. Shukla , S. K. Bhargava , and V. Bansal . 2013. Finetuning the antimicrobial profile of biocompatible gold nanoparticles by sequential surface functionalization using polyoxometalates and lysine. PloS one 8(10). doi: 10.1371/journal.pone.0079676 Dalle-Donne, I. , R. Rossi , D. Giustarini , R. Colombo , and A. Milzani . 2007. Sglutathionylation in protein redox regulation. Free Radic Biol Med 43(6):883898. doi: 10.1016/j.freeradbiomed.2007.06.014 De, M. , P. S. Ghosh , and V. M. Rotello . 2008. Applications of nanoparticles in biology. Advanced Materials 20(22):42254241. doi: 10.1002/adma.200703183 Docter, D. , D. Westmeier , M. Markiewicz , S. Stolte , S. K. Knauer , and R. H. Stauber . 2015. The nanoparticle biomolecule corona: Lessons learnedchallenge accepted? Chem Soc Rev 44(17):60946121. doi: 10.1039/c5cs00217f Dong, C. and J. Irudayaraj . 2012. Hydrodynamic size-dependent cellular uptake of aqueous QDs probed by fluorescence correlation spectroscopy. J Phys Chem B 116(40):1212512132. doi: 10.1021/jp305563p Drechsler, U. , B. Erdogan , and V. M. Rotello . 2004. Nanoparticles: Scaffolds for molecular recognition. Chemistry A European Journal 10(22):55705579. Drexler, K. E. and C. Peterson . 1989. Nanotechnology and enabling technologies. Foresight Briefing 2. Dubey, K. , B. G. Anand , R. Badhwar , G. Bagler , P. N. Navya , H. K. Daima , and K. Kar . 2015. Tyrosine-and tryptophan-coated gold nanoparticles inhibit amyloid aggregation of insulin. Amino Acids 47(12):110. Duncan, R. and R. Gaspar . 2011. Nanomedicine(s) under the microscope. Molecular Pharmaceutics 8(6):21012141. doi: 10.1021/mp200394t Esposito, L. A. , S. Melov , A. Panov , B. A. Cottrell , and D. C. Wallace . 1999. Mitochondrial disease in mouse results in increased oxidative stress. Proceedings of the National Academy of Sciences of the United States of America 96(9):48204825.56 Faraday, M. 1857. The bakerian lecture: Experimental relations of gold (and Other Metals) to light. Philosophical Transactions of the Royal Society of London 147:145181. Farokhzad, O. C. and R. Langer . 2009. Impact of nanotechnology on drug delivery. ACS Nano 3(1):1620. doi: 10.1021/nn900002m

Gaffet, E. , M. Tachikart , O. El Kedim , and R. Rahouadj . 1996. Nanostructural materials formation by mechanical alloying: Morphologic analysis based on transmission and scanning electron microscopic observations. Materials Characterization 36(45):185190. Gao, L. , J. Zhuang , L. Nie , J. Zhang , Y. Zhang , N. Gu , T. Wang , J. Feng , D. Yang , S. Perrett , and X. Yan . 2007. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles. Nature Nanotechnology 2(9):577583. Geys, J. , A. Nemmar , E. Verbeken , E. Smolders , M. Ratoi , M. F. Hoylaerts , B. Nemery , and P. H. M. Hoet . 2008. Acute toxicity and prothrombotic effects of quantum dots: Impact of surface charge. Environmental Health Perspectives 116(12):16071613. doi: 10.1289/ehp.11566 Ghosh, P. , G. Han , M. De , C. K. Kim , and V. M. Rotello . 2008a. Gold nanoparticles in delivery applications. Advanced Drug Delivery Reviews 60(11):13071315. Ghosh, P. S. , G. Han , B. Erdogan , O. Rosado , and V. M. Rotello . 2008b. Binding of nanoparticle receptors to peptide -helices using amino acid-functionalized nanoparticles. Journal of Peptide Science 14(2):134138. doi: 10.1002/psc.947 Ghosh, P. S. , C. K. Kim , G. Han , N. S. Forbes , and V. M. Rotello . 2008c. Efficient gene delivery vectors by tuning the surface charge density of amino acid-functionalized gold nanoparticles. ACS Nano 2(11):22132218. Goodman, C. , C. McCusker , T. Yilmaz , and V. Rotello . 2004. Toxicity of gold nanoparticles functionalized with cationic and anionic side chains. Bioconjug Chem 15:897900. Halliwell, B. and J. Gutteridge . 2007. Free Radicals in Biology and Medicine. 4th ed. New York: Oxford University Press, Inc. Han, G. , P. Ghosh , M. De , and V. M. Rotello . 2007. Drug and gene delivery using gold nanoparticles. Nanobiotechnology 3(1):4045. Hobson, D. W. 2009. Commercialization of nanotechnology. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 1(2):189202. doi: 10.1002/wnan.28 Hoshino, A. , K. Fujioka , T. Oku , M. Suga , Y. F. Sasaki , T. Ohta , M. Yasuhara , K. Suzuki , and K. Yamamoto . 2004. Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification. Nano Letters 4(11):21632169. doi: 10.1021/nl048715d http://www.nature.com/articles/srep11398#supplementary-information. http://www.nature.com/nnano/journal/v8/n10/abs/nnano.2013.181.html#supplementaryinformation. Huang, K. , H. Ma , J. Liu 2012. Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. ACS Nano 6(5):44834493. doi: 10.1021/nn301282m Hhn, D. , K. Kantner , C. Geidel 2013. Polymer-coated nanoparticles interacting with proteins and cells: Focusing on the sign of the net charge. ACS Nano 7(4):32533263. doi: 10.1021/nn3059295 Ivask, A. , I. Kurvet , K. Kasemets 2014. Size-dependent toxicity of silver nanoparticles to bacteria, yeast, algae, crustaceans and mammalian cells in vitro. PLoS One 9(7):e102108. doi: 10.1371/journal.pone.0102108 57 Jiang, W. , Y. S. KimBetty , J. T. Rutka , and C. W. ChanWarren . 2008. Nanoparticle-mediated cellular response is size-dependent. Nat Nano 3(3):145150. doi: http://www.nature.com/nnano/journal/v3/n3/suppinfo/nnano.2008.30_S1.html Jiang, X. , S. Weise , M. Hafner , C. Rocker , F. Zhang , W. J. Parak , and G. U. Nienhaus . 2010. Quantitative analysis of the protein corona on FePt nanoparticles formed by transferrin binding. J R Soc Interface 7(Suppl 1):S5S13. doi: 10.1098/rsif.2009.0272.focus Kallay, N. and S. Zalac . 2002. Stability of nanodispersions: A model for kinetics of aggregation of nanoparticles. Journal of Colloid and Interface Science 253(1):7076. Kang, S. , M. Herzberg , D. F. Rodrigues , and M. Elimelech . 2008. Antibacterial effects of carbon nanotubes: Size does matter! Langmuir 24(13):64096413. doi: 10.1021/la800951v Kim, I. Y. , E. Joachim , H. Choi , and K. Kim . 2015. Toxicity of silica nanoparticles depends on size, dose, and cell type. Nanomedicine 11(6):14071416. doi: 10.1016/j.nano.2015.03.004 Kim, S. T. , A. Chompoosor , Y. C. Yeh , S. S. Agasti , D. J. Solfiell , and V. M. Rotello . 2012. Dendronized gold nanoparticles for siRNA delivery. Small 8(21):32533256. doi: 10.1002/smll.201201141 Kirchner, C. , T. Liedl , S. Kudera , T. Pellegrino , A. M. Javier , H. E. Gaub , S. Stlzle , N. Fertig , and W. J. Parak . 2005. Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. Nano Letters 5(2):331338. doi: 10.1021/nl047996m Klaine, S. J. , P. J. J. Alvarez , G. E. Batley , T. F. Fernandes , R. D. Handy , D. Y. Lyon , S. Mahendra , M. J. McLaughlin , and J. R. Lead . 2008. Nanomaterials in the environment: Behavior, fate, bioavailability, and effects. Environmental Toxicology and Chemistry 27(9):18251851. doi: 10.1897/08-090.1

Krug, H. F. and P. Wick . 2011. Nanotoxicology: An interdisciplinary challenge. Angewandte Chemie International Edition 50(6):12601278. doi: 10.1002/anie.201001037 Lee, M. K. , S. J. Lim , and C. K. Kim . 2007. Preparation, characterization and in vitro cytotoxicity of paclitaxel-loaded sterically stabilized solid lipid nanoparticles. Biomaterials 28(12):21372146. doi: 10.1016/j.biomaterials.2007.01.014 Lesniak, A. , A. Salvati , M. J. Santos-Martinez , M. W. Radomski , K. A. Dawson , and C. berg . 2013. Nanoparticle adhesion to the cell membrane and its effect on nanoparticle uptake efficiency. Journal of the American Chemical Society 135(4):14381444. doi: 10.1021/ja309812z Li, N. , T. Xia , and A. E. Nel . 2008. The role of oxidative stress in ambient particulate matterinduced lung diseases and its implications in the toxicity of engineered nanoparticles. Free Radic Biol Med 44(9):16891699. doi: 10.1016/j.freeradbiomed.2008.01.028 Li, X. , S. M. Robinson , A. Gupta , K. Saha , Z. Jiang , D. F. Moyano , A. Sahar , M. A. Riley , and V. M. Rotello . 2014. Functional gold nanoparticles as potent antimicrobial agents against multi-drug-resistant bacteria. ACS Nano 8(10):1068210686. doi: 10.1021/nn5042625 Li, X. , Y.-C. Yeh , K. Giri , R. Mout , R. F. Landis , Y. S. Prakash , and V. M. Rotello . 2015. Control of nanoparticle penetration into biofilms through surface design. Chemical Communications 51(2):282285. doi: 10.1039/C4CC07737G Lockman, P. R. , J. M. Koziara , R. J. Mumper , and D. D. Allen . 2004. Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J Drug Target 12(910):635641. doi: 10.1080/10611860400015936 58 Longmire, M. , P. L. Choyke , and H. Kobayashi . 2008. Clearance properties of nano-sized particles and molecules as imaging agents: Considerations and caveats. Nanomedicine 3(5):703717. doi: 10.2217/17435889.3.5.703 Lundqvist, M. , J. Stigler , G. Elia , I. Lynch , T. Cedervall , and K. A. Dawson . 2008. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proceedings of the National Academy of Sciences 105(38):1426514270. doi: 10.1073/pnas.0805135105 Lynch, I. , K. A. Dawson , and S. Linse . 2006. Detecting cryptic epitopes created by nanoparticles. Sci. STKE 2006(327):pe14. doi: 10.1126/stke.3272006pe14 Lynch, I. , A. Salvati , and K. A. Dawson . 2009. Protein-nanoparticle interactions: What does the cell see? Nature Nanotechnology 4(9):546547. Maffre, P. , K. Nienhaus , F. Amin , W. J. Parak , and G. U. Nienhaus . 2011. Characterization of protein adsorption onto FePt nanoparticles using dual-focus fluorescence correlation spectroscopy. Beilstein J Nanotechnol 2:374383. doi: 10.3762/bjnano.2.43 Mahmoudi, M. , K. Azadmanesh , M. A. Shokrgozar , W. S. Journeay , and S. Laurent . 2011a. Effect of nanoparticles on the cell life cycle. Chemical Reviews 111(5):34073432. Mahmoudi, M. , I. Lynch , M. R. Ejtehadi , M. P. Monopoli , F. B. Bombelli , and S. Laurent . 2011b. Protein-nanoparticle interactions: Opportunities and challenges. Chemical Reviews 111(9):56105637. Mahmoudi, M. , J. Meng , X. Xue 2014. Interaction of stable colloidal nanoparticles with cellular membranes. Biotechnol Adv 32(4):679692. doi: 10.1016/j.biotechadv.2013.11.012 Manshian, B. B. , D. F. Moyano , N. Corthout , S. Munck , U. Himmelreich , V. M. Rotello , and S. J. Soenen . 2014. High-content imaging and gene expression analysis to study cellnanomaterial interactions: The effect of surface hydrophobicity. Biomaterials 35(37):99419950. doi: http://dx.doi.org/10.1016/j.biomaterials.2014.08.031 Mauter, M. S. and M. Elimelech . 2008. Environmental applications of carbon-based nanomaterials. Environmental Science & Technology 42(16):58435859. doi: 10.1021/es8006904 Migliore, L. , C. Uboldi , S. Di Bucchianico , and F. Coppede . 2015. Nanomaterials and neurodegeneration. Environ Mol Mutagen 56(2):149170. doi: 10.1002/em.21931 Mironava, T. , M. Hadjiargyrou , M. Simon , V. Jurukovski , and M. H. Rafailovich . 2010. Gold nanoparticles cellular toxicity and recovery: Effect of size, concentration and exposure time. Nanotoxicology 4(1):120137. doi: 10.3109/17435390903471463 Moller, P. , N. R. Jacobsen , J. K. Folkmann , P. H. Danielsen , L. Mikkelsen , J. G. Hemmingsen , L. K. Vesterdal , L. Forchhammer , H. Wallin , and S. Loft . 2010. Role of oxidative damage in toxicity of particulates. Free Radic Res 44(1):146. doi: 10.3109/10715760903300691 Monnappa, S. , N. Firdose , M. Shree , K. Nath , P. N. Navya , and H. K. Daima . 2017. Influence of amino acid corona, metallic core and surface functionalization of nanoparticles on their in-vitro biological behaviour. Int J Nanotechnology 14(9/10/11):816832. Monopoli, M. P. , D. Walczyk , A. Campbell , G. Elia , I. Lynch , F. B. Bombelli , and K. A. Dawson . 2011. Physical-Chemical Aspects of Protein Corona: Relevance to in Vitro and in Vivo Biological Impacts of Nanoparticles. Journal of the American Chemical Society 133(8):25252534. doi: 10.1021/ja107583h 59

Morones, J. R. , J. L. Elechiguerra , A. Camacho , K. Holt , J. B. Kouri , J. T. Ramirez , and M. J. Yacaman . 2005. The bactericidal effect of silver nanoparticles. Nanotechnology 16(10):23462353. Mout, R. , D. F. Moyano , S. Rana , and V. M. Rotello . 2012. Surface functionalization of nanoparticles for nanomedicine. Chemical Society Reviews 41(7):25392544. Moyano, D. F. and V. M. Rotello . 2011. Nano meets biology: Structure and function at the nanoparticle interface. Langmuir 27(17):1037610385. doi: 10.1021/la2004535 Navya, P. N. and H. K. Daima . 2016. Rational engineering of physicochemical properties of nanomaterials for biomedical applications with nanotoxicological perspectives. Nano Convergence 3(1):14. Nel, A. , T. Xia , L. Mdler , and N. Li . 2006. Toxic potential of materials at the nanolevel. Science 311(5761):622627. doi: 10.1126/science.1114397 Nel, A. E. , L. Mdler , D. Velegol , T. Xia , E. M. V. Hoek , P. Somasundaran , F. Klaessig , V. Castranova , and M. Thompson . 2009. Understanding biophysicochemical interactions at the nanobio interface. Nature Materials 8(7):543557. Niemz V. A. and V. M. Rotello . 1999. From enzyme to molecular device. Exploring the interdependence of redox and molecular recognition. Accounts of Chemical Research 32(1):4452. Oberdorster, E. 2004. Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass. Environ Health Perspect 112(10):10581062. Oberdorster, G. , E. Oberdorster , and J. Oberdorster . 2005. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives 113(7):823839. Oberdrster, G. 2010. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. Journal of Internal Medicine 267(1):89105. doi: 10.1111/j.13652796.2009.02187.x Oh, E. , J. B. Delehanty , K. E. Sapsford 2011. Cellular uptake and fate of PEGylated gold nanoparticles is dependent on both cell-penetration peptides and particle size. ACS Nano 5(8):64346448. doi: 10.1021/nn201624c Pal, S. , Y. K. Tak , and J. M. Song . 2007. Does the antibacterial activity of silver nanoparticles depend on the shape of the nanoparticle? A study of the gram-negative bacterium Escherichia coli. Applied and Environmental Microbiology 73(6):17121720. Park, K. H. , M. Chhowalla , Z. Iqbal , and F. Sesti . 2003. Single-walled carbon nanotubes are a new class of ion channel blockers. Journal of Biological Chemistry 278(50):5021250216. doi: 10.1074/jbc.M310216200 Petersen, E. J. and B. C. Nelson . 2010. Mechanisms and measurements of nanomaterialinduced oxidative damage to DNA. Anal Bioanal Chem 398(2):613650. doi: 10.1007/s00216010-3881-7 Pietroiusti, A. , M. Massimiani , I. Fenoglio 2011. Low doses of pristine and oxidized single-wall carbon nanotubes affect mammalian embryonic development. ACS Nano 5(6):46244633. doi: 10.1021/nn200372g Rallo, R. , B. France , R. Liu , S. Nair , S. George , R. Damoiseaux , F. Giralt , A. Nel , K. Bradley , and Y. Cohen . 2011. Self-organizing map analysis of toxicity-related cell signaling pathways for metal and metal oxide nanoparticles. Environmental Science & Technology 45(4):16951702. doi: 10.1021/es103606x Richards, R. and H. Bnnemann . 2005. Synthetic Approaches to Metallic Nanomaterials. In Nanofabrication Towards Biomedical Applications, 132. Wiley-VCH Verlag GmbH & Co. KGaA.60 Rocker, C. , M. Potzl , F. Zhang , W. J. Parak , and G. U. Nienhaus . 2009. A quantitative fluorescence study of protein monolayer formation on colloidal nanoparticles. Nat Nanotechnol 4(9):577580. doi: 10.1038/nnano.2009.195 dos Santos, T. , J. Varela , I. Lynch , A. Salvati , and K. A. Dawson . 2011. Quantitative assessment of the comparative nanoparticle-uptake efficiency of a range of cell lines. Small 7(23):33413349. doi: 10.1002/smll.201101076 Saxena, R. K. , W. Williams , J. K. McGee , M. J. Daniels , E. Boykin , and M. I. Gilmour . 2007. Enhanced in vitro and in vivo toxicity of poly-dispersed acid-functionalized single-wall carbon nanotubes. Nanotoxicology 1(4):291300. doi: 10.1080/17435390701803110 Sayes, C. M. , A. M. Gobin , K. D. Ausman , J. Mendez , J. L. West , and V. L. Colvin . 2005. Nano-C60 cytotoxicity is due to lipid peroxidation. Biomaterials 26(36):75877595. doi: http://dx.doi.org/10.1016/j.biomaterials.2005.05.027 Scaletti, F. , C. S. Kim , L. Messori , and V. M. Rotello . 2014. Rapid purification of gold nanorods for biomedical applications. MethodsX 1(0):118123. doi: http://dx.doi.org/10.1016/j.mex.2014.07.007

Shang, L. , K. Nienhaus , and G. U. Nienhaus . 2014. Engineered nanoparticles interacting with cells: size matters. J Nanobiotechnology 12:5. doi: 10.1186/1477-3155-12-5 Shankar, S. , S. K. Soni , H. K. Daima , P. R. Selvakannan , J. M. Khire , S. K. Bhargava , and V. Bansal . 2015. Charge-switchable gold nanoparticles for enhanced enzymatic thermostability. Physical Chemistry Chemical Physics 17(33):2151721524. doi: 10.1039/C5CP03021H Sharifi, S. , S. Behzadi , S. Laurent , M. Laird Forrest , P. Stroeve , and M. Mahmoudi . 2012. Toxicity of nanomaterials. Chemical Society Reviews 41(6):23232343. doi: 10.1039/c1cs15188f Sharma, T. K. , R. Ramanathan , P. Weerathunge , M. Mohammadtaheri , H. K. Daima , R. Shukla , and V. Bansal . 2014. Aptamer-mediated turn-off/turn-on nanozyme activity of gold nanoparticles for kanamycin detection. Chemical Communications 50(100):1585615859. doi: 10.1039/C4CC07275H Shenhar, R. and V. M. Rotello . 2003. Nanoparticles: Scaffolds and building blocks. Accounts of Chemical Research 36(7):549561. Stark, W. J. 2011. Nanoparticles in biological systems. Angew Chem Int Ed Engl 50(6):12421258. doi: 10.1002/anie.200906684 Suh, W. H. , K. S. Suslick , G. D. Stucky , and Y.-H. Suh . 2009. Nanotechnology, nanotoxicology, and neuroscience. Progress in Neurobiology 87(3):133170. Sun, H. , F. Zhang , H. Wei , and B. Yang . 2013. The effects of composition and surface chemistry on the toxicity of quantum dots. Journal of Materials Chemistry B 1(47):64856494. doi: 10.1039/C3TB21151G Templeton, A. C. , W. P. Wuelfing , and R. W. Murray . 2000. Monolayer-Protected Cluster Molecules. Accounts of Chemical Research 33(1):2736. doi: 10.1021/ar9602664 Tenzer, S. , D. Docter , J. Kuharev 2013. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nano 8(10):772781. doi: 10.1038/nnano.2013.181 61 Turkevich, J. 1985. Colloidal gold. Part I. Historical and preparative aspects, morphology and structure. Gold Bulletin 18:8691. Turkevich, J. and G. Kim . 1970. Palladium: Preparation and catalytic properties of particles of uniform size. Science 169(3948):873879. Turkevich, J. , P. C. Stevenson , and J. Hillier . 1951. A study of the nucleation and growth processes in the synthesis of colloidal gold. Discussions of the Faraday Society 11:5575. Unfried, K. , C. Albrecht , L.-O. Klotz , A. V. Mikecz , S. Grether-Beck , and R. P. F. Schins . 2007. Cellular responses to nanoparticles: Target structures and mechanisms. Nanotoxicology 1(1):5271. doi: 10.1080/00222930701314932 Verma, A. and F. Stellacci . 2010. Effect of surface properties on nanoparticle-cell interactions. Small 6(1):1221. doi: 10.1002/smll.200901158 Walczyk, D. , F. B. Bombelli , M. P. Monopoli , I. Lynch , and K. A. Dawson . 2010. What the cell sees in bionanoscience. Journal of the American Chemical Society 132(16):57615768. doi: 10.1021/ja910675v Wan, J. , J.-H. Wang , T. Liu , Z. Xie , X.-F. Yu , and W. Li . 2015. Surface chemistry but not aspect ratio mediates the biological toxicity of gold nanorods in vitro and in vivo. Scientific Reports 5:11398. doi: 10.1038/srep11398 Wang, T. , J. Bai , X. Jiang , and G. U. Nienhaus . 2012. Cellular uptake of nanoparticles by membrane penetration: A study combining confocal microscopy with FTIR spectroelectrochemistry. ACS Nano 6(2):12511259. doi: 10.1021/nn203892h Warheit, D. B. , B. R. Laurence , K. L. Reed , D. H. Roach , G. A. Reynolds , and T. R. Webb . 2004. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol Sci 77(1):117125. doi: 10.1093/toxsci/kfg228 Whitesides, G. M. 2003. The right size in nanobiotechnology. Nat Biotech 21(10):11611165. Xia, T. , M. Kovochich , J. Brant , M. Hotze , J. Sempf , T. Oberley , C. Sioutas , J. I. Yeh , M. R. Wiesner , and A. E. Nel . 2006. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6(8):17941807. doi: 10.1021/nl061025k You, C.-C. , A. Verma , and V. M. Rotello . 2006. Engineering the nanoparticlebiomacromolecule interface. Soft Matter 2(3):190204. Zhao, F. , Y. Zhao , Y. Liu , X. Chang , C. Chen , and Y. Zhao . 2011a. Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small 7(10):13221337. Zhao, J. and V. Castranova . 2011. Toxicology of nanomaterials used in nanomedicine. Journal of Toxicology and Environmental Health, Part B 14(8):593632. doi: 10.1080/10937404.2011.615113 Zhao, Y. , X. Sun , G. Zhang , B. G. Trewyn , Slowing, I. I. , and V. S. Lin . 2011b. Interaction of mesoporous silica nanoparticles with human red blood cell membranes: size and surface effects. ACS Nano 5(2):13661375. doi: 10.1021/nn103077k

Zhou, Z. , J. Son , B. Harper , Z. Zhou , and S. Harper . 2015. Influence of surface chemical properties on the toxicity of engineered zinc oxide nanoparticles to embryonic zebrafish. Beilstein Journal of Nanotechnology 6:15681579. doi: 10.3762/bjnano.6.160 Zhu, Z. J. , R. Carboni , M. J. Quercio , B. Yan , O. R. Miranda , D. L. Anderton , K. F. Arcaro , V. M. Rotello , and R. W. Vachet . 2010. Surface properties dictate uptake, distribution, excretion, and toxicity of nanoparticles in fish. Small 6(20):22612265.

Application of Nanomaterials in Food, Cosmetics, and Other Related Process Industries Alin, Y. and . nal . 2012. Nanomaterials and cosmetics. Istanbul Ecz. Fak. Derg./J. Fac. Pharm. Istanbul, 42(1):4370. Aschberger, K. , S. Gottardo , and V. Amenta 2015. Nanomaterials in food current and future applications and regulatory aspects. Journal of Physics: Conference Series, 617, Conference 1, 617012032. doi: 10.1088/1742-6596/617/1/012032 Bouwmeester, H. , R. J. B. Peters , S. Gottardo 2016. Nanomaterials for products and application in agriculture, feed and food, a review. Trends Food Sci Technol 54:155164. Chau, C. , S. Wu , and G. Yen . 2007. The development of regulations for food nanotechnology. Trends Food Sci Technol 18:269280. Chaudhry, Q. and L. Castle . 2011. Food applications of nanotechnologies: An overview of opportunities and challenges for developing countries. Trends Food Sci Technol 22:595603.78 Chaudhry, Q. , R. Watkins , and L. Castle . 2010. Nanotechnologies in the food arena: New opportunities, new questions, and new concerns. In: Nanotechnologies in Food, eds. Chaudhry Q. , Castle L. , and Watkins R. , Cambridge, UK: Royal Society of Chemistry, pp: 117. Chellaram, C. , G. Murugaboopathi , A. A. John , R. Sivakumar , S. Ganesan , S. Krithika , and G. Priya . 2014. Significance of nanotechnology in food industry. APCBEE Procedia 8:109113. Cummins E. , M. Cushen , J. Kerry , M. Morris , and M. Cruz-Romero . 2012. Nanotechnologies in the food industry-recent developments, risks and regulations. Trends Food Sci Technol 24:3046. Daniela, M. 2013. Nanotechnologies and novel foods in European law. NanoEthics 7:177188. doi 10.1007/s11569-013-0176-4 Dewan, K. , L. M. Katz , and R. L. Bronaugh . 2015. Nanotechnology in cosmetics. Food Chem Toxicol 85:127137. Echegoyen, Y. 2015. Nanotechnologies in food and agriculture-nano-developments for food packaging and labeling applications. In: Nanotechnologies in Food and Agriculture, eds. M. Rai Switzerland: Springer International Publishing, pp: 141166. doi 10.1007/978-3-319-14024-7_7 EFSA European Food Safety Authority , 2000. The potential risks arising from nanoscience and nanotechnologies on food and feed safety (EFSA-Q-2007-124a). EFSA J., 958:139. Farhang, B. 2009. Nanotechnology and applications in food safety. In: IUFoST World Congress Book: Global Issues in Food Science and Technology, Elsevier Inc., pp. 401410. Gergely, A. and L. Coroyannakis . 2009. Nanotechnology in the EU cosmetics regulation: Household and personal care today. Nanotechnology 2830. Grimshaw, D. J. , L. D. Gudza , and J. Stilgoe . 2014. How can nanotechnologies fulfill the needs of developing countries? Street, Sustich, Duncan and Savage. In: Nanotechnology Applications for Clean Water, 2nd ed. pp. 595609. Elsevier Inc. doi: 10.1016/B978-1-45573116-9.00039-1 Henkler, F. , T. Tralau , J. Tentschert , C. Kneuer , A. Haase , T. Platzek , A. Luch , and E. M. Gtz . 2012. Risk assessment of nanomaterials in cosmetics: A European Union Perspective. Arch Toxicol 86:16411646. Hong, J. , J. R. Peralta-Videa , and J. L. Gardea-Torresdey . 2013. Nanomaterials in agricultural production: Benefits and possible threats. In: Sustainable Nanotechnology and the Environment: Advances and Achievements, Washington, DC: American Chemical Society: ACS Symposium Series, pp. 7490. Huang, S. , L. Wang , L. Liu , H. Hou , and L. Li . 2015. Nanotechnology in agriculture, livestock, and aquaculture in China. A review. Agron Sustain Dev 35:369400. Mu, L. and R. L. Sprando . 2010. Application of nanotechnology in cosmetics. Pharmaceutical Research, 27:17461749. Nanda S. , A. Nanda , S. Lohan , R. Kaur , and B. Singh . 2016. Nanocosmetics: Performance enhancement and safety assurance. In: Nanobiomaterials in Galenic Formulations and Cosmetics. ed. Grumezescu, A. , Cambridge, UK: Elsevier Inc., pp. 4767.

Ng, C. and M. Van de Voorde . 2014. Nanomaterials and cosmetics. In: Nanotechnology in a Nutshell, Atlantis Press, pp. 311319. doi: 10.2991/978-94-6239-012-6_18 zer, E. A. , M. zcan , and M. Didin . 2015. Nanotechnology in food and agriculture industry. Food processing: Strategies for quality assessment. Food Engineering Series 477497.79 Raj, S. , S. Jose , U. S. Sumod , and M. Sabitha . 2012. Nanotechnology in cosmetics: Opportunities and challenges. J Pharm Bioall Sci 4:186193. SCENIHR . 2009. Risk assessment of products of nanotechnologies. In: Scientific Committee on Emerging and Newly Identified Health Risks. http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_023.pdf Singh, N. A. 2016. Nanotechnology definitions, research, industry and property rights. In: Nanoscience in Food and Agriculture, Volume 1, eds. Ranjan, S. , D. Nandita , and E. Lichtfouse . Sustainable Agriculture Reviews, Switzerland: Springer International Publishing, pp. 4364. Sozer, N. and J. L. Kokini . 2009. Nanotechnology and its applications in the food sector. Trends Biotechnol 27(2):8289. Waterhouse, G. I. N. and D. Sun-Waterhouse . 2016. Recent advances in the application of nanomaterials and nanotechnology in food research. In: Novel Approaches of Nanotechnology in Food, Volume 1, ed. Grumezescu, A. M. , London, UK: Elsevier Inc., pp. 2166. doi 10.1016/B978-0-12-804308-0.00002-9 Yin, H. and W. Tsai . 2015. Advances of nanomaterials for food processing. Handbook of Food Chemistry 118. doi 10.1007/978-3-642-41609-5_27-1

Effect of Route of Exposure on the Toxicity Behavior of Nanomaterials Adachi, K. , N. Yamada , K. Yamamoto , Y. Yoshida , and O. Yamamoto . 2010. In vivo effect of industrial titanium dioxide nanoparticles experimentally exposed to hairless rat skin. Nanotoxicology 4:296306. Adamcakova-Dodd, A. , M. M. Monick , L. S. Powers , K. N. Gibson-Corley , and P. S. Thorne . 2015. Effects of prenatal inhalation exposure to copper nanoparticles on murine dams and offspring. Part Fibre Toxicol 12:30. Alarifi, S. , D. Ali , S. Alakhtani , E. S. Al Suhaibani , and A. A. Al-Qahtani . 2014. Reactive oxygen species-mediated dna damage and apoptosis in human skin epidermal cells after exposure to nickel nanoparticles. Biol Trace Elem Res 157:8493. Albanese, A. , P. S. Tang , and W. C. W. Chan . 2012. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 14:116. Bacchetta, R. , E. Moschini , N. Santo 2014. Evidence and uptake routes for zinc oxide nanoparticles through the gastrointestinal barrier in Xenopus laevis . Nanotoxicology 8:728744. Chen, Z. , H. Meng , G. Xing 2006. Acute toxicological effects of copper nanoparticles in vivo . Toxicol Lett 163:109120. Choi, J. , H. Kim , P. Kim 2015. Toxicity of zinc oxide nanoparticles in rats treated by two different routes: Single intravenous injection and single oral administration. J Toxicol Environ Health A 78:226243. Cifuentes, Z. , L. Custardoy , J. M. Fuente 2010. Absorption and translocation to the aerial part of magnetic carbon-coated nanoparticles through the root of different crop plants. J Nanobiotechnology 8:26. Crosera, M. , M. Bovenzi , G. Maina 2009. Nanoparticle dermal absorption and toxicity: A review of the literature. Int Arch Occup Environ Health 82:10431055. Donaldson, K. , D. Brown , A. Clouter 2002. The pulmonary toxicology of ultrane particles. J Aerosol Med 15:213220. El-Temsah, Y. S. and E. J. Joner . 2012. Impact of Fe and Ag nanoparticles on seed germination and differences in bioavailability during exposure in aqueous suspension and soil. Environ Toxicol 27:4249. Esch, M. B. , G. J. Mahler , T. Stokol , and M. L. Shuler . 2014. Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. Lab Chip 14:30813092. Florence, A. T. 2005. Nanoparticle uptake by the oral route: Fullling its potential? Drug Discov Today Technol 2:7581. Geisler-Lee, J. , M. Brooks , J. R. Gerfen 2014. Reproductive toxicity and life history study of silver nanoparticle effect, uptake and transport in Arabidopsis thaliana . Nanomaterials 4:301318.

Georgantzopoulou, A. , T. Serchi , S. Cambier 2016. Effects of silver nanoparticles and ions on a co-culture model for the gastrointestinal epithelium. Part Fibre Toxicol 13:9.94 Ghosh, M. , M. Bandyopadhyay , and A. Mukherjee . 2010. Genotoxicity of titanium dioxide TiO2 nanoparticles at two trophic levels: Plant and human lymphocytes. Chemosphere 81:12531262. Grafmueller, S. , P. Manser , L. Diener 2015. Bidirectional transfer study of polystyrene nanoparticles across the placental barrier in an ex vivo human placental perfusion model. Environ Health Perspect 123:12801286. Hillyer, J. F. and R. M. Albrecht . 2001. Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. J Pharm Sci 90:19271936. Hu, R. , G. Xiaolan , D. Yanmei 2010. Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials 31:80438050. Husen, A. and K. S. Siddiqi . 2014. Carbon and fullerene nanomaterials in plant system. J Nanobiotechnology 12:1626. Hussain, S. , J. A. J. Vanoirbeek , K. Luyts 2011. Lung exposure to nanoparticles modulates an asthmatic response in a mouse model. Eur Respir J 37:299309. Jacobsen, N. R. , T. Stoeger , S. Van den Brule 2015. Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories. Food Chem Toxicol 85:8495. Kumar, V. , S. K. Kansal , and S. K. Mehta . 2014. Toxicity of nanomaterials: Present scenario and future scope. In: Nanotechnology: Recent Trends, Emerging Issues and Future Directions, ed. I. Nazrul . New York, USA: Nova Science Publishers, pp. 461486. Kumar, V. , A. Kumari , P. Guleria , and S. K. Yadav . 2012. Evaluating the toxicity of selected types of nanochemicals. Rev Environ Contam Toxicol 215:39121. Liu, Y. , Y. Gao , L. Zhang 2009. Potential health impact on mice after nasal instillation of nanosized copper particles and their translocation in mice. J Nanosci Nanotechnol 9:63356343. Lpez-Moreno, M. L. , G. de la Rosa , J. A. Hernndez-Viezcas 2010. X-ray absorption spectroscopy (XAS) corroboration of the uptake and storage of CeO(2) nanoparticles and assessment of their differential toxicity in four edible plant species. J Agric Food Chem 58:36893693. Mao, L. , M. Hu , B. Pan , Y. Xie , and E. J. Petersen . 2016. Biodistribution and toxicity of radiolabeled few layer graphene in mice after intratracheal instillation. Part Fibre Toxicol 13:7. Mercer, R. R. , J. F. Scabilloni , A. F. Hubbs 2013. Extrapulmonary transport of MWCNT following inhalation exposure. Part Fibre Toxicol 10:38. Moller, P. , J. K. Folkmann , P. H. Danielsen , K. Jantzen , and S. Loft . 2012. Oxidative stress generated damage to DNA by gastrointestinal exposure to insoluble particles. Curr Mol Med 12:732745. Oberdrster, G. , A. Maynard , K. Donaldson 2005. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part Fibre Toxicol 2:8. Oberdrster, G. , Z. Sharp , V. Atudorei 2002. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 65:15311543. Ocsoy, I. , M. L. Paret , M. A. Ocsoy 2013. Nanotechnology in plant disease management: DNA-directed silver nanoparticles on graphene oxide as an antibacterial against Xanthomonas perforans . ACS Nano 7:89728980.95 Park, E. J. , E. Bae , J. Yi 2010. Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles. Environ Toxicol Pharmacol 30:162168. Patlolla, A. K. , D. Hackett , and P. B. Tchounwou . 2015. Silver nanoparticle-induced oxidative stress-dependent toxicity in Sprague-Dawley rats. Mol Cell Biochem 399:257268. Ray, P. C. , H. Yu , and P. P. Fu . 2009. Toxicity and environmental risks of nanomaterials: Challenges and future needs. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev 27:135. Rico, C. M. , S. Majumdar , M. Duarte-Gardea , J. R. Peralta-Videa , and J. L. GardeaTorresdey . 2011. Interaction of nanoparticles with edible plants and their possible implications in the food chain. J Agric Food Chem 59:34853498. Roduner, E. 2006. Size matters: Why nanomaterials are different. Chem Soc Rev 35:583592. Samberg, M. E. , S. J. Oldenburg , and N. A. Monteiro-Riviere . 2010. Evaluation of silver nanoparticle toxicity in in vivo and keratinocytes in vitro . Environ Health Perspect 118:407413. Sayes, C. M. , K. L. Reed , and D. B. Warheit . 2007. Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 97:163180.

Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) . 2006. The appropriateness of existing methodologies to assess the potential risks associated with engineered and adventitious products of nanotechnologies. Luxembourg. Shang, L. , K. Nienhaus , and G. U. Nienhaus . 2014. Engineered nanoparticles interacting with cells: Size matters. J Nanobiotechnology 12:5. Taylor, A. F. , E. L. Rylott , C. W. N. Anderson , and N. C. Bruce . 2014. Investigating the toxicity, uptake, nanoparticle formation and genetic response of plants to gold. PLoS ONE 9:e93793. Thakur, M. , H. Gupta , D. Singh 2014. Histopathological and ultra structural effects of nanoparticles on rat testis following 90 days (chronic study) of repeated oral administration. J Nanobiotechnology 12:4254. Valappil, M. P. , S. Santhakumar , and S. Arumugam . 2014. Determination of oxidative stress related toxicity on repeated dermal exposure of hydroxyapatite nanoparticles in rats. Int J Biomater 2014:18. Vannini, C. , G. Domingo , E. Onelli 2013. Morphological and proteomic responses of Eruca sativa exposed to silver nanoparticles or silver nitrate. PLoS ONE 8:e68752. Walczak, A. P. , R. Fokkink , R. Peters 2012. Behaviour of silver nanoparticles and silver ions in an in vitro human gastrointestinal digestion model. Nanotoxicology 7:11981210. Wang, B. , W. Feng , M. Wang 2008a. Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice. J Nanoparticle Res 10:263276. Wang, S. , W. Lu , O. Tovmachenko , U. S. Rai , H. Yu , and P. C. Ray . 2008b. Challenge in understanding size and shape dependent toxicity of gold nanomaterials in human skin keratinocytes. Chem Phys Lett 463:145149. Wang, Z. , X. Xie , J. Zhao 2012. Xylem- and phloem-based transport of CuO Nanoparticles in Maize (Zea mays L.). Environ Sci Technol 46:44344441.96 Wu, J. , W. Liu , C. Xue 2009. Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett 191:18. Yacobi, N. R. , N. Malmstadt , F. Fazlollahi 2010. Mechanisms of alveolar epithelial translocation of a dened population of nanoparticles. Am J Respir Cell Mol Biol 42:604614. Yamashita, K. , Y. Yoshioka , K. Higashisaka 2011. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol 6:321328. Yin, L. , B. P. Colman , B. M. McGill , J. P. Wright , and E. S. Bernhardt . 2012. Effects of silver nanoparticle exposure on germination and early growth of eleven wetland plants. PLoS ONE 7:e47674. Zhang, C. , S. Zhai , L. Wu 2015. Induction of size-dependent breakdown of blood-milk barrier in lactating mice by TiO2 nanoparticles. PLoS ONE 10:e0122591. Zhang, X. D. , H. Y. Wu , D. Wu 2010. Toxicologic effects of gold nanoparticles in vivo by different administration routes. Int J Nanomedicine 5:771781.

Factors Affecting the Toxicity of Engineered Nanomaterials: Interference and Limitations of In Vitro Assays Alpatova, A. L. , W. Shan , P. Babica , B. L. Upham , A. R. Rogensues , S. J. Masten , E. Drown , A. K. Mohanty , E. C. Alocilja , and V. V. Tarabara . 2010. Single-walled carbon nanotubes dispersed in aqueous media via non-covalent functionalization: Effect of dispersant on the stability, cytotoxicity, and epigenetic toxicity of nanotube suspensions. Water Res 44(2):505520. Asuri, P. , S. S. Bale , R. C. Pangule , D. A. Shah , R. S. Kane , and J. S. Dordick . 2007. Structure, function, and stability of enzymes covalently attached to single-walled carbon nanotubes. Langmuir 23(24):1231812321. Bajpayee, M. , A. Kumar , and A. Dhawan . 2013. The comet assay: Assessment of in vitro and in vivo DNA damage. Methods Mol Biol 1044:325345. Bohnsack, J. P. , S. Assemi , J. D. Miller , and D. Y. Furgeson . 2012. The primacy of physicochemical characterization of nanomaterials for reliable toxicity assessment: A review of the zebrafish nanotoxicology model. Methods Mol Biol 926:261316. Brown, D. M. , C. Dickson , P. Duncan , F. Al-Attili , and V. Stone . 2010. Interaction between nanoparticles and cytokine proteins: Impact on protein and particle functionality. Nanotechnology 21(21):215104. Casals, E. , T. Pfaller , A. Duschl , G. J. Oostingh , and V. Puntes . 2010. Time evolution of the nanoparticle protein corona. ACS Nano 4(7):36233632.119

Casey, A. , E. Herzog , M. Davoren , F. M. Lyng , H. J. Byrne , and G. Chambers . 2007. Spectroscopic analysis confirms the interactions between single walled carbon nanotubes and various dyes commonly used to assess cytotoxicity. Carbon 45(7):14251432. Cho, W. S. , R. Duffin , S. E. Howie , C. J. Scotton , W. A. Wallace , W. Macnee , M. Bradley , I. L. Megson , and K. Donaldson . 2011. Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part Fibre Toxicol 8:27. Das, D. and P. K. Das . 2009. Superior activity of structurally deprived enzyme-carbon nanotube hybrids in cationic reverse micelles. Langmuir 25(8):44214428. Davis, R. R. , P. E. Lockwood , D. T. Hobbs , R. L. Messer , R. J. Price , J. B. Lewis , and J. C. Wataha . 2007. In vitro biological effects of sodium titanate materials. J Biomed Mater Res B Appl Biomater 83(2):505511. Diaz, B. , C. Sanchez-Espinel , M. Arruebo 2008. Assessing methods for blood cell cytotoxic responses to inorganic nanoparticles and nanoparticle aggregates. Small 4(11):20252034. Doak, S. H. , S. M. Griffiths , B. Manshian , N. Singh , P. M. Williams , A. P. Brown , and G. J. Jenkins . 2009. Confounding experimental considerations in nanogenotoxicology. Mutagenesis 24(4):285293. Doak, S. H. , B. Manshian , G. J. Jenkins , and N. Singh . 2012. In vitro genotoxicity testing strategy for nanomaterials and the adaptation of current OECD guidelines. Mutat Res 745(12):104111. Dobrovolskaia, M. A. , B. W. Neun , J. D. Clogston , J. H. Grossman , and S. E. McNeil . 2014. Choice of method for endotoxin detection depends on nanoformulation. Nanomedicine (Lond) 9(12):18471856. Docter, D. , D. Westmeier , M. Markiewicz , S. Stolte , S. K. Knauer , and R. H. Stauber . 2015. The nanoparticle biomolecule corona: Lessons learnedchallenge accepted? Chem Soc Rev 44(17):60946121. El Badawy, A. M. , R. G. Silva , B. Morris , K. G. Scheckel , M. T. Suidan , and T. M. Tolaymat . 2011. Surface charge-dependent toxicity of silver nanoparticles. Environ Sci Technol 45(1):283287. Elsaesser, A. , A. Taylor , G. S. de Yanes , G. McKerr , E. M. Kim , E. O'Hare , and C. V. Howard . 2010. Quantification of nanoparticle uptake by cells using microscopical and analytical techniques. Nanomedicine (Lond) 5(9):14471457. Garcia-Alfonso, C. , J. Lopez-Barea , P. Sanz , G. Repetto , and M. Repetto . 1996. Changes in antioxidative activities induced by Fe (II) and Fe (III) in cultured Vero cells. Arch Environ Contam Toxicol 30(4):431436. Gerber, L. C. , N. Moser , N. A. Luechinger , W. J. Stark , and R. N. Grass . 2012. Phosphate starvation as an antimicrobial strategy: The controllable toxicity of lanthanum oxide nanoparticles. Chem Commun (Camb) 48(32):38693871. Gilmour, P. S. , D. M. Brown , P. H. Beswick , W. MacNee , I. Rahman , and K. Donaldson . 1997. Free radical activity of industrial fibers: Role of iron in oxidative stress and activation of transcription factors. Environ Health Perspect 105 Suppl 5:13131317. Guadagnini, R. , B. Halamoda Kenzaoui , L. Walker 2015. Toxicity screenings of nanomaterials: Challenges due to interference with assay processes and components of classic in vitro tests. Nanotoxicology 9 Suppl 1:1324. Han, X. , R. Gelein , N. Corson , P. Wade-Mercer , J. Jiang , P. Biswas , J. N. Finkelstein , A. Elder , and G. Oberdorster . 2011. Validation of an LDH assay for assessing nanoparticle toxicity. Toxicology 287(13):99104.120 Hasan, S. S. , S. Singh , R. Y. Parikh , M. S. Dharne , M. S. Patole , B. L. Prasad , and Y. S. Shouche . 2008. Bacterial synthesis of copper/copper oxide nanoparticles. J Nanosci Nanotechnol 8(6):31913196. He, W. L. , Y. Feng , X. L. Li , Y. Y. Wei , and X. E. Yang . 2008. Availability and toxicity of Fe(II) and Fe(III) in Caco-2 cells. J Zhejiang Univ Sci B 9(9):707712. Heckert, E. G. , S. Seal , and W. T. Self . 2008. Fenton-like reaction catalyzed by the rare earth inner transition metal cerium. Environ Sci Technol 42(13):50145019. Holder, A. L. , R. Goth-Goldstein , D. Lucas , and C. P. Koshland . 2012. Particle-induced artifacts in the MTT and LDH viability assays. Chem Res Toxicol 25(9):18851892. Holder, A. L. , D. Lucas , R. Goth-Goldstein , and C. P. Koshland . 2007. Inflammatory response of lung cells exposed to whole, filtered, and hydrocarbon denuded diesel exhaust. Chemosphere 70(1):1319. Hsu, P-C. , P-C. Chen , C-M. Ou , H-Y. Chang , and H-T. Chang . 2013. Extremely high inhibition activity of photoluminescent carbon nanodots toward cancer cells. J Mater Chem B 1(13):17741781. Jin, X. , M. Li , J. Wang , C. Marambio-Jones , F. Peng , X. Huang , R. Damoiseaux , and E. M. Hoek . 2010. High-throughput screening of silver nanoparticle stability and bacterial inactivation in aquatic media: Influence of specific ions. Environ Sci Technol 44(19):73217328.

Jones, C. F. and D. W. Grainger . 2009. In vitro assessments of nanomaterial toxicity. Adv Drug Deliv Rev 61(6):438456. Kain, J. , H. L. Karlsson , and L. Moller . 2012. DNA damage induced by micro- and nanoparticles--interaction with FPG influences the detection of DNA oxidation in the comet assay. Mutagenesis 27(4):491500. Karajanagi, S. S. , A. A. Vertegel , R. S. Kane , and J. S. Dordick . 2004. Structure and function of enzymes adsorbed onto single-walled carbon nanotubes. Langmuir 20(26):1159411599. Karakoti, A. S. , S. Singh , A. Kumar , M. Malinska , S. V. Kuchibhatla , K. Wozniak , W. T. Self , and S. Seal . 2009. PEGylated nanoceria as radical scavenger with tunable redox chemistry. J Am Chem Soc 131(40):1414414145. Karakoti, A. , S. Singh , J. M. Dowding , S. Seal , and W. T. Self . 2010. Redox-active radical scavenging nanomaterials. Chem Soc Rev 39(11):44224432. Karlsson, H. L. , J. Nygren , and L. Moller . 2004. Genotoxicity of airborne particulate matter: The role of cell-particle interaction and of substances with adduct-forming and oxidizing capacity. Mutat Res 565(1):110. Kroll, A. , M. H. Pillukat , D. Hahn , and J. Schnekenburger . 2012. Interference of engineered nanoparticles with in vitro toxicity assays. Arch Toxicol 86(7):11231136. Kuhnel, D. , W. Busch , T. Meissner , A. Springer , A. Potthoff , V. Richter , M. Gelinsky , S. Scholz , and K. Schirmer . 2009. Agglomeration of tungsten carbide nanoparticles in exposure medium does not prevent uptake and toxicity toward a rainbow trout gill cell line. Aquat Toxicol 93(23):9199. Kumar, A. , A. K. Pandey , S. S. Singh , R. Shanker , and A. Dhawan . 2011. A flow cytometric method to assess nanoparticle uptake in bacteria. Cytometry A 79(9):707712. Lee, K. J. , L. M. Browning , P. D. Nallathamby , and X. H. Xu . 2013. Study of chargedependent transport and toxicity of peptide-functionalized silver nanoparticles using zebrafish embryos and single nanoparticle plasmonic spectroscopy. Chem Res Toxicol 26(6):904917. Li, Y. , S. H. Doak , J. Yan , D. H. Chen , M. Zhou , R. A. Mittelstaedt , Y. Chen , C. Li , and T. Chen . 2017. Factors affecting the in vitro micronucleus assay for evaluation of nanomaterials. Mutagenesis 32(1):151159.121 Li, Y. , P. Italiani , E. Casals , N. Tran , V. F. Puntes , and D. Boraschi . 2015. Optimising the use of commercial LAL assays for the analysis of endotoxin contamination in metal colloids and metal oxide nanoparticles. Nanotoxicology 9(4):462473. Lim, S. I. and C. J. Zhong . 2009. Molecularly mediated processing and assembly of nanoparticles: Exploring the interparticle interactions and structures. Acc Chem Res 42(6):798808. MacCormack, T. J. , R. J. Clark , M. K. Dang , G. Ma , J. A. Kelly , J. G. Veinot , and G. G. Goss . 2012. Inhibition of enzyme activity by nanomaterials: Potential mechanisms and implications for nanotoxicity testing. Nanotoxicology 6(5):514525. Macewan, S. R. and A. Chilkoti . 2012. Digital switching of local arginine density in a genetically encoded self-assembled polypeptide nanoparticle controls cellular uptake. Nano Lett 12(6):33223328. Magdolenova, Z. , Y. Lorenzo , A. Collins , and M. Dusinska . 2012. Can standard genotoxicity tests be applied to nanoparticles? J Toxicol Environ Health A 75(1315):800806. Maiti, S. , D. Das , A. Shome , and P. K. Das . 2010. Influence of gold nanoparticles of varying size in improving the lipase activity within cationic reverse micelles. Chemistry 16(6):19411950. Marches, R. , C. Mikoryak , R. H. Wang , P. Pantano , R. K. Draper , and E. S. Vitetta . 2011. The importance of cellular internalization of antibody-targeted carbon nanotubes in the photothermal ablation of breast cancer cells. Nanotechnology 22(9):095101. Minozzo, R. , L. I. Deimling , L. P. Gigante , and R. Santos-Mello . 2004. Micronuclei in peripheral blood lymphocytes of workers exposed to lead. Mutat Res 565(1):5360. Monteiro-Riviere, N. A. , A. O. Inman , and L. W. Zhang . 2009. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol Appl Pharmacol 234(2):222235. Moore, T. L. , L. Rodriguez-Lorenzo , V. Hirsch , S. Balog , D. Urban , C. Jud , B. RothenRutishauser , M. Lattuada , and A. Petri-Fink . 2015. Nanoparticle colloidal stability in cell culture media and impact on cellular interactions. Chem Soc Rev 44(17):62876305. Nachlas, M. M. , S. I. Margulies , J. D. Goldberg , and A. M. Seligman . 1960. The determination of lactic dehydrogenase with a tetrazolium salt. Anal Biochem 1:317326. North, M. and C. D. Vulpe . 2010. Functional toxicogenomics: Mechanism-centered toxicology. Int J Mol Sci 11(12):47964813. Oberdorster, G. 2010. Safety assessment for nanotechnology and nanomedicine: Concepts of nanotoxicology. J Intern Med 267(1):89105. Oberdorster, G. , A. Maynard , K. Donaldson 2005. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part

Fibre Toxicol 2:8. Ong, K. J. , T. J. MacCormack , R. J. Clark 2014. Widespread nanoparticle-assay interference: Implications for nanotoxicity testing. PLoS One 9(3):e90650. Oostingh, G. J. , E. Casals , P. Italiani 2011. Problems and challenges in the development and validation of human cell-based assays to determine nanoparticle-induced immunomodulatory effects. Part Fibre Toxicol 8(1):8. Panyam, J. , W. Z. Zhou , S. Prabha , S. K. Sahoo , and V. Labhasetwar . 2002. Rapid endolysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: Implications for drug and gene delivery. FASEB J 16(10):12171226.122 Park, J. , J. H. Park , K. S. Ock , E. O. Ganbold , N. W. Song , K. Cho , S. Y. Lee , and S. W. Joo . 2011. Preferential adsorption of fetal bovine serum on bare and aromatic thiolfunctionalized gold surfaces in cell culture media. J Colloid Interface Sci 363(1):105113. Pfaller, T. , R. Colognato , I. Nelissen 2010. The suitability of different cellular in vitro immunotoxicity and genotoxicity methods for the analysis of nanoparticle-induced events. Nanotoxicology 4(1):5272. Phanse, Y. , A. E. Ramer-Tait , S. L. Friend , B. Carrillo-Conde , P. Lueth , C. J. Oster , G. J. Phillips , B. Narasimhan , M. J. Wannemuehler , and B. H. Bellaire . 2012. Analyzing cellular internalization of nanoparticles and bacteria by multi-spectral imaging flow cytometry. J Vis Exp (64):e3884. Pirmohamed, T. , J. M. Dowding , S. Singh , B. Wasserman , E. Heckert , A. S. Karakoti , J. E. King , S. Seal , and W. T. Self . 2010. Nanoceria exhibit redox state-dependent catalase mimetic activity. Chem Commun (Camb) 46(16):27362738. Pourmand, A. and M. Abdollahi . 2012. Current opinion on nanotoxicology. Daru 20(1):95. Rivera-Gil, P. , D. Jimenez de Aberasturi , V. Wulf 2013. The challenge to relate the physicochemical properties of colloidal nanoparticles to their cytotoxicity. Acc Chem Res 46(3):743749. Savaliya, R. , D. Shah , R. Singh , A. Kumar , R. Shanker , A. Dhawan , and S. Singh . 2015. Nanotechnology in disease diagnostic techniques. Curr Drug Metab 16(8):645661. Savaliya, R. , P. Singh , and S. Singh . 2016. Pharmacological Drug delivery strategies for improved therapeutic effects: Recent advances. Curr Pharm Des 22(11):15061520. Sayes, C. and I. Ivanov . 2010. Comparative study of predictive computational models for nanoparticle-induced cytotoxicity. Risk Anal 30(11):17231734. Semisch, A. and A. Hartwig . 2014. Copper ions interfere with the reduction of the water-soluble tetrazolium salt-8. Chem Res Toxicol 27(2):169171. Shukla, R. K. , A. Kumar , D. Gurbani , A. K. Pandey , S. Singh , and A. Dhawan . 2013. TiO(2) nanoparticles induce oxidative DNA damage and apoptosis in human liver cells. Nanotoxicology 7(1):4860. Shukla, R. K. , A. Kumar , A. K. Pandey , S. S. Singh , and A. Dhawan . 2011. Titanium dioxide nanoparticles induce oxidative stress-mediated apoptosis in human keratinocyte cells. J Biomed Nanotechnol 7(1):100101. Singh, R. , A. S. Karakoti , W. Self , S. Seal , and S. Singh . 2016. Redox-sensitive cerium oxide nanoparticles protect human keratinocytes from oxidative stress induced by glutathione depletion. Langmuir 32(46):1220212211. Singh, R. and S. Singh . 2015. Role of phosphate on stability and catalase mimetic activity of cerium oxide nanoparticles. Colloids Surf B Biointerfaces 132:7884. Singh, S. 2016. Cerium oxide based nanozymes: Redox phenomenon at biointerfaces. Biointerphases 11(4):04B202. Singh, S. , T. Dosani , A. S. Karakoti , A. Kumar , S. Seal , and W. T. Self . 2011. A phosphatedependent shift in redox state of cerium oxide nanoparticles and its effects on catalytic properties. Biomaterials 32(28):67456753. Singh, S. , A. Kumar , A. Karakoti , S. Seal , and W. T. Self . 2010a. Unveiling the mechanism of uptake and sub-cellular distribution of cerium oxide nanoparticles. Mol Biosyst 6(10):18131820. Singh, S. , V. D'Britto , A. A. Prabhune , C. V. Ramana , Alok Dhawan , and B. L. V. Prasad . 2010b. Cytotoxic and genotoxic assessment of glycolipid-reduced and -capped gold and silver nanoparticles. New J Chem 34(2):294301.123 Singh, S. , V. D'Britto , A. Bharde , M. Sastry , A. Dhawan , and B. L. V. Prasad . 2010c. Bacterial synthesis of photocatalytically active and biocompatible TiO2 and ZnO nanoparticles. In J Green Nanotechnol: Phys Chem 2(2):P80P99. Singh, S. , R. Pasricha , U. M. Bhatta , P. V. Satyam , M. Sastry , and B. L. V. Prasad . 2007. Effect of halogen addition to monolayer protected gold nanoparticles. J Mater Chem 17(16):16141619. Singh, S. , P. Patel , S. Jaiswal , A. A. Prabhune , C. V. Ramana , and B. L. V. Prasad . 2009. A direct method for the preparation of glycolipid-metal nanoparticle conjugates: Sophorolipids as

reducing and capping agents for the synthesis of water re-dispersible silver nanoparticles and their antibacterial activity. New J Chem 33(3):646652. Singh, S. and B. L. V. Prasad . 2007. Nearly Complete Oxidation of Au in Hydrophobized Nanoparticles to Au3+ Ions by N-Bromosuccinimide. J Phys Chem C 111(39):1434814352. Singh, V. , S. Singh , S. Das , A. Kumar , W. T. Self , and S. Seal . 2012. A facile synthesis of PLGA encapsulated cerium oxide nanoparticles: Release kinetics and biological activity. Nanoscale 4(8):25972605. Smulders, S. , J. P. Kaiser , S. Zuin , K. L. Van Landuyt , L. Golanski , J. Vanoirbeek , P. Wick , and P. H. Hoet . 2012. Contamination of nanoparticles by endotoxin: Evaluation of different test methods. Part Fibre Toxicol 9:41. Srivastava, M. , S. Singh , and W. T. Self . 2012. Exposure to silver nanoparticles inhibits selenoprotein synthesis and the activity of thioredoxin reductase. Environ Health Perspect 120(1):5661. Stone, V. , H. Johnston , and R. P. Schins . 2009. Development of in vitro systems for nanotoxicology: Methodological considerations. Crit Rev Toxicol 39(7):613626. Stone, V. , J. Shaw , D. M. Brown , W. Macnee , S. P. Faux , and K. Donaldson . 1998. The role of oxidative stress in the prolonged inhibitory effect of ultrafine carbon black on epithelial cell function. Toxicol In Vitro 12(6):649659. Stueker, O. , V. A. Ortega , G. G. Goss , and M. Stepanova . 2014. Understanding interactions of functionalized nanoparticles with proteins: A case study on lactate dehydrogenase. Small 10(10):20062021. Worle-Knirsch, J. M. , K. Pulskamp , and H. F. Krug . 2006. Oops they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Lett 6(6):12611268. Wright, P. C. , H. Qin , M. M. Choi , N. H. Chiu , and Z. Jia . 2014. Carbon nanodots interference with lactate dehydrogenase assay in human monocyte THP-1 cells. Springerplus 3:615. Xie, Y. , N. G. Williams , A. Tolic , W. B. Chrisler , J. G. Teeguarden , B. L. Maddux , J. G. Pounds , A. Laskin , and G. Orr . 2012. Aerosolized ZnO nanoparticles induce toxicity in alveolar type II epithelial cells at the air-liquid interface. Toxicol Sci 125(2):450461. Xu, H. , L. Li , H. Lv , X. Liu , and H. Jiang . 2016. pH-dependent phosphatization of ZnO nanoparticles and its influence on subsequent lead sorption. Environ Pollut 208 (Pt B):723731. Yang, Shikuan , Weiping Cai , Guangqiang Liu , Haibo Zeng , and Peisheng Liu . 2009. Optical Study of Redox Behavior of Silicon Nanoparticles Induced by Laser Ablation in Liquid. J Phys Chem C 113(16):64806484. Zhang, T. , L. Wang , Q. Chen , and C. Chen . 2014. Cytotoxic potential of silver nanoparticles. Yonsei Med J 55(2):283291.

Influence of Test Model Selection on Nanotoxicity Evaluation Adamcakova-Dodd, A. , L. Stebounova , J. Kim , S. Vorrink , A. Ault , P. O'Shaughnessy , V. Grassian , and P. Thorne . 2014. Toxicity assessment of zinc oxide nanoparticles using subacute and sub-chronic murine inhalation models. Part Fibre Toxicoly 11(1):15. Springer Nature. Adeyemi, O. and I. Adewumi . 2014. Biochemical evaluation of silver nanoparticles in wistar rats. Int Sch Res Notices 2014:18. Hindawi Publishing Corporation. Adeyemi, O. , I. Adewumi , and T. Faniyan . 2016. Silver nanoparticles influenced rat serum metabolites and tissue morphology. J Basic Clin Physiol Pharmacol 26(4):355361. Walter de Gruyter GmbH. Adeyemi, O. and T. Faniyan . 2014. Antioxidant status of rats administered silver nanoparticles orally. J Taibah Univ Med Sci 9(3):182186. Elsevier BV. Adeyemi, O. , F. Sulaiman , M. Akanji 2016. Biochemical and morphological changes in rats exposed to platinum nanoparticles. Comp Clin Pathol 25(4):855864. Springer Nature. Adeyemi, O. and C. Whiteley . 2013. Interaction of nanoparticles with arginine kinase from trypanosoma brucei: Kinetic and mechanistic evaluation. Int J Biol Macromol 62:450456. Elsevier BV. Akhter, S. , M. Ahmad , F. Ahmad , G. Storm , and R. Kok . 2012. Gold nanoparticles in theranostic oncology: Current state-of-the-art. Expert Opin Drug Deliv 9(10):12251243. Informa Healthcare. Albanese, A. , P. Tang , and W. Chan . 2012. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Ann Rev Biomed Eng 14(1):116. Annual Reviews. AL-Hadedee, L. , A. Al-Mosowy , and A. Taha . 2016. Toxic effects of fabricated gold nanoparticles in albino mice. Int Res J Agric Food Sci 1(1):116.

Arami, H. , A. Khandhar , D. Liggitt , and K. Krishnan . 2015. In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles. Chem Soc Rev 44(23):85768607. Royal Society of Chemistry.163 Asharani, P. , Y. Lianwu , Z. Gong , and S. Valiyaveettil . 2011. Comparison of the toxicity of silver, gold and platinum nanoparticles in developing zebrafish embryos. Nanotoxicology 5(1):4354. Informa UK Limited. Baan, R . 2007. Carcinogenic hazards from inhaled carbon black, titanium dioxide, and talc not containing asbestos or asbestiform fibers: Recent evaluations by an IARC monographs working group. Inhal Toxicol 19(1):213228. Informa UK Limited. Bhattacharya, R. and P. Mukherjee . 2008. Biological properties of naked metal nanoparticles. Adv Drug Deliv Rev 60(11):12891306. Elsevier BV. Bianco, A. , K. Kostarelos , C. Partidos , and M. Prato . 2005. Biomedical applications of functionalised carbon nanotubes. Chem Commun 2005(5):571. Royal Society of Chemistry. Bilberg, K. , M. Hovgaard , F. Besenbacher , and E. Baatrup . 2012. In vivo toxicity of silver nanoparticles and silver ions in Zebrafish (Danio Rerio). J Toxicol 2012:19. Hindawi Publishing Corporation. Brown, K. , D. Walter , and M. Natan . 2000. Seeding of colloidal au nanoparticle solutions. 2. Improved control of particle size and shape. Chem Mater 12(2):306313. American Chemical Society. Chen, H. , A. Dorrigan , S. Saad , D. Hare , M. Cortie , and S. Valenzuela . 2013. In vivo study of spherical gold nanoparticles: Inflammatory effects and distribution in mice. Plos ONE 8(2):e58208. Public Library of Science. Chen, H. , S. Su , C. Chien , W. Lin , S. Yu , C. Chou , J. Chen , and P. Yang . 2006. Titanium dioxide nanoparticles induce emphysema-like lung injury in mice. FASEB J 20(13):23932395. FASEB. Chen, Y. , Y. Hung , I. Liau , and G. Huang . 2009. Assessment of the in vivo toxicity of gold nanoparticles. Nanoscale Res Lett 4(8):858864. Springer Science. Cho, W. , R. Duffin , C. Poland , A. Duschl , G. Oostingh , W. MacNee , M. Bradley , I. Megson , and K. Donaldson . 2011. Differential pro-inflammatory effects of metal oxide nanoparticles and their soluble ions in vitro and in vivo; zinc and Copper Nanoparticles, But Not Their Ions, Recruit Eosinophils To The Lungs. Nanotoxicology 6(1):2235. Informa UK Limited. Cho, W. , R. Duffin , C. Poland , S. Howie , W. MacNee , M. Bradley , I. Megson , and K. Donaldson . 2010. Metal oxide nanoparticles induce unique inflammatory footprints in the lung: Important implications for nanoparticle testing. Environ Health Perspect 118(12):16991706. Environmental Health Perspectives. Comanescu, M. , M. Mocanu , L. Anghelache , B. Marinescu , F. Dumitrache , A. Badoi , and G. Manda . 2015. Toxicity Of L-DOPA coated iron oxide nanoparticles in intraperitoneal delivery setting: Preliminary preclinical study. Rom J Morphol Embryo 56(2):691696. Connolly, M. , M. Fernandez-Cruz , A. Quesada-Garcia , L. Alte , H. Segner , and J. Navas . 2015. Comparative cytotoxicity study of silver nanoparticles (AgNPs) in a variety of rainbow trout cell lines (RTL-W1, RTH-149, RTG-2) and primary hepatocytes. I J Environ Res Publ Health 12(5):53865405. MDPI AG. Connor, E. , J. Mwamuka , A. Gole , C. Murphy , and M. Wyatt . 2005. Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small 1(3):325327. WileyBlackwell. Cunningham, C. , T. Arai , P. Yang , M. McConnell , J. Pauly , and S. Conolly . 2005. Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles. Magn Reson Med 53(5):9991005. Wiley-Blackwell.164 Doudi, M. and M. Setorki . 2014. The effect of gold nanoparticle on renal function in rats. Nanomedicine 1(3):171179. Duan, Y. , J. Liu , L. Ma 2010. Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials 31(5):894899. Elsevier BV. Dumitrache, F. , I. Morjan , C. Fleaca 2015. Highly magnetic Fe2O3 nanoparticles synthesized by laser pyrolysis used for biological and heat transfer applications. Appl Surf Sci 336:297303. Elsevier BV. Elhusseiny, A. and H. Hassan . 2013. Antimicrobial and antitumor activity of platinum and palladium complexes of novel spherical aramides nanoparticles containing flexibilizing linkages: Structureproperty relationship. Spectrochim Acta A: Mol Biomol Spectrosc 103:232245. Elsevier BV. Faddah, L. , N. Baky , N. Al-Rasheed , and N. Al-Rasheed . 2013. Biochemical responses of nanosize titanium dioxide in the heart of rats following administration of idepenone and quercetin. Afr J Pharm Pharmacol 7(38):26392651. Academic Journals. Filho, J. , E. Matsubara , L. Franchi , I. Martins , L. Rivera , J. Rosolen , and C. Grisolia . 2014. Evaluation of carbon nanotubes network toxicity in zebrafish (Danio Rerio) model. Environ Res

134:916. Elsevier BV. Firme, C. and P. Bandaru . 2010. Toxicity issues in the application of carbon nanotubes to biological systems. Nanomed: Nanotechnol, Biol Med 6(2):245256. Elsevier BV. Fischer, H. and W. Chan . 2007. Nanotoxicity: The growing need for in vivo study. Curr Opin Biotechnol 18(6):565571. Elsevier BV. Fratoddi, I. , I. Venditti , C. Cametti , and M. Russo . 2015. How toxic are gold nanoparticles? the state-of-the-art. Nano Research 8(6):17711799. Springer Science. Fujita, K. , M. Fukuda , S. Endoh , J. Maru , H. Kato , A. Nakamura , N. Shinohara , K. Uchino , and K. Honda . 2015. Size effects of single-walled carbon nanotubes onin vivoandin vitropulmonary toxicity. Inhal Toxicol 27(4):207223. Informa Healthcare. Girigoswami, K. , M. Viswanathan , R. Murugesan , and A. Girigoswami . 2015. Studies on polymer-coated zinc oxide nanoparticles: UV-blocking efficacy and in vivo toxicity. Mater Sci Eng 56:501510. Elsevier BV. Hu, R. , X. Gong , Y. Duan , N. Li , Y. Che , Y. Cui , M. Zhou , C. Liu , H. Wang , and F. Hong . 2010. Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials 31(31):80438050. Elsevier BV. Iavicoli, I. , V. Leso , and A. Bergamaschi . 2012. Toxicological effects of titanium dioxide nanoparticles: A review of in vivo studies. J Nanomater 2012:136. Hindawi Publishing Corporation. Jalilian, A. , A. Panahifar , M. Mahmoudi , M. Akhlaghi , and A. Simchi . 2009. Preparation and biological evaluation of [67Ga]-labeled-superparamagnetic nanoparticles in normal rats. Radiochimica Acta 97(1). Walter de Gruyter GmbH. Jo, M. , S. Bae , M. Go , H. Kim , Y. Hwang , and S. Choi . 2015. Toxicity and biokinetics of colloidal gold nanoparticles. Nanomaterials 5(2):835850. MDPI AG. Kajita, M. , K. Hikosaka , M. Iitsuka , A. Kanayama , N. Toshima , and Y. Miyamoto . 2007. Platinum nanoparticle is a useful scavenger of superoxide anion and hydrogen peroxide. Free Radic Res 41(6):615626. Informa UK Limited. Kang, S. , B. Kim , Y. Lee , and H. Chung . 2008. Titanium dioxide nanoparticles trigger P53mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen 49(5):399405. Wiley-Blackwell.165 Khalid, P. , M. Hussain , V. Suman , and A. Arun . 2016. Toxicology of carbon nanotubes: A review. Int J Appl Eng Res 11(1):148157. Kim, J. , M. Takahashi , T. Shimizu , T. Shirasawa , M. Kajita , A. Kanayama , and Y. Miyamoto . 2008a. Effects of a potent antioxidant, platinum nanoparticle, on the lifespan of caenorhabditis elegans. Mech Ageing Dev 129(6):322331. Elsevier BV. Kim, Y. , J. Kim , H. Cho 2008b. Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of Silver nanoparticles in sprague-dawley rats. Inhal Toxicol 20(6):575583. Informa UK Limited. Kim, Y. R. , J. I. Park , E. J. Lee 2014. Toxicity of 100 Nm zinc oxide nanoparticles: A report of 90-day repeated oral administration in Sprague Dawley rats. Int J Nanomed 9:109126. Dove Medical Press Ltd. Kobayashi, N. , M. Naya , S. Endoh , J. Maru , K. Yamamoto , and J. Nakanishi . 2009. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats: Different short- and long-term post-instillation results. Toxicology 264(12):110118. Elsevier BV. Koyama, S. , Y. Kim , T. Hayashi , K. Takeuchi , C. Fujii , N. Kuroiwa , H. Koyama , T. Tsukahara , and M. Endo . 2009. In vivo immunological toxicity in mice of carbon nanotubes with impurities. Carbon 47(5):13651372. Elsevier BV. Krug, H. and P. Wick . 2011. Nanotoxicology: An interdisciplinary challenge. Angew Chem Int Ed 50(6):12601278. Wiley-Blackwell. Ksiyk, M. , M. Asztemborska , R. Stborowski , and G. Bystrzejewska-Piotrowska . 2015. Toxic effect of silver and platinum nanoparticles toward the freshwater microalga pseudokirchneriella subcapitata. Bull Environ Contam Toxicol 94(5):554558. Springer Science. Kushwaha, A. , V. Singh , M. Aslam , A. Garg , R. Mittal , and R. Mukhopadhyay . 2011. Energy efficient and size tunable synthesis of colloidal zinc oxide nanoparticles by simple beaker chemistry. AIP Conference Proceedings 1349(1):391392. AIP Publishing. Lasagna-Reeves, C. , D. Gonzalez-Romero , M. Barria , I. Olmedo , A. Clos , V. Sadagopa Ramanujam , A. Urayama , L. Vergara , M. Kogan , and C. Soto . 2010. Bioaccumulation and toxicity of gold nanoparticles after repeated administration in mice. Biochem Biophys Res Commun 393(4):649655. Elsevier BV. Lathamuthiah, B. , Inbakandan , and R. Devij . 2015. In vivo toxicity studies of biosynthesized silver nanoparticles using brassica oleraceae in zebra fish model. Int J Pharm Pharmaceut 7(2):425430. Innovare Academic Sciences

Li, H. , T. Zhang , G. Liang , Y. Zhang , and X. Wang . 2011. In vivo evaluation of acute toxicity of water-soluble carbon nanotubes. Toxicol Environ Chem 93(3):603615. Informa UK Limited. Li, J. , Q. Li , J. Xu , J. Li , X. Cai , R. Liu , Y. Li , J. Ma , and W. Li . 2007. Comparative study on the acute pulmonary toxicity induced by 3 and 20 nm TiO2 primary particles in mice. Environ Toxicol Pharmacol 24(3):239244. Elsevier BV. Liang, G. , Y. Pu , L. Yin , R. Liu , B. Ye , Y. Su , and Y. Li . 2009. Influence of different sizes of titanium dioxide nanoparticles on hepatic and renal functions in rats with correlation to oxidative stress. J Toxicol Environ Health, Part A 72(1112):740745. Informa UK Limited. Liu, Z. , C. Davis , W. Cai , L. He , X. Chen , and H. Dai . 2008. Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by raman spectroscopy. Proc Natl Acad Sci 105(5):14101415. Proceedings of the National Academy of Sciences.166 Ma, L. , J. Liu , N. Li , J. Wang , Y. Duan , J. Yan , H. Liu , H. Wang , and F. Hong . 2010. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 31(1):99105. Elsevier BV. Mahmoudi, M. , H. Hofmann , B. Rothen-Rutishauser , and A. Petri-Fink . 2012. Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide Nanoparticles. Chemical Reviews 112(4):23232338. American Chemical Society. Marisa, I. , V. Matozzo , M. Munari , A. Binelli , M. Parolini , A. Martucci , E. Franceschinis , N. Brianese , and M. Marin . 2016. In vivo exposure of the marine clam ruditapes philippinarum to zinc oxide nanoparticles: Responses in gills, digestive gland and haemolymph. Environ Sci Pollut Res 23(15):1527515293. Springer Nature. Martinez, D. , L. Franchi , C. Freria , O. Ferreira , A. Filho , O. Alves , and C. Takahashi . 2013. Carbon nanotubes: From synthesis to genotoxicity. Nanotoxicology 125152. Springer Science. Mercer, R. , J. Scabilloni , L. Wang , E. Kisin , A. Murray , D. Schwegler-Berry , A. Shvedova , and V. Castranova . 2007. Alteration of deposition pattern and pulmonary response as a result of improved dispersion of aspirated single-walled carbon nanotubes in a mouse model. Am J Physiol, Lung Cell Mol Physiol 294(1):L87L97. American Physiological Society. Miller, T. , A. Knapton , O. Adeyemo 2007. Toxicology of titanium dioxide (TiO2) nanoparticles: In vitro and in vivo evaluation of macrophage uptake of TiO2 . FASEB J. 21(6):12. Federation of American Societies for Experimental Biology Journal publishers. Monteiro-Riviere, N. , K. Wiench , R. Landsiedel , S. Schulte , A. Inman , and J. Riviere . 2011. Safety evaluation of sunscreen formulations containing titanium dioxide and zinc oxide nanoparticles in UVB sunburned skin: An in vitro and in vivo study. Toxicological Sciences 123(1):264280. Oxford University Press. Moon, C. , H. Park , Y. Choi , E. Park , V. Castranova , and J. Kang . 2010. Pulmonary inflammation after intraperitoneal administration of ultrafine titanium dioxide (TiO2) At rest or in lungs primed with lipopolysaccharide. J Toxicol Environ Health, Part A 73(56):396409. Informa UK Limited. Morimoto, Y. , T. Oyabu , A. Ogami , T. Myojo , E. Kuroda , M. Hirohashi , M. Shimada , W. Lenggoro , K. Okuyama , and I. Tanaka . 2011. Investigation of gene expression of mmp-2 and timp-2 mrna in rat lung in inhaled nickel oxide and titanium Dioxide nanoparticles. Ind Health 49(3):344352. National Institute of Industrial Health. Morishige, T. , Y. Yoshioka , A. Tanabe , X. Yao , S. Tsunoda , Y. Tsutsumi , Y. Mukai , N. Okada , and S. Nakagawa . 2010. Titanium dioxide induces different levels of IL-1 production dependent on its particle characteristics through caspase-1 activation mediated by reactive oxygen species and cathepsin B. Biochem Biophys Res Commun 392(2):160165. Elsevier BV. Muller, J. , F. Huaux , N. Moreau , P. Misson , J. Heilier , M. Delos , M. Arras , A. Fonseca , J. Nagy , and D. Lison . 2005. Respiratory toxicity of multi-wall carbon nanotubes. Toxicol Appl Pharmacol 207(3):221231. Elsevier BV. Muller, J. , I. Decordier , P. Hoet , N. Lombaert , L. Thomassen , F. Huaux , D. Lison , and M. Kirsch-Volders . 2008. Clastogenic and aneugenic effects of multi-wall carbon nanotubes in epithelial cells. Carcinogenesis 29(2):427433. Oxford University Press. NIOSH , 2011. National Institute for Occupational Safety and Health. CDC. https://www.cdc.gov/niosh/docs/2011-160/pdfs/2011-160.pdf.167 Olin, S. 2000. The relevance of the rat lung response to particle overload for human risk assessment: A workshop consensus report. Inhal Toxicol 12(12):117. Informa UK Limited. Ong, K. , T. MacCormack , R. Clark 2014. Widespread nanoparticle-assay interference: Implications for nanotoxicity testing. Plos ONE 9(3):e90650. Public Library of Science. Onizawa, S. , K. Aoshiba , M. Kajita , Y. Miyamoto , and A. Nagai . 2009. Platinum nanoparticle antioxidants inhibit pulmonary inflammation in mice exposed to cigarette smoke. Pulm Pharmacol Ther 22(4):340349. Elsevier BV. Osmond, M. and M. Mccall . 2010. Zinc oxide nanoparticles in modern sunscreens: An analysis of potential exposure and hazard. Nanotoxicology 4(1):1541. Informa UK Limited.

Pasupuleti, S. , S. Alapati , S. Ganapathy , G. Anumolu , N. Pully , and B. Prakhya . 2011. Toxicity of zinc oxide nanoparticles through oral route. Toxicol Ind Health 28(8):675686. SAGE Publications. Patlolla, A. K. , A. Berry , L. May , and P. B. Tchounwou . 2012. Genotoxicity of silver nanoparticles in Vicia faba: A Pilot study on the environmental monitoring of nanoparticles. Int J Environ Res Public Health 9:16491662. Pissuwan, D. , C. Cortie , S. Valenzuela , and M. Cortie . 2007. Gold nanosphere-antibody conjugates for hyperthermal therapeutic applications. Gold Bulletin 40(2):121129. Springer Science. Pissuwan, D. , T. Niidome , and M. Cortie . 2011. The forthcoming applications of gold nanoparticles in drug and gene delivery systems. J Control Release 149(1):6571. Elsevier BV. Prabhu, S. , S. Mutalik , S. Rai , N. Udupa , and B. Rao . 2015. Pegylation of superparamagnetic iron oxide nanoparticle for drug delivery applications With decreased toxicity: An in vivo study. J Nanopart Res 17(10):412. Springer Science. Prasek, M. , E. Sawosz , S. Jaworski , M. Grodzik , T. Ostaszewska , M. Kamaszewski , M. Wierzbicki , and A. Chwalibog . 2013. Influence of nanoparticles of platinum on chicken embryo development and brain morphology. Nanoscale Res Lett 8(1):251. Springer Nature. Prodan, A. , S. Iconaru , C. Ciobanu , M. Chifiriuc , M. Stoicea , and D. Predoi . 2013. Iron oxide magnetic nanoparticles: Characterization and toxicity evaluation by in vitro and in vivo assays. J Nanomater 2013: 110. Hindawi Publishing Corporation. Recordati, C. , M. De Maglie , S. Bianchessi 2015. Tissue distribution and acute toxicity of silver after single intravenous administration in mice: Nano-specific and size-dependent effects. Part Fibre Toxicol 13(1):117. Springer Science. Ruiz, P. , B. Morn , H. Becker 2017. Titanium dioxide nanoparticles exacerbate DSS-induced colitis: Role of the NLRP3 inflammasome. Gut 66(7):12161224. BMJ. Ryu, H. J. , M. Y. Seo , S. K. Jung 2014. Zinc oxide nanoparticles: A 90-day repeated-dose dermal toxicity study in rats. Int J Nanomed 9:137144. Dove Medical Press Ltd. Sadauskas, E. , G. Danscher , M. Stoltenberg , U. Vogel , A. Larsen , and H. Wallin . 2009. Protracted elimination of gold nanoparticles from mouse liver. Nanomed: Nanotechnol, Biol, Med 5(2):162169. Elsevier BV. Sapsford, K. , W. Algar , L. Berti , K. Gemmill , B. Casey , E. Oh , M. Stewart , and I. Medintz . 2013. Functionalizing nanoparticles with biological molecules: Developing chemistries that facilitate nanotechnology. Chem Rev 113(3):19042074. American Chemical Society.168 Saptarshi, S. R. , A. Duschl , and A. L. Lopata . 2013. Interaction of nanoparticles with proteins: Relation to bio-reactivity of the nanoparticle. J Nanobiotechnol 11:26. Springer Science. Saravanan, M. , R. Suganya , M. Ramesh , R. Poopal , N. Gopalan , and N. Ponpandian . 2015. Iron oxide nanoparticles induced alterations in haematological, biochemical and ionoregulatory responses of an indian major carp labeo rohita. J Nanopart Res 17(6):112. Springer Science. Sayes, C. M. , K. L. Reed , and D. B. Warheit . 2007. Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 97:163180. Oxford University Press. Schellenberger, E. , F. Reynolds , R. Weissleder , and L. Josephson . 2004. Surfacefunctionalized nanoparticle library yields probes for apoptotic cells. Chembiochem 5(3):275279. Wiley-Blackwell. Schipper, M. , N. Nakayama-Ratchford , C. Davis , N. Kam , P. Chu , Z. Liu , X. Sun , H. Dai , and S. Gambhir . 2008. A pilot toxicology study of single-walled carbon nanotubes in a small sample of mice. Nature Nanotech 3(4):216221. Nature Publishing Group. Semmler-Behnke, M. , W. Kreyling , J. Lipka , S. Fertsch , A. Wenk , S. Takenaka , G. Schmid , and W. Brandau . 2008. Biodistribution of 1.4- And 18-Nm gold particles in rats. Small 4(12):21082111. Wiley-Blackwell. Shibuya, S. , Y. Ozawa , K. Watanabe , N. Izuo , T. Toda , K. Yokote , and T. Shimizu . 2014. Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice. Plos ONE 9(10):e109288. Public Library of Science. Sivaraman, S. , I. Elango , S. Kumar , and Santhanam . 2009. A green protocol for room temperature synthesis of silver nanoparticles in seconds. Current Science 97(7):10551059. Sulaiman, F. , M. Akanji , H. Oloyede 2015a. Oral exposure to silver/gold nanoparticles: Status of rat lipid Profile, serum metabolites and tissue morphology. J Med Sci (Faisalabad) 15(2):7179. Science Alert. Sulaiman, F. , O. Adeyemi , M. Akanji 2015b. Biochemical and morphological alterations caused by silver nanoparticles in wistar rats. J Acute Med 5(4):96102. Elsevier BV. Sung, J. , J. Ji , J. Park 2011. Subchronic inhalation toxicity of gold nanoparticles. Par Fibre Toxicol 8(1):16. Springer Nature. Sung, J. , J. Ji , J. Yoon 2008. Lung function changes in sprague-dawley rats after prolonged inhalation exposure to silver nanoparticles. Inhal Toxicol 20(6):567574. Informa UK Limited.

Sung, J. H. , J. H. Ji , K. S. Song , J. H. Lee , K. H. Choi , S. H. Lee , and I. J. Yu . 2010. Acute inhalation toxicity of silver nanoparticles. Toxicol Ind Health 27(2):149154. SAGE Publications. Surekha, P. , A. Kishore , A. Srinivas , G. Selvam , A. Goparaju , P. Reddy , and P. Murthy . 2011. Repeated dose dermal toxicity study of nano zinc oxide with sprague-Dawley Rats. Cutan Ocul Toxicol 31(1):2632. Informa UK Limited. Takagi, A. , A. Hirose , M. Futakuchi , H. Tsuda , and J. Kanno . 2012. Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes In p53 heterozygous mice. Cancer Science 103(8):14401444. Wiley-Blackwell.169 Teixeira da Silva, R. 2014. The Effect Of Silver Nanoparticles: A Chronic In Vivo Study For The Evaluation Of Hepatic Mitochondrial Toxicity. Departamento De Cincias Da Vida. https://estudogeral.sib.uc.pt/bitstream/10316/28174/1/The%20effect%20of%20silver%20nanop articles%20a%20chronic%20in%20vivo%20study%20for%20the%20evaluation%20of%20hepa tic%20mitochondrial%20toxicity%20-%20Rui%20Silva.pdf. (Accessed October 10, 2016). Turkevich, J. , P. Stevenson , and J. Hillier . 1951. A study of the nucleation and growth processes in the synthesis of colloidal gold. Discussions of the Faraday Society 11: 5574. Royal Society of Chemistry. Vandebriel, R. and W. De Jong . 2012. A review of mammalian toxicity of ZnO nanoparticles. Nanotechnol, Sci Appl 5: 6171. Dove Medical Press Limited. Wang, J. , C. Chen , Y. Liu , F. Jiao , W. Li , F. Lao , Y. Li , B. Li , C. Ge , and G. Zhou . 2008a. Potential neurological lesion after nasal instillation of TiO2 Nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183(1-3):7280. Elsevier BV. Wang, J. , Y. Li , W. Li , C. Chen , B. Li , and Y. Zhao . 2008b. Biological effect of intranasally instilled titanium dioxide nanoparticles on female mice. Nano 03(04):279285. World Scientific Pub Co Pte Limited. Wang, L. , V. Castranova , A. Mishra , B. Chen , R. Mercer , D. Schwegler-Berry , and Y. Rojanasakul . 2010. Dispersion of single-walled carbon nanotubes by a natural lung surfactant for pulmonary in vitro and in vivo toxicity studies. Part Fibre Toxicol 7(1):31. Springer Nature. Wang, X. , J. Guo , T. Chen , H. Nie , H. Wang , J. Zang , X. Cui , and G. Jia . 2012. Multiwalled carbon nanotubes induce apoptosis via mitochondrial pathway and scavenger receptor. Toxicol In Vitro 26(6):799806. Elsevier BV. Warheit, D. , R. Hoke , C. Finlay , E. Donner , K. Reed , and C. Sayes . 2007. Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicol Lett 171(3):99110. Elsevier BV. Xiao, L. , C. Liu , X. Chen , and Z. Yang . 2016. Zinc oxide nanoparticles induce renal toxicity through reactive oxygen species. Food Chem Toxicol 90: 7683. Elsevier BV. Xie, J. , Y. Zheng , and J. Ying . 2009. Protein-directed synthesis of highly fluorescent gold nanoclusters. J Am Chem Soc 131(3):888889. American Chemical Society. Xu, J. , M. Futakuchi , H. Shimizu 2012. Multi-Walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats. Cancer Science 103(12):20452050. Wiley-Blackwell. Yah, C . 2013. The toxicity of gold nanoparticles in relation to their physiochemical properties. Biomed Rese 24(3):400413. Yamagishi, Y. , A. Watari , Y. Hayata , X. Li , M. Kondoh , Y. Yoshioka , Y. Tsutsumi , and K. Yagi . 2013. Acute and chronic nephrotoxicity of platinum nanoparticles in mice. Nanoscale Res Lett 8(1):395. Springer Nature. Yang, S. , K. Fernando , J. Liu 2008. Covalently pegylated carbon nanotubes with stealth character in vivo . Small 4(7):940944. Wiley-Blackwell. Yazdan Madani, S. , A. Mandel , and A. Seifalian . 2013. A concise review of carbon nanotube's toxicology. Nano Reviews 4:114. Co-Action Publishing. Yin, H. , P. Casey , M. McCall , and M. Fenech . 2010. Effects of surface chemistry on cytotoxicity, genotoxicity, and the generation of reactive oxygen species induced by ZnO nanoparticles. Langmuir 26(19):1539915408. American Chemical Society.170 Yogesh, B. , B. Vineeta , N. Rammesh , and P. Saili . 2016. Biosynthesized platinum nanoparticles inhibit the proliferation of human lung-cancer cells in vitro and delay the growth of a human lung-tumor xenograft In vivo . J Pharmacopunct 19(2):114121. Korean Pharmacopuncture Institute. Zhang, X. , D. Wu , X. Shen , P. Liu , F. Fan , and S. Fan . 2012. In vivo renal clearance, biodistribution, toxicity of gold nanoclusters. Biomaterials 33(18):46284638. Elsevier BV. Zhang, X. D. 2010. Toxicologic effects of gold nanoparticles in vivo by different administration routes. Int J Nanomedicine 5: 771781. Dove Medical Press Ltd. Zhao, J. , L. Xu , T. Zhang , G. Ren , and Z. Yang . 2009. Influences of nanoparticle zinc oxide on acutely isolated rat hippocampal CA3 pyramidal neurons. Neurotoxicology 30(2):220230. Elsevier BV.

Zhu, X. , S. Tian , and Z. Cai . 2012. Toxicity assessment of iron oxide nanoparticles in zebrafish (Danio Rerio) early life stages. Plos ONE 7(9):e46286. Public Library of Science.

Nanotoxicity In Vitro: Limitations of the Main Cytotoxicity Assays Asare, N. , C. Instanes , W. J. Sandberg 2012. Cytotoxic and genotoxic effects of silver nanoparticles in testicular cells. Toxicology 291:6572. Belyanskaya, L. , P. Manser , P. Spohn , A. Bruinink , and P. Wick . 2007. The reliability and limits of the MTT reduction assay for carbon nanotubes-cell interaction. Carbon 45:26432648. Boczkowski, J. and P. Hoet . 2010. What's new in nanotoxicology? Implications for public health from a brief review of the 2008 literature. Nanotoxicology 4:114.190 Borenfreund, E. and J. A. Puerner . 1985. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol Lett 24:119124. Breccia, J. D. , M. M. Andersson , and R. Hatti-Kaul . 2002. The role of poly(ethyleneimine) in stabilization against metal-catalyzed oxidation of proteins: A case study with lactate dehydrogenase. Biochim Biophys Acta 1570:165173. Casey, A. , E. Herzog , M. Davoren , F. M. Lyng , H. J. Byrne , and G. Chambers . 2007. Spectroscopic analysis confirms the interactions between single walled carbon nanotubes and various dyes commonly used to assess cytotoxicity. Carbon 45:14251432. Chlopek, J. , B. Czajkowska , B. Szaraniec , E. Frackowiak , K. Szostak , and F. Bguin . 2006. In vitro studies of carbon nanotubes biocompatibility. Carbon 44:11061111. Connolly, M. , M. L. Fernandez-Cruz , A. Quesada-Garcia , L. Alte , H. Segner , and J. M. Navas . 2015. Comparative Cytotoxicity Study of Silver Nanoparticles (AgNPs) in a Variety of Rainbow Trout Cell Lines (RTL-W1, RTH-149, RTG-2) and Primary Hepatocytes. Int J Environ Res Public Health 12:53865405. Costa, C. , F. Brando , M. J. Bessa 2016. In vitro cytotoxicity of superparamagnetic iron oxide nanoparticles on neuronal and glial cells. Evaluation of nanoparticle interference with viability tests. J Appl Toxicol 36:361372. Davis, R. R. , P. E. Lockwood , D. T. Hobbs 2007. In vitro biological effects of sodium titanate materials. J Biomed Mater Res B Appl Biomater 83:505511. Doak, S. H. , S. M. Griffiths , B. Manshian 2009. Confounding experimental considerations in nanogenotoxicology. Mutagenesis 24:285293. Dusinska, M. , S. Boland , M. Saunders 2015. Towards an alternative testing strategy for nanomaterials used in nanomedicine: Lessons from NanoTEST. Nanotoxicology 9:118132. Fadeel, B. and K. Savolainen . 2013. Broaden the discussion. Nat Nanotechnol 8:71. Farcal, L. , F. T. Andn , L. Di Cristo 2015. Comprehensive in vitro toxicity testing of a panel of representative oxide nanomaterials: First steps towards an intelligent testing strategy. PLoS One 10:e0127174. Forest, V. , A. Figarol , D. Boudard , M. Cottier , P. Grosseau , and J. Pourchez . 2015. Adsorption of lactate dehydrogenase enzyme on carbon nanotubes: How to get accurate results for the cytotoxicity of these nanomaterials. Langmuir 31:36353643. Gao, X. , X. Zhang , Y. Wang , Y. Wang , S. Peng , and C. Fan . 2015. An in vitro study on the cytotoxicity of bismuth oxychloride nanosheets in human HaCaT keratinocytes. Food Chem Toxicol 80:5261. Guadagnini, R. , B. H. Kenzaoui , L. Walker 2015. Toxicity screenings of nanomaterials: Challenges due to interference with assay processes and components of classic in vitro tests. Nanotoxicology 9:1324. Guo, L. , A. Von Dem Bussche , M. Buechner , A. Yan , A. B. Kane , and R. H. Hurt . 2008. Adsorption of essential micronutrients by carbon nanotubes and the implications for nanotoxicity testing. Small 4:721727. Han, X. , R. Gelein , N. Corson 2011. Validation of an LDH assay for assessing nanoparticle toxicity. Toxicology 287:99104. Hikosaka, K. , J. Kim , M. Kajita , A. Kanayama , and Y. Miyamoto . 2008. Platinum nanoparticles have an activity similar to mitochondrial NADH:ubiquinone oxidoreductase. Colloids Surf B Biointerfaces 66:195200. Hirsch, C. , M. Roesslein , H. F. Krug , and P. Wick . 2011. Nanomaterial cell interactions: Are current in vitro tests reliable? Nanomedicine 6:837847.191 Hoet, P. and J. Boczkowski . 2009. What's new in Nanotoxicology? Brief review of the 2007 literature. Nanotoxicology 2:171182. Holder, A. L. , R. Goth-Goldstein , D. Lucas , and C. P. Koshland . 2012. Particle-induced artifacts in the MTT and LDH viability assays. Chem Res Toxicol 25:18851892.

Hoskins, C. , L. Wang , W. P. Cheng , and A. Cuschieri . 2012. Dilemmas in the reliable estimation of the in-vitro cell viability in magnetic nanoparticle engineering: Which tests and what protocols? Nanoscale Res Lett 7:77. Hsiao, I. L. and Y. J. Huang . 2011. Improving the interferences of methyl thiazolyl tetrazolium and IL-8 assays in assessing the cytotoxicity of nanoparticles. J Nanosci Nanotechnol 11:52285233. Huang, X. , I. H. El-Sayed , X. Yi , and M. A. El-Sayed . 2005. Gold nanoparticles: Catalyst for the oxidation of NADH to NAD(+). J Photochem Photobiol B 81:7683. Jia, G. , H. Wang , L. Yan 2005. Cytotoxicity of carbon nanomaterials: Single-wall nanotube, multi-wall nanotube, and fullerene. Environ Sci Technol 39:13781383. Johnston, H. , D. M. Brown , N. Kanase 2015. Mechanism of neutrophil activation and toxicity elicited by engineered nanomaterials. Toxicol In Vitro 29:11721184. Karajanagi, S. S. , A. A. Vertegel , R. S. Kane , and J. S. Dordick . 2004. Structure and function of enzymes adsorbed onto single-walled carbon nanotubes. Langmuir 20:1159411599. Karlsson, H. L. , S. Di Bucchianico , A. R. Collins , and M. Dusinska . 2015. Can the comet assay be used reliably to detect nanoparticle-induced genotoxicity? Environ Mol Mutagen 56:8296. Koh, J. Y. and D. W. Choi . 1987. Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods 20:8390. Kroll, A. , C. Dierker , C. Rommel 2011. Cytotoxicity screening of 23 engineered nanomaterials using a test matrix of ten cell lines and three different assays. Part Fibre Toxicol 8:9. Kroll, A. , M. H. Pillukat , D. Hahn , and J. Schnekenburger . 2009. Current in vitro methods in nanoparticle risk assessment: Limitations and challenges. Eur J Pharm Biopharm 72:370377. Kroll, A. , M. H. Pillukat , D. Hahn , and J. Schnekenburger . 2012. Interference of engineered nanoparticles with in vitro toxicity assays. Arch Toxicol 86:11231136. Krug, H. F. and P. Wick . 2011. Nanotoxicology: An interdisciplinary challenge. Angew Chem Int Ed Engl 50:12601278. Latiff, N. M. , W. Z. Teo , Z. Sofer , A. C. Fisher , and M. Pumera . 2015. The cytotoxicity of layered black phosphorus. Chemistry 21:1399113995. Li, L. , M. L. Fernndez-Cruz , M. Connolly 2015. The potentiation effect makes the difference: Non-toxic concentrations of ZnO nanoparticles enhance Cu nanoparticle toxicity in vitro . Sci Total Environ 505:253260. Manna, S. K. , S. Sarkar , J. Barr 2005. Single-walled carbon nanotube induces oxidative stress and activates nuclear transcription factor-B in human keratinocytes. Nano Lett 5:16761684. Monteiro-Riviere, N. A. and A. O. Inman . 2006. Challenges for assessing carbon nanomaterial toxicity to the skin. Carbon 44:10701078. Monteiro-Riviere, N. A. , R. A. Nemanich , A. O. Inman , Y. Y. Wang , and J. E. Riviere . 2005. Multi-walled carbon nanotube interactions with human epidermal keratinocytes. Toxicol Lett 155:377384.192 Monteiro-Riviere, N. A. , A. O. Inman , and L. W. Zhang . 2009. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol Appl Pharm 234:222235. Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 65:5563. Ong, K. J. , T. J. MacCormack , R. J. Clark 2014. Widespread nanoparticle-assay interference: Implications for nanotoxicity testing. PLoS One 9:e90650. Panessa-Warren, B. J. , J. B. Warren , S. S. Wong , and J. A. Misewich . 2006. Biological cellular response to carbon nanoparticle toxicity. J Phys Cond Matter 18:S2185S2201. Pfaller, T. , R. Colognato , I. Nelissen 2010. The suitability of different cellular in vitro immunotoxicity and genotoxicity methods for the analysis of nanoparticle-induced events. Nanotoxicology 4:5272. Pulskamp, K. , S. Diabat , and H. F. Krug . 2007. Carbon nanotubes show no sign of acute toxicity but induce intracellular reactive oxygen species in dependence on contaminants. Toxicol Lett 168:5874. Regiel-Futyra, A. , M. Kus-Likiewicz , V. Sebastian 2015. Development of noncytotoxic chitosan-gold nanocomposites as efficient antibacterial materials. ACS Appl Mater Interfaces 7:10871099. Seog, J. H. , B. Kong , D. Kim , L. M. Graham , J. S. Choi , and S. B. Lee . 2015. Short-term effects of ultrahigh concentration cationic silica nanoparticles on cell internalization, cytotoxicity, and cell integrity with human breast cancer cell line (MCF-7). J Nanopart Res 17:6. Shatkin, J. A. and K. J. Ong . 2016. Alternative testing strategies for nanomaterials: State of the science and considerations for risk analysis. Risk Analysis 36(8):15641580. doi: 10.1111/risa.12642

Shvedova, A. A. , E. R. Kisin , A. R. Murray , V. Z. Gandelsman , A. Maynard , and P. Baron . 2003. Exposure to carbon nanotube material: Assessment of nanotube cytotoxicity using human keratinocyte cells. J Toxicol. Environ Health, Part A 66:19091926. Tian, F. , D. Cui , H. Schwartz , G. G. Estrada , and H. Kobayashi . 2006. Cytotoxicity of single wall carbon nanotubes on human fibroblasts. Toxicol In Vitro 20:12021212. Tomankova, K. , J. Horakova , M. Harvanova 2015. Reprint of: Cytotoxicity, cell uptake and microscopic analysis of titanium dioxide and silver nanoparticles in vitro . Food Chem Toxicol 85:2030. Veranth, J. M. , E. G. Kaser , M. M. Veranth , M. Koch , and G. S. Yost . 2007. Cytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Part Fibre Toxicol 4:2. Wrle-Knirsch, J. M. , K. Pulskamp , and H. F. Krug . 2006. Oops they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Lett 6:12611268. Zhang, L. W. , L. Zeng , A. R. Barron , and N. A. Monteiro-Riviere . 2007. Biological interactions of functionalized single-wall carbon nanotubes in human epidermal keratinocytes. Int J Toxicol 26:103113.

Genotoxicity and Carcinogenicity of Daily Used Nanoparticles: In Vivo Studies Ackroyd, R. , C. Kelty , N. Brown , and M. Reed . 2001. The history of photodetection and photodynamic therapy. Photochem Photobiol 74(5):656669. Afaq, F. , P. Abidi , R. Matin , and Q. Rahman . 1998. Cytotoxicity, pro-oxidant effects and antioxidant depletion in rat lung alveolar macrophages exposed to ultrafine titanium dioxide. J Appl Toxicol 18(5):307312. Ahamed, M. , R. Posgai , T. J. Gorey , M. Nielsen , S. M. Hussain , and J. J. Rowe . 2010. Silver nanoparticles induced heat shock protein 70, oxidative stress and apoptosis in Drosophila melanogaster. Toxicol Appl Pharmacol 242: 263269. Asharani, P. V. , Y. Lianwu , Z. Gong , and S. Valiyaveettil . 2011. Comparison of the toxicity of silver, gold and platinum nanoparticles in developing zebrafish embryos. Nanotoxicology 5:4354. Asharani, P. V. , Y. L. Wu , Z. Gong 2008. Toxicity of silver nanoparticles in zebra fish models. Nanotechnology 19(25):255102. Attia, A. A. 2014. Evaluation of the testicular alterations induced by silver nanoparticles in male mice: Biochemical, histological and ultrastructural studies. Res J Pharm, Biol Chem Sci (4):15581589. Ayala-Nez, N. V. , H. H. Lara , C. I. Turrent Liliana del , and C. R. Padilla . 2009. Silver nanoparticles tox-icity and bactericidal effect against Methicillin-resistant Staphylococcus aureus: Nanoscale does matter. Nanobiotechnology 5:29. Baan, R. A. 2007. Carcinogenic hazards from inhaled carbon black, titanium dioxide, and talc not containing asbestos or asbestiform fibers: Recent evaluations by an IARC Monographs Working Group. Inhal Toxicol 19(supplement 1):213228. Baek, M. , H. E. Chung , J. Yu 2012. Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles. Int J Nanomedicine 7:30813097. Bakare, A. A. , A. J. Udoakang , A. T. Anifowoshe 2016. Genotoxicity of titanium dioxide nanoparticles using the mouse bone marrow micronucleus and sperm morphology assays. J Pollut Eff Cont 4:156. Balasubramanyam, A. , N. Sailaja , M. Mahboob , M. F. Rahman , S. M. Hussain , and P. Grover . 2009b. In vivo genotoxicity assessment of aluminium oxide nanomaterials in rat peripheral blood cells using the comet assay and micronucleus test. Mutagenesis 24:245251. Balasubramanyam, A. , N. Sailaja , M. Mahboob , M. F. Rahman , S. Misra , S. M. Hussain , and P. Grover . 2009a. Evaluation of genotoxic effects of oral exposure to aluminum oxide nanomaterials in rat bone marrow. Mutat Res 676:4147.210 Ben-Slama, I. , I. Mrad , N. Rihane 2015. Sub-acute oral toxicity of zinc oxide nanoparticles in male rats. J Nanomed Nanotechnol 6: 284. Borm, P. J. , D. Robbins , S. Haubold 2006. The potential risks of nanomaterials: A review carried out for ECETOC. Part Fibre Toxicol 3:11. Brun, E. , F. Barreau , G. Veronesi 2014. Titanium dioxide nanoparticle impact and translocation through ex vivo, in vivo and in vitro gut epithelia. Part Fibre Toxicol 11(13):216. Carinci, F. , S. Volinia , F. Pezzetti , F. Francioso , L. Tosi , and A. Piattelli . 2003. Titanium-cell interaction: Analysis of gene expression profiling. J Biomed Mater Res 66B(1):341346.

Cerkez, I. , H. B. Kocer , S. D. Worley , R. M. Broughton , and T. S. Huang . 2012. Multifunctional cotton fabric: Antimicrobial and durable press. J Appl Polym Sc. 124, 42304238. Chekman, I. S. 2008. [Nanopharmacology: Experimental and clinic aspect]. LikSprava 4(3):104109. Chen, J. , X. Dong , J. Zhaoa , and G. Tang . 2009. In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection. J Appl Toxicol 29:330337. Cho, H. S. , J. H. Sung , K. S. Song , J. S. Kim , J. S. Ji , J. H. Lee , H. R. Ryu , K. Ahn , and J. Yu . 2013. Genotoxicity of silver nanoparticles in lung cells of sprague dawley rats after 12 weeks of inhalation exposure. Toxics 1:3645. Cho, K. H. , J. E. Park , T. Osaka , and S. G. Park . 2005. The study of antimicrobial activity and preservative effects of nanosilver ingredient. Electrochim. Acta 51:956960. Cho, M. , H. Chung , W. Choi , and J. Yoon . 2004. Linear correlation between inactivation of E. coli and OH radical concentration in TiO2 photocatalytic disinfection. Water Res 38(4):10691077. Choi, H. S. , W. Liu , P. Misra 2007. Renal clearance of quantum dots. Nat Biotechnol 25(10):11651170. Choi, J. E. , S. Kim , J. H. Ahn , P. Youn , J. S. Kang , K. Park , J. Yi , and D. Y. Ryu . 2010. Induction of oxidative stress and apoptosis by silver nanoparticles in the liver of adult zebrafish. Aquat Toxicol 100:151159. Choi, S. Y. , S. Jeong , S. H. Jang , J. Park , K. S. Ock , S. Y. Lee , and S.-W. Joo . 2012. In vitro toxicity protein-adsorbed citrate-reduced gold nanoparticles in human lung adenocarcinoma cells. Toxicol In Vitro 26:229237. Cui, Y. , H. Liu , M. Zhou 2011. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. J Biomed Mater Res A 96(1):221229. Cui, Y. , H. Liu , M. Zhou , Y. Duan , N. Li , X. Gong , R. Hu , M. Hong , and F. Hong . 2010. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. J Biomed Mater Res A 96:221229. Dankovic, D. , E. Kuempel , and M. Wheeler . 2007. An approach to risk assessment for TiO2 . Inhal Toxicol 19(1):205212. Dorszewska, J. , A. Oczkowska , M. Suwalska 2014. Mutations in the exon 7 of Trp53 gene and the level of p53 protein in double transgenic mouse model of Alzheimer's disease. Folia Neuropathol 52(1):3040. Downs, T. R. , M. E. Crosby , T. Hu 2012. Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not. Mutat Res 745(12):3850. Edwards-Jones, V. 2009. The benefits of silver in hygiene, personal care and healthcare. Lett Appl Microbiol 49(2):147152.211 El-Ansary, A. and S. Al-Daihan . 2009. Review article: On the toxicity of therapeutically used nanoparticles: An overview. J Toxicol 2009:19. Elechiguerra, J. L. , J. L. Burt , J. R. Morones 2005. Interaction of silver nanoparticles with HIV1. J Nano Biotechnol 3:6. El Ghor, A. A. , M. M. Noshy , A. Galal , and H. R. H. Mohamed . 2014. Normalization of nanosized TiO2-induced clastogenicity, genotoxicity and mutagenicity by chlorophyllin administration in mice brain, liver, and bone marrow cells. Toxicol Sci 142(1):2132. Epub 2014 Aug 16. El Mahdya, M. M. , T. A. Salah Eldinb , H. S. Alyd , F. F. Mohammed , and M. I. Shaalan . 2014. Evaluation of hepatotoxic and genotoxic potential of silver nanoparticles in albino rats. Exp Toxicol Pathol 67:2129. Faddah, L. M. , N. A. Baky , N. M. Al-Rasheed , and N. M. Al-Rasheed . 2013. Full Length Research Paper: Biochemical responses of nanosize titanium dioxide in the heart of rats following administration of idepenone and quercetin. AJPP 7:26392651. Fisichella, M. , F. Berenguer , G. Steinmetz , M. Auffan , J. Rose , and O. Prat . 2012. Intestinal toxicity evaluation of TiO2 degraded surface-treated nanoparticles: A combined physicochemical and toxicogenomics approach in caco-2 cells. Part Fibre Toxicol 9:17438977. Furukawa, F. , Y. Doi , M. Suguro 2011. Lack of skin carcinogenicity of topically applied titanium dioxide nanoparticles in the mouse. Food Chem Toxicol 49(4):744749. Gelover, S. , L. A. Gmez , K. Reyes , and M. T. Leal . 2006. A practical demonstration of water disinfection using TiO2 films and sunlight. Water Res 40:32743280. Girgis, E. , W. K. Khalil , A. N. Emam , M. B. Mohamed , and K. V. Rao . 2012. Nanotoxicity of gold and gold-cobalt nanoalloy. Chem Res Toxicol 25:10861098. Gopinath, P. , S. K. Gogoi , A. Chattopadhyay , and S. S. Ghosh . 2008. Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy. Nanotechnology 19:075104. Gottesman, R. , S. Shukla , N. Perkas , L. A. Solovyov , Y. Nitzan , and A. Gedanken . 2011. Sonochemical coating of paper by microbiocidal silver nanoparticles. Langmuir 27:720726. doi: 10.1021/la103401z

Gromadzka-Ostrowska, J. , K. Dziendzikowska , A. Lankoff 2012. Silver Nanoparticles effects on epididymal sperm in rats. Toxicol Lett 214:251258. Guo, H. , Zhang, J. , Boudreau, M. , Meng, J. , Yin, J.-J. , Liu, J. and Xu, H. 2016. Intravenous administration of silver nanoparticles causes organ toxicity through intracellular ROS-related loss of inter-endothelial junction. Part Fibre Toxicol 13:21. Gurr, J. , A. S. S. Wang , C. Chen , and K. Jan . 2005. Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. Toxicology 213:6673. Hajkova, P. , P. Spatenka , J. Horsky , I. Horska , and A. Kolouch . 2007. Photocatalytic effect of TiO2 films on viruses and bacteria. Plasma Process Polym 4:S397S401. Heinreich, U. , R. Fuhst , S. Rittinghause 1995. Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black and titanium dioxide. Inhal Toxicol 7:533556. Hext, P. M. , J. A. Tomenson , and P. Thompson . 2005. Titanium dioxide: Inhalation toxicology and epidemiology. Ann Occup Hyg 49:461472. Hirakawa, K. , M. Mori , M. Yoshida , S. Oikawa , and S. Kawanishi . 2004. Photo-irradiated titanium dioxide catalyzes site specific DNA damage via generation of hydrogen peroxide. Free Radic Res 38(5):439447.212 Hohr, D. , Y. Steinfartz , R. P. F. Schins 2002. The surface area rather than the surface coating determines the acute inflammatory response after instillation of fine and ultrafine TiO2 in the rat. Int J Hyg Environ Health 205(3):239244. Holtz, R. D. , B. A. Lima , A. G. Souza Filho , M. Brocchi , and O. L. Alves . 2012. Nanostructured silvervanadate as a promising antibacterial additive to water-based paints. Nanomed: Nanotechnol, Biol Med 6:935940. Hoshino, A. , K. Fujioka , T. Oku 2004. Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification. Nano Lett 4(11):21632169. Hu, C. W. , M. Lia , Y. B. Cui , D. S. Li , J. Chen , and L. Y. Yang . 2010. Toxicological effects of TiO2 and ZnO nanoparticles in soil on earthworm Eisenia fetida. Soil Biol Biochem 42:586591. Hwang, d. W. , Lee, D. S. , and Kim, S. 2012. Gene expression profiles for genotoxic effects of silica-free and silica-coated cobalt ferrite nanoparticles. J Nucl Med 53:106112. IARC (International Agency for Research on Cancer) . 2006. Titanium dioxide group 2B. in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 9, International Agency for Research on Cancer, World Health Organization, Lyon, France. IARC (International Agency for Research on Cancer) . 2010. Carbon black, titanium dioxide, and talc. in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 93, International Agency for Research on Cancer, World Health Organization, Lyon, France. ILSI Workshop 2000. The relevance of the rat lung response to particle overload for human risk assessment: A workshop consensus report. Inhal Toxicol 12(12), 117. Jacobsen, N. R. , G. Pojana , P. White , P. Mller , C. A. Cohn , K. S. Korsholm , U. Vogel , A. Marcomini , S. Loft , and H. K. Wallin . 2008. Genotoxicity, cytotoxicity, and reactive oxygen species induced by single-walled carbon nanotubes and C60 fullerenes in the FE1-MutaTM mouse lung epithelial cells. Environ Mol Mutagen 49:476487. Jeon, Y. M. , S. K. Park , and M. Y. Lee . 2011. Toxicoproteomic identification of TiO2 nanoparticle-induced protein expression changes in mouse brain. Animal Cells and Systems 15(2):107114. Jeon, Y. M. , S. K. Park , S. K. Rhee , and M. Y. Lee . 2010. Proteomic profiling of the differentially expressed proteins by TiO2 nanoparticles in mouse kidney. Mol Cell Toxicol 6:419425. Kang, G. S. , P. A. Gillespie , A. Gunnison ., A. L. Moreira , K. M. Tchou-Wong , and L. C. Chen . 2011. Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model. Environ Health Perspect 119:176181. Katsnelson, B. A. , L. I. Privalova , V. B. Gurvich 2013. Comparative in vivo assessment of some adverse bioeffects of equidimensional gold and silver nanoparticles and the attenuation of nanosilver's effects with a complex of innocuous bioprotectors. Int J Mol Sci 14(2):24492483. doi: 10.3390/ijms14022449 Kim, K. J. , W. S. Sung , S. K. Moon , J. S. Choi , J. G. Kim , and D. G. Lee . 2008a. Antifungal effect of silver nanoparticles on dermatophytes. J Microbiol Biotechnol 18:14821484. Kim, J. S. , E. Kuk , K. N. Yu 2007. Antimicrobial effects of silvernanoparticles. Nanomed: Nanotechnol, Biol Med 3:95101.213 Kim, J. S. , J. H. Sung , J. H. Ji , K. S. Song , J. H. Lee , C. S. Kang , and I. J. Yu . 2011. In vivo genotoxicity of silver nanoparticles after 90 day silver nanoparticle inhalation exposure. Saf. Health Work 2:6569. Kim, S. , J. E. Choi , J. Choi , K. H. Chung , K. Park , J. Yi , and D. Y. Ryu . 2009. Oxidative stress-dependent toxicity of silver nanoparticles in human hepatoma cells. Toxicol. In Vitro

23:10761084. Kim, Y. S. , J. S. Kim , H. S. Cho 2008b. Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats. Inhal Toxicol 20:575583. Klapper, M. , S. Nenov R. Haschick , K. Mller , and K. Mllen . 2008. Oil-in-oil emulsions: A unique tool for the formation of polymer nanoparticles. Acc Chem Res 41:11901201. Kobayashi, N. , M. Naya , S. Endoh , J. Maru , K. Yamamoto , and J. Nakanishi . 2009. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats: Different short- and long-term post-instillation results. Toxicology 264(12):110118. Konaka, R. , Kasahara, E. , Dunlap, W. C. , Yamamoto, Y. , Chien, K. C. and M. Inoue . 2001. Ultraviolet irradiation of titanium dioxide in aqueous dispersion generates singlet oxygen. Redox Rep 6(5):319325. Kwon, J. Y. , J. L. Kim , J. Y. Lee 2014. Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests. Int J Nanomedicine 9(2):173181. Lam, C.-W. , J. T. James , R. McCluskey , and R. L. Hunter . 2004. Pulmonary toxicity of singlewall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicol Sci 77:126134. Landsiedel, R. , L. Ma-Hock , B. Van Ravenzwaay , M. Schulz , K. Wiench , S. Champ , S. Schulte , W. Wohlleben , and F. Oesch . 2010. Gene toxicity studies on titanium dioxide and zinc oxide nanomaterials used for UV-protection in cosmetic formulations. Nanotoxicology 4:364381. Laura, K. , Braydich-Stolle , N. M. Schaeublin 2009. Crystal structure mediates mode of cell death in TiO2 nanotoxicity. J Nanoparticle Res 11:13611374. Lee, D. Y. , C. Fortin , and P. G. Campbell . 2005. Contrasting effects of chloride on the toxicity of silver to two green algae, Pseudokirchneriella subcapitata and Chlamydomonas reinhardtii . Aquat Toxicol 75:127135. Lee, K. P. , H. J. Trochimowicz , and C. F. Reinhardt . 1985. Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years. Toxicology and Applied Pharmacology 79(2):179192. Lewis, S. E. and R. J. Aitken . 2005. DNA damage to spermatozoa has impacts on fertilization and pregnancy. Cell Tissue Res 322: 3341. Li, F. , M. D. Weir , J. Chen , and H. H. Xu . 2013. Comparison of quaternary ammoniumcontaining with nano-silver-containing adhesive in antibacterial properties and cytotoxicity. Dent Mater 29(4):450461. Li, J. J. , S. L. Lo C. T. Ng R. L. Gurung D. Hartono M. P. Hande C. N. Ong B. H. Bay and L. Y. Yung . 2011. Genomic instability of gold nanoparticle treated human lung fibroblast cells. Biomaterials 32:55155523. Li, N. , Y. Duan , M. Hong 2010a. Spleen injury and apoptotic pathway in mice caused by titanium dioxide nanoparticules. Toxicol Lett 195(23):161168. Li, Q. , S. Mahendra , D. Y. Lyon 2008. Antimicrobial nanoma-terials for water disinfection and microbial control: Potential applications andimplications. Water Res 42:45914602.214 Li, P. W. , T. H. Kuo , J. H. Chang , J. M. Yeh , and W. H. Chan . 2010b. Induction of cytotoxicity and apoptosis in mouse blastocysts by silver nanoparticles. Toxicol Lett 2:8287. Liang, G. , Y. Pu , L. Yin 2009. Influence of different sizes of titanium dioxide nanoparticles on hepatic and renal functions in rats with correlation to oxidative stress. Journal of Toxicology and Environmental Health. Part A 72(11):740745. Lin, W. , Y. W. Huang , X. D. Zhou , and Y. Ma . 2006. In vitro toxicity of silica nanoparticles in human lung cancer cells. Toxicol Appl Pharmac 217:252259. Liu, H. , L. Ma , J. Liu , J. Zhao , J. Yan , and F. Hong . 2010. Toxicity of nano-anatase TiO2 to mice: Liver injury, oxidative stress. Toxicol Environ Chem 92(1):175186. Liu, K. , X. Lin , and J. Zhao . 2013. Toxic effects of the interaction of titanium dioxide nanoparticles with chemicals or physical factors. Int J Nanomedicine 8:25092520. doi: 10.2147/IJN.S46919 Lockman, P. R. , J. M. Koziara , R. J. Mumper , and D. D. Allen . 2004. Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J Drug Target 12(910):635641. Lok, C. N. , C. M. Ho , R. Chen 2006. Proteomic analysis of the mode of antibacterial action of silver nanoparticles. J Proteome Res 5:916924. Long, T. C. , J. Tajuba ., P. Sama ., N. Saleh ., C. Swartz ., J. Parker ., S. Hester , G. V. Lowry , and B. Veronesi . 2007. Nanosize Titanium Dioxide Stimulates Reactive Oxygen Species in Brain Microglia and Damages Neurons in vitro. Environ Health Perspect 115(11):16311637. Loo, S. L. , A. G. Fane , T. T. Lim , W. B. Krantz , Y. N. Liang , X. Liu , and X. Hu . 2013. Superabsorbent cryogels decorated with silver nanoparticles as a novel water technology for point-of-use disinfection. Environ Sci Technol 47:93639371.

Lv, Y. , H. Liu , Z. Wang 2009. Silver nanoparticle-decorated porousceramic composite for water treatment. J Membr Sci 331:5056. Ma, L. , J. Liu , N. Li 2010. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 31(1):99105. Ma, L. , J. Zhao , J. Wang 2009. The acute liver injury in mice caused by nano-anatase TiO2 . Nanoscale Res Lett 4(11):12751285. Magaye, R. , J. Zhao , L. Bowman , and M. Ding . 2012. Genotoxicity and carcinogenicity of cobalt-, nickel- and copper-based nanoparticles. Exp Ther Med 4(4):551561. Masoud, R. , T. Bizouarn , S. Trepout 2015. Titanium dioxide nanoparticles increase superoxide anion production by acting on NADPH oxidase. PLoS ONE 10(12):e0144829. McShan, D. , P. C. Ray and H. Yu . 2014. Molecular toxicity mechanism of nanosilver. J. Food Drug Anal 22(1):116127. Mehrbod, P. , N. Motamed , M. Tabatabaian 2009. In vitro anti viral effect of nanosilver on influenza virus. DARU 17:8893. Mohamed, H. R. H. 2015. Estimation of TiO2 nanoparticle-induced genotoxicity persistence and possible chronic gastritis-induction in mice. Food Chem Toxicol 83:7683. Epub 2015 Jun 11. Mohamed and N. A. Hussien . 2016. Genotoxicity studies of titanium dioxide nanoparticles (TiO2NPs) in the brain of mice. Scientifica, Article ID 6710840, 7 p., doi: 10.1155/2016/6710840 Mohamed, H. R. H. 2014. Attenuation of nano-Tio2 induced genotoxicity, mutagenicity and apoptosis by chlorophyllin in mice cardiac cells. Int J Sci Res 3(6):26252636.215 Mohamed, H. R. H. 2016. Studies on the genotoxicity behavior of silver nanoparticles in the presence of heavy metal cadmium chloride in mice. J Nanomater, Article ID 5283162, 12 p. Moon, E. Y. , G. H. Yi , J. S. Kang , J. S. Lim , H. M. Kim , and S. Pyo . 2011. An increase in mouse tumor growth by an in vivo immunomodulating effect of titanium dioxide nanoparticles. J Immunotoxicol 8(1):5667. Morsy, G. M. , K. S. Abou El-Ala , and A. A. Ali . 2013. Studies on fate and toxicity of nanoalumina in male albino rats: Lethality, bioaccumulation and genotoxicity. Toxicol Ind Health 116. Muller, J. , I. Decordier , P. Hoet 2008. Clastogenic and aneugenic effects of multi-wall carbon nanotubes in epithelial cells. Carcinigenesis 29:427433. Napierska, D. , L. C. Thomassen , D. Lison , J. A. Martens , and P. H. Hoet . 2010. The nanosilica hazard: Another variable entity. Part Fibre Toxicol 7:39. Naya, M. , N. Kobayashi , M. Ema , S. Kasamoto , M. Fukumuro , S. Takami , M. Nakajima , M. Hayashi , and J. Nakanishi . 2011. In vivo genotoxicity study of titanium dioxide nanoparticles using comet assay following intratracheal instillation in rats. Regul Toxicol Pharmacol 62:16. NIOSH (National Institute for Occupational Safety and Health) . 2011. Occupational exposure to titanium dioxide, Publication No. 2011-160, US Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute of Occupational Safety and Health, DHHS (NIOSH), Cincinnati, Ohio, USA. Oberdrster, G. 2001. Pulmonary effects of inhaled ultrafine particles. International Archives of Occupational and Environmental Health 74(1), 18. Oberdrster, G. 1996. Significance of particle parameters in the evaluation of exposure-doseresponse relationships of inhaled particles. Inhal Toxicol 8, 7389. Oberdorster, G. , A. Maynard , K. Donaldson 2005. Research foundation/risk science institute nanomaterial toxicity screening working group. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part Fibre Toxicol 2:8. Onuma, K. , Y. Sato , S. Ogawara 2009. Nano-scaled particles of titanium dioxide convert benign mouse fibrosarcoma cells into aggressive tumor cells. Am J Pathol 175(5):21712183. Ordzhonikidze, C. G. , L. K. Ramaiyya , E. M. Egorova , and A. V. Rubanovich . 2009. Genotoxic effects of silver nanoparticles on mice in vivo . Acta Naturae 1:99101. Park, S. , Y. K. Lee , and M. Jung . 2007. Cellular toxicity of various inhalable metal nanoparticles on human alveolar epithelial cells. Inhal Toxicol 19:5965. Patlolla, A. K. , D. Hackett , and P. Tchounwou . 2015. Genotoxicity study of silver nanoparticles in bone marrow cells of Sprague-Dawley rats. Food Chem Toxicol 85:5260. Pott, F. , G. H. Althoff , M. Roller , D. Hohr , and J. Friemann . 1998. High acute toxicity of hydrophobic ultrafine titantium dioxide in an intratracheal study with several dusts in rats. In: ILSI Monographs Relationship Between Respiratory Disease and Exposure to Air Pollution, eds. U. Mohr and D. L. Dungworth , Washington, DC, USA: ILSI Press, pp. 270277. Powers, K. W. , S. C. Brown , V. B. Krishna , S. C. Wasdo , B. M. Moudgil , and S. M. Roberts . 2006. Research strategies for safety evaluation of nanomaterials. Part VI. Characterization of nanoscale particles for toxicological evaluation. Toxicol Sci 90(2):296303.216 Powers, K. W. , M. Palazuelos , B. M. Moudgil , and S. M. Roberts . 2007. Characterization of the size, shape, and state of dispersion of nanoparticles for toxicological studies.

Nanotoxicology 1(1):4251. Rahman, M. F. , J. Wang , T. A. Patterson , U. T. Saini , B. L. Robinson , G. D. Newport , R. C. Murdock , J. J. Schlager , S. M. Hussain , and S. F. Ali . 2009. Expression of genes related to oxidative stress in the mouse brain after exposure to silver-25 nanoparticles. Toxicol. Lett 187:1521. Rai, M. , A. Yadav , and A. Gade . 2009. Silver nanoparticles as a new generation of antimicrobials. Biotechnol Adv 27:7683. Rasmussen, J. W. , E. Martinez , P. Louka , and D. G. Wingett . 2010. Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opin Drug Deliv 7:10631077. Renwick, L. C. , K. Donaldson , and A. Clouter . 2001. Impairment of alveolar macrophage phagocytosis by ultrafine particles. Toxicol Appl Pharmacol 172(2):119127. Ribeiro, M. , P. Morgado , S. Miguel , P. Coutinho , and I. Correia . 2013. Dextran-based hydrogel containing chitosan microparticles loaded with growth factors to be used in wound healing. Mater Sci Eng, C 33:29582966. Rossi, E. M. , L. Pylkknen , A. J. Koivisto 2010. Inhalation exposure to nanosized and fine TiO2 particles inhibits features of allergic asthma in a murine model. Part Fibre Toxicol 7, article 35. Saber, A. T. , N. R. Jacobsen , A. Mortensen 2012. Nanotitanium dioxide toxicity in mouse lung is reduced in sanding dust from paint. Part Fibre Toxicol 9:4. Schulz, M. , L. Ma-Hock , S. Brill , V. Strauss , S. Treumann , S. Groters , B. van Ravenzwaay , and R. Landsiedel . 2011. Investigation on the genotoxicity of different sizes of gold nanoparticles administered to the lungs of rats. Mutat Res 745:5157. Sekhon, B. S. 2010. Food nanotechnology-an overview. Nanotechnol Sci Appl 3:115. Sharma, V. , P. Singh , A. K. Pandey , and A. Dhawan . 2012. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res 745:8491. Shimizu, M. , H. Tainaka , T. Oba , K. Mizuo , M. Umezawa , and K. Takeda . 2009. Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse. Part Fibre Toxicol 6, article 20. Shin J. A. , E. J. Lee , S. M. Seo , H. S. Kim , J. L. Kang , and E. M. Park . 2010. Nanosized titanium dioxide enhanced inflammatory responses in the septic brain of mouse. Neuroscience 165(2):445454. Shin, S. , M. Ye , H. Kim , and H. Kang . 2007. The effects of nano-silver on the proliferation and cytokine expression by peripheral blood mononuclear cells. Int Immunopharmacol 7:18131818. Sriram, M. I. , S. B. Kanth , K. Kalishwaralal , and S. Gurunathan . 2010. Antitumor activity of silver nanoparticles in Dalton's lymphoma ascites tumor model. Int J Nanomedicine 5:753762. Stone, V. , H. Johnston , and M. J. Clift . 2007. Air pollution, ultrafine and nanoparticle toxicology: Cellular and molecular interactions. IEEE Trans Nanobioscience 6:331340. Stone, V. , B. Nowack , and A. Baun . 2010. Nanomaterials for environmental studies: Classication, reference material issues, and strategies for physico-chemical characterisation. Sci Total Environ 408:17451754.217 Sycheva, L. P. , V. S. Zhurkov , V. V. Iurchenko , N. O. Daugel-Dauge , M. A. Kovalenko , E. K. Krivtsova , and A. D. Durnev . 2011. Investigation of genotoxic and cytotoxic effects of microand nanosized titanium dioxide in six organs of mice in vivo . Mutat Res 726:814. Takahashi, Y. , Y. Shinkai , K. Mizuo , S. Oshio , and K. Takeda . 2010. Prenatal exposure to titanium dioxide nanoparticles increases dopamine levels in the prefrontal cortex and neostriatum ofmice. J Toxicol Sci 35(5):749756. Takeda, K. , K. I. Suzuki , A. Ishihara 2009. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 55(1):95102. Tang, J. , L. Xiong , S. Wang 2009. Distribution, translocation and accumulation of silver nanoparticles in rats. J Nanosci Nanotechnol 9:49244932. Tappin, A. D. , J. L. Barriada , C. B. Braungardt , E. H. Evans , M. D. Patey , and E. P. Achterberg . 2010. Dissolved silver in European estuarine and coastal waters. Water Res 44:42044216. Thakur, M. , H. Gupta , and D. Singh . 2014. Histopathologicaland ultra-structural effects of nanoparticles on rat testis following 90 days (Chronic study) of repeated oral administration. J Nanobiotechnol 12:42. Tiwari, D. K. , T. Jin , and J. Behari . 2011. Dose-dependent in vivo toxicity assessment of silver nanoparticle in Wistar rats. Toxicol Mech Methods 21:1324. Trickler, W. J. , S. M. Lantz , R. C. Murdock 2011. Brain microvessel endothelial cells responses to gold microparticles: In vitro pro-inflammatory mediators and permeability. Nanotoxicology 5:479492.

Trouiller, B. , R. Relience , A. Westbrook , P. Solaimani , and R. H. Schiesll . 2009. Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Research 69:87848789. Tsuji, J. S. , A. D. Maynard , P. C. Howard , J. T. James , C. Lam , D. B. Warheit , and B. S. Annette . 2006. Research strategies for safety evaluation of nanomaterials, Part IV: Risk assessment of nanoparticles. Toxicol Sci 89(1):4250. Wang, J. , C. Chen , Y. Liu 2008b. Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183(13):7280. Wang, J. , N. Li , L. Zheng 2011. P38-Nrf-2 signaling pathway of oxidative stress in mice caused by nanoparticulate TiO2 . Biol Trace Elem Res 140(2):186197. Wang, J. , Y. Liu , F. Jiao 2008a. Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles. Toxicology 254(12), 8290. Wang, J. J. , B. J. Sanderson , and H. Wang . 2007. Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. Mutat Res 628:99106. Wang, Y. , Z. Chen , T. Ba 2013. Susceptibility of young and adult rats to the oral toxicity of titanium dioxide nanoparticles. Small 9:17421752. Warheit, D. B. , R. A. Hoke , C. Finlay , E. M. Donner , K. L. Reed , and C. M. Sayes . 2007. Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicol Lett 171(3):99110. Wei, C. , W. Y. Lin , Z. Zainal , N. E. Williams , K. Zhu , A. P. Kruzic , R. L. Smith , and K. Rajeshwar . 1994. Bactericidal activity of TiO2 photocatalyst in aqueous media: Toward a solarassisted water disinfection system. Environ Sci Technol 28(5):934938. Weir, A. , P. Westerhoff , L. Fabricius , and N. Goetz von . 2012. Titanium dioxide nanoparticles in food and personal care products. Environ Sci Technol. 2012;46(4):22422250.218 Williams, K. , J. Milner , M. D. Boudreau , K. Gokulan , C. E. Cerniglia , and S. Khare 2014. Effects of subchronic exposure of silver nanoparticles on intestinal microbiota and gutassociated immune responses in the ileum of sprague-dawley rats. Nanotoxicology 9(3):279289. Wong, K. K. , S. O. Cheung , L. Huang , J. Niu , C. Tao , and C. M. Ho . 2009. Further evidence of the anti-inflammatory effects of silver nanoparticles. Chem Med Chem 4:1129L1135. Wu, J. , W. Liu , C. Xue 2009. Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett 191(1):18. Xu, J. , H. Shi , M. Ruth , H. Yu , L. Lazar , B. Zou , C. Yang , A. Wu , and J. Zhao . 2013. Acute toxicity of intravenously administered titanium dioxide nanoparticles in mice. PLOS 8:e70618. Yamashita, K. , Y. Yoshioka , K. Higashisaka 2011. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol 6(5):321328. Yue-Wern, H. , W. Chi-Hung , and R. Aronstam 2010. Toxicity of transition metal oxide nanoparticles: Recent insights from in vitro studies. Materials 3(10):48424859. Zhang, A. and Y. Sun . 2004. Photocatalytic killing effect of TiO2 nanoparticles on Ls-174-t human colon carcinoma cells. World J Gastroenterol 10:31913193. Zhang, Q. , Y. Kusaka , K. Sato , K. Nakakuki , N. Kohyama , and K. Donaldson . 1998. Differences in the extent of inflammation caused by intratracheal exposure to three ultrafine metals: Role of free radicals. J Toxicol Environ Health Part A 53(6):423438. Zhang, R. , Y. Bai , B. Zhang , L. Chen , and B. Yan . 2012. The potential health risk of titaniananoparticles. J Haz Mat 211-212: 404413. Zhao, J. F. , N. Li , S. S. Wangy 2010. The mechanism of oxidative damage in the nephrotoxicity of mice caused by nano-anatase TiO2 . J Exp Nanosci 5(5):447462. Zini, A. 2011. Are sperm chromatin and DNA defects relevant in the clinic? Syst Biol Reprod Med 57:7885.

Influence of Nanomaterials on Human Health Andujar, P. , S. Lanone , P. Brochard , and J. Boczkowski . 2011. Respiratory effects of manufactured nanoparticles. Rev Mal Respir 28(8):e66e75. Armenti, A. E. , A. M. Zama , L. Passantino , and M. Uzumcu . 2008. Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats. Toxicol Appl Pharmacol 233(2):286296. Bahari Javan, N. , L. R. Shirmard , N. J. Omid , H. A. Javar , M. R. Tehrani , and F. A. Dorkoosh . 2016. Preparation, statistical optimisation and in vitro characterisation of poly (3hydroxybutyrate-co-3-hydroxyvalerate)/poly (lactic-co-glycolic acid) blend nanoparticles for prolonged delivery of teriparatide. J Microencapsul 33(5):460474.

Beer, C. 2016. Nanotoxicology and regulatory affairs. In Nanomedicine, eds, A. Kenneth Howard , T. Vorup-Jensen and D. Peer . New York, NY: Springer New York, pp. 279310. Bellmann, S. , D. Carlander , A. Fasano , D. Momcilovic , J. A. Scimeca , W. James Waldman , L. Gombau , L. Tsytsikova , R. Canady , and D. I. A. Pereira . 2015. Mammalian gastrointestinal tract parameters modulating the integrity, surface properties, and absorption of food-relevant nanomaterials. Wiley Interdiscip Rev Nanomed Nanobiotechnol 7(5):609622. Bennett, W. D. 2002. Rapid translocation of nanoparticles from the lung to the bloodstream? Am J Respir Crit Care Med 165(12):16711672; author reply 1672. doi: 10.1164/ajrccm.165.12.165125 Bergin, I. L. and F. A. Witzmann . 2013. Nanoparticle toxicity by the gastrointestinal route: Evidence and knowledge gaps. Int J Biomed Nanosci Nanotechnol 3(12):163210. Binnemars-Postma, K. A. , H. W. M. ten Hoopen , G. Storm , and J. Prakash . 2016. Differential uptake of nanoparticles by human M1 and M2 polarized macrophages: Protein corona as a critical determinant. Nanomedicine 11(22):28892902. Blum, J. L. , J. Q. Xiong , C. Hoffman , and J. T. Zelikoff . 2012. Cadmium associated with inhaled cadmium oxide nanoparticles impacts fetal and neonatal development and growth. Toxicol Sci 126(2):478486. kfs008. Borzelleca, J. F. 2000. Paracelsus: Herald of modern toxicology. Toxicol Sci 53(1):24. doi: 10.1093/toxsci/53.1.2 230 Bouwmeester, H. , J. Poortman , R. J. Peters , E. Wijma , E. Kramer , S. Makama , K. Puspitaninganindita , H. J. P. Marvin , A. A. C. M. Peijnenburg , and P. J. M. Hendriksen . 2011. Characterization of translocation of silver nanoparticles and effects on whole-genome gene expression using an in vitro intestinal epithelium coculture model. ACS Nano 5(5):40914103. Brenner, S. A. , N. M. Neu-Baker , C. Caglayan , and I. G. Zurbenko . 2015. Occupational exposure to airborne nanomaterials: An assessment of worker exposure to aerosolized metal oxide nanoparticles in semiconductor wastewater treatment. J Occup Environ Hyg 12(7):469481. doi: 10.1080/15459624.2015.1018515 Brouwer, D. , E. Kuijpers , C. Bekker , C. Asbach , and T. A. J. Kuhlbusch . 2014. 13 Field and Laboratory Measurements Related to Occupational and Consumer Exposures. Brouwer, D. H. , S. Spaan , M. Roff , A. Sleeuwenhoek , I. Tuinman , H. Goede , B. van Duuren-Stuurman , F. L. Filon , D. Bello , and J. W. Cherrie . 2016. Occupational dermal exposure to nanoparticles and nano-enabled products: Part 2, exploration of exposure processes and methods of assessment. Int J Hyg Environ Health 219:503512. Brunekreef, B. , R. M. J. Beelen , G. Hoek , L. J. Schouten , S. Bausch-Goldbohm , P. Fischer , B. Armstrong , E. Hughes , and M. Jerrett . 2009. Effects of long-term exposure to traffic-related air pollution on respiratory and cardiovascular mortality in the Netherlands: The NLCS-AIR study. Res Rep Health Eff Inst 139(3):571; discussion 7389. Bussy, C. , L. Methven , and K. Kostarelos . 2013. Hemotoxicity of carbon nanotubes. Adv Drug Delivery Rev 65(15):21272134. Buzea, C. , I. I. Pacheco , and K. Robbie . 2007. Nanomaterials and nanoparticles: Sources and toxicity. Biointerphases 2(4):MR17MR71. Catalan-Figueroa, J. , S. Palma-Florez , G. Alvarez , H. F. Fritz , M. O. Jara , and J. O. Morales . 2016. Nanomedicine and nanotoxicology: The pros and cons for neurodegeneration and brain cancer. Nanomedicine 11(2):171187. Chen, H. , B. W. Di Gao , M. Guan , L. Zheng , H. Ouyang , Z. Chai , Y. Zhao , and W. Feng . 2013. Broad-spectrum antibacterial activity of carbon nanotubes to human gut bacteria. Small 9(16):27352746. Chen, H. , B. Wang , Y. Zhao , and W. Feng . 2016. Nanoparticle effects on gastrointestinal microbiome. Nanomed: Nanotechnol, Biol and Med 12(2):457. Cuna, M. , M. Alonso-Sandel , C. Remunan-Lopez , J. P. Pivel , J. L. Alonso-Lebrero , and M. J. Alonso . 2006. Development of phosphorylated glucomannan-coated chitosan nanoparticles as nanocarriers for protein delivery. J Nanosci Nanotechnol 6(910):28872895. Dbrowska, A. K. , G.-M. Rotaru , S. Derler , F. Spano , M. Camenzind , S. Annaheim , R. Stmpfli , M. Schmid , and R. M. Rossi . 2016. Materials used to simulate physical properties of human skin. Skin Res Technol 22(1):314. De Angelis, I. , F. Barone , A. Zijno 2013. Comparative study of ZnO and TiO(2) nanoparticles: Physicochemical characterisation and toxicological effects on human colon carcinoma cells. Nanotoxicology 7(8):13611372. doi: 10.3109/17435390.2012.741724 De Berardis, B. , G. Civitelli , M. Condello , P. Lista , R. Pozzi , G. Arancia , and S. Meschini . 2010. Exposure to ZnO nanoparticles induces oxidative stress and cytotoxicity in human colon carcinoma cells. Toxicol Appl Pharmacol 246(3):116127. Devasena, T. and A. P. Francis . 2015. Alzheimers disease & parkinsonism. Brain 29:31. Dobson, A. W. , K. M. Erikson , and M. Aschner . 2004. Manganese neurotoxicity. Ann NY Acad Sci 1012:115128.231

Donaldson, K. , V. Stone , C. L. Tran , W. Kreyling , and P. J. Borm . 2004. Nanotoxicology. Occup Environ Med 61(9):727728. doi: 10.1136/oem.2004.013243 Dooley, K. and L. I. Zon . 2000. Zebrafish: A model system for the study of human disease. Curr Opin Genet Dev 10(3):252256. Eisenbarth, S. C. , O. R. Colegio , W. O'Connor , F. S. Sutterwala , and R. A. Flavell . 2008. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453 7198:11221126. Elsaesser, A. , and C. Vyvyan Howard . 2012. Toxicology of nanoparticles. Adv Drug Delivery Rev 64(2):129137. doi: http://dx.doi.org/10.1016/j.addr.2011.09.001 Escobar-Chvez, J. J. , A. L. Revilla-Vzquez , C. L. Domnguez-Delgado , I. M. Rodrguez-Cruz , N. Casas Alncaster , and R. Daz-Torres . 2012. Nanocarrier Systems for Transdermal Drug Delivery. Res Rep Transdermal Drug Deliv 1:317. Esmaeili, F. , M. H. Ghahremani , B. Esmaeili , M. R. Khoshayand , F. Atyabi , and R. Dinarvand . 2008. PLGA nanoparticles of different surface properties: Preparation and evaluation of their body distribution. Int J Pharm 349(1):249255. Filon, F. L. , D. Bello , J. W. Cherrie , A. Sleeuwenhoek , S. Spaan , and D. H. Brouwer . 2016. Occupational dermal exposure to nanoparticles and nano-enabled products: Part IFactors affecting skin absorption. Int J Hyg Environ Health 219(6):536544. Frhlich, E. , and E. Roblegg . 2016. Oral uptake of nanoparticles: Human relevance and the role of in vitro systems. Arch Toxicol 90(10):22972314. Fu, P. P. , Q. Xia , H.-M. Hwang , P. C. Ray , and H. Yu . 2014. Mechanisms of nanotoxicity: Generation of reactive oxygen species. J Food Drug Anal 22(1):6475. Gaiser, B. K. , T. F. Fernandes , M. A. Jepson , J. R. Lead , C. R. Tyler , M. Baalousha , A. Biswas , G. J. Britton , P. A. Cole , and B. D. Johnston . 2012. Interspecies comparisons on the uptake and toxicity of silver and cerium dioxide nanoparticles. Environ Toxicol Chem 31(1):144154. Gao, G. , Y. Ze , B. Li , X. Zhao , T. Zhang , L. Sheng , R. Hu , S. Gui , X. Sang , and Q. Sun . 2012. Ovarian dysfunction and gene-expressed characteristics of female mice caused by longterm exposure to titanium dioxide nanoparticles. J Hazard Mater 243:1927. Gehrke, H. , A. Frhmesser , J. Pelka , M. Esselen , L. L. Hecht , H. Blank , H. P. Schuchmann , D. Gerthsen , C. Marquardt , and S. Diabat . 2012. In vitro toxicity of amorphous silica nanoparticles in human colon carcinoma cells. Nanotoxicology 7(3):274293. Georgantzopoulou, A. , T. Serchi , S. Cambier , C. C. Leclercq , J. Renaut , J. Shao , M. Kruszewski , E. Lentzen , P. Grysan , and S. Eswara . 2016. Effects of silver nanoparticles and ions on a co-culture model for the gastrointestinal epithelium. Part Fibre Toxicol 13(1):1. Gerloff, K. , C. Albrecht , A. W. Boots , I. Frster , and R. P. F. Schins . 2009. Cytotoxicity and oxidative DNA damage by nanoparticles in human intestinal Caco-2 cells. Nanotoxicology 3(4):355364. doi: 10.3109/17435390903276933 Giovanni, M. , C. Y. Tay , M. I. Setyawati , J. Xie , C. N. Ong , R. Fan , J. Yue , L. Zhang , and D. T. Leong . 2015. Toxicity profiling of water contextual zinc oxide, silver, and titanium dioxide nanoparticles in human oral and gastrointestinal cell systems. Environ Toxicol 30(12):14591469. Han, D. , Y. Tian , T. Zhang , G. Ren , and Z. Yang . 2011. Nano-zinc oxide damages spatial cognition capability via over-enhanced long-term potentiation in hippocampus of Wistar rats. Int J Nanomedicine 6:14531461. doi: 10.2147/ijn.s18507 232 Hirai, T. , Y. Yoshioka , K. Higashisaka , and Y. Tsutsumi . 2016. Potential hazards of skin exposure to nanoparticles. In Biological Effects of Fibrous and Particulate Substances, eds. T. Otsuki , Y. Yoshioka , and A. Holian . Springer, Japan, pp. 123135. Ho, Y. T. , B. Poinard , and J. C. Yong Kah . 2016. Nanoparticle drug delivery systems and their use in cardiac tissue therapy. Nanomedicine 11(6):693714. Hong, F. , Nan W. , X. Zhao , Y. Tian , Y. Zhou , T. Chen , Y. Zhai , and L. Ji . 2016. Titanium dioxide nanoparticle-induced dysfunction of cardiac hemodynamics is involved in cardiac inflammation in mice. J Biomed Mater Res A 104(12):29172927. Hu, Y.-L. , and J.-Q. Gao . 2010. Potential neurotoxicity of nanoparticles. Int J Pharm 394(1):115121. Ilinskaya, A. N. , and M. A. Dobrovolskaia . 2013. Nanoparticles and the blood coagulation system. Part II: Safety concerns. Nanomedicine 8(6):969981. Jatana, S. , L. M. Callahan , A. P. Pentland , and L. A. DeLouise . 2016. Impact of cosmetic lotions on nanoparticle penetration through ex Vivo C57BL/6 hairless mouse and human skin: A comparison study. Cosmetics 3(1):6. Journeay, W. S. , and R. H. Goldman . 2014. Occupational handling of nickel nanoparticles: A case report. Am J Ind Med 57(9):10731076. Karmakar, A. , Q. Zhang , and Y. Zhang . 2014. Neurotoxicity of nanoscale materials. J Food Drug Anal 22(1):147160.

Kotchey, G. P. , S. A. Hasan , A. A. Kapralov , S. H. Ha , K. Kim , A. A. Shvedova , V. E. Kagan , and A. Star . 2012. A natural vanishing act: The enzyme-catalyzed degradation of carbon nanomaterials. Acc Chem Res 45(10):17701781. Kreyling, W. G. 2016. Discovery of unique and ENMspecific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats. Toxicol Appl Pharmacol 299:4146. Kulamarva, A. , J. Bhathena , M. Malhotra , S. Sebak , O. Nalamasu , P. Ajayan , and S. Prakash . 2008. In vitro cytotoxicity of functionalized single walled carbon nanotubes for targeted gene delivery applications. Nanotoxicology 2(4):184188. Lafuente, D. , T. Garcia , J. Blanco , D. J. Snchez , J. J. Sirvent , J. L. Domingo , and M. Gmez . 2016. Effects of oral exposure to silver nanoparticles on the sperm of rats. Reprod Toxicol 60:133139. Lai, X. , B. L. Blazer-Yost , J. W. Clack , S. L. Fears , S. Mitra , Su. A. Ntim , H. N. Ringham , and F. A. Witzmann . 2013. Protein expression profiles of intestinal epithelial co-cultures: Effect of functionalised carbon nanotube exposure. Int J Biomed Nanosci Nanotechnol 3(12):127162. Lee, J. S. , Y. C. Choi , J. H. Shin , J. H. Lee , Y. Lee , S. Y. Park , J. E. Baek , J. D. Park , K. Ahn , and I. J. Yu . 2015. Health surveillance study of workers who manufacture multi-walled carbon nanotubes. Nanotoxicology 9(6):802811. Leite-Silva, V. R. , W. Y. Sanchez , H. Studier , D. C. Liu , Y. H. Mohammed , A. M. Holmes , E. M. Ryan , I. N. Haridass , N. C. Chandrasekaran , and W. Becker . 2016. Human skin penetration and local effects of topical nano zinc oxide after occlusion and barrier impairment. Eur J Pharm Biopharm 104:140147. Li, R. , X. Wang , Z. Ji 2013. Surface charge and cellular processing of covalently functionalized multiwall carbon nanotubes determine pulmonary toxicity. ACS Nano 7(3):23522368. doi: 10.1021/nn305567s 233 Li, X. , X. Yang , L. Yuwen , W. Yang , L. Weng , Z. Teng , and L. Wang . 2016. Evaluation of toxic effects of CdTe quantum dots on the reproductive system in adult male mice. Biomaterials 96:2432. Liao, H.-Y. , Y.-T. Chung , C.-H. Lai 2014. Six-month follow-up study of health markers of nanomaterials among workers handling engineered nanomaterials. Nanotoxicology 8(sup1):100110. doi: 10.3109/17435390.2013.858793 Lieder, R. , P. H. Petersen , and . E. Sigurjnsson . 2013. Endotoxinsthe invisible companion in biomaterials research. Tissue Eng Part B Rev 19(5):391402. Liu, Q. , C. Xu , G. Ji , H. Liu , Y. Mo , D. J. Tollerud , A. Gu , and Q. Zhang . 2016. Sublethal effects of zinc oxide nanoparticles on male reproductive cells. Toxicol In Vitro 35:131138. Lobatto, M. E. , V. Fuster , Z. A. Fayad , and W. J. M. Mulder . 2011. Perspectives and opportunities for nanomedicine in the management of atherosclerosis. Nat Rev Drug Discov 10(11):835852. Loretz, B. , and A. Bernkop-Schnrch . 2007. In vitro cytotoxicity testing of non-thiolated and thiolated chitosan nanoparticles for oral gene delivery. Nanotoxicology 1(2):139148. doi: 10.1080/17435390701554200 Lutsiak, M. E. , G. S. Kwon , and J. Samuel . 2006. Biodegradable nanoparticle delivery of a Th2-biased peptide for induction of Th1 immune responses. J Pharm Pharmacol 58(6):739747. Mahmoud, N. N. , K. M. Al-Qaoud , A. G. Al-Bakri , A. M. Alkilany , and E. A. Khalil . 2016. Colloidal stability of gold nanorod solution upon exposure to excised human skin: Effect of surface chemistry and protein adsorption. Int J Biochem Cell Biol 75:223231. Mahon, E. , A. Salvati , F. B. Bombelli , I. Lynch , and K. A. Dawson . 2012. Designing the nanoparticlebiomolecule interface for targeting and therapeutic delivery. J Control Release 161(2):164174. Manolova, V. , A. Flace , M. Bauer , K. Schwarz , P. Saudan , and M. F. Bachmann . 2008. Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol 38(5):14041413. Martirosyan, A. , and Y.-J. Schneider . 2014. Engineered nanomaterials in food: Implications for food safety and consumer health. Int J Environ Res Public Health 11(6):57205750. Medina, C. , M. J. Santos-Martinez , A. Radomski , O. I. Corrigan , and M. W. Radomski . 2007. Nanoparticles: Pharmacological and toxicological significance. Br J Pharmacol 150(5):552558. Mihranyan, A. , N. Ferraz , and M. Strmme . 2012. Current status and future prospects of nanotechnology in cosmetics. Prog Mater Sci 57(5):875910. Miyani, V. A. , and M. F. Hughes . 2017. Assessment of the in vitro dermal irritation potential of cerium, silver and titanium nanoparticles in a human skin equivalent model. Cutan Ocul Toxicol 36(2):145151. Mller, P. , C. Yi , L. K. Vesterdal , P. H. Danielsen , M. Roursgaard , H. Klingberg , D. V. Christophersen , and S. Loft . 2014. 17 Carbon Nanotubes and Cardiovascular Disease. Nanotoxicology: Progress toward Nanomedicine 451:331.

Monteiro-Riviere, N. A. 2016. Safety of nanoparticle skin penetration. In Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Nanocarriers, eds, N. Dragicevic and I. H. Maibach . Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 363376.234 Moos, P. J. , K. Chung , D. Woessner , M. Honeggar , N. S. Cutler , and J. M. Veranth . 2010. ZnO particulate matter requires cell contact for toxicity in human colon cancer cells. Chem Res Toxicol 23(4):733739. doi: 10.1021/tx900203v Moos, P. J. , K. Olszewski , M. Honeggar , P. Cassidy , S. Leachman , D. Woessner , N. Shane Cutler , and J. M. Veranth . 2011. Responses of human cells to ZnO nanoparticles: A gene transcription study. Metallomics 3(11):11991211. Mytych, J. , M. Wnuk , and S. I. S. Rattan . 2016. Low doses of nanodiamonds and silica nanoparticles have beneficial hormetic effects in normal human skin fibroblasts in culture. Chemosphere 148:307315. Nunes, A. , K. T. Al-Jamal , and K. Kostarelos . 2012. Therapeutics, imaging and toxicity of nanomaterials in the central nervous system. J Control Release 161(2):290306. Oberdrster, G. , E. Oberdrster , and J. Oberdrster . 2005. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 823839. Omlor, A. J. , J. Nguyen , R. Bals , and Q. T. Dinh . 2015. Nanotechnology in respiratory medicine. Respir Res 16(1):19. doi: 10.1186/s1293101502235 Palekar, R. U. , A. P. Jallouk , G. M. Lanza , H. Pan , and S. A. Wickline . 2015. Molecular imaging of atherosclerosis with nanoparticle-based fluorinated MRI contrast agents. Nanomedicine 10(11):18171832. Paul, A. 2015. Nanocomposite hydrogels: An emerging biomimetic platform for myocardial therapy and tissue engineering. Nanomedicine 10(9):13711374. Pelka, J. , H. Gehrke , A. Rechel , M. Kappes , F. Hennrich , C. G. Hartinger , and D. Marko . 2013. DNA damaging properties of single walled carbon nanotubes in human colon carcinoma cells. Nanotoxicology 7(1):220. doi: 10.3109/17435390.2011.626536 Pietroiusti, A. , A. Magrini , and L. Campagnolo . 2016. New frontiers in nanotoxicology: Gut microbiota/microbiome-mediated effects of engineered nanomaterials. Toxicol Appl Pharmacol 299:9095. Piret, J.-P. , S. Vankoningsloo , J. Mejia , F. Nol , E. Boilan , F. Lambinon , C. C. Zouboulis , B. Masereel , S. Lucas , and C. Saout . 2012. Differential toxicity of copper (II) oxide nanoparticles of similar hydrodynamic diameter on human differentiated intestinal Caco-2 cell monolayers is correlated in part to copper release and shape. Nanotoxicology 6(7):789803. Powell, J. J. , N. Faria , E. Thomas-McKay , and L. C. Pele . 2010. Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. J Autoimmun 34(3):J226J233. Radomska, A. , J. Leszczyszyn , and M. W. Radomski . 2016. The nanopharmacology and nanotoxicology of nanomaterials: New opportunities and challenges. Adv Clin Exp Med 25(1):151. Reddy, S. T. , A. J. van der Vlies , E. Simeoni , V. Angeli , G. J. Randolph , C. P. O'Neil , L. K. Lee , M. A. Swartz , and J. A. Hubbell . 2007. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol 25(10):11591164. Rhoads, L. S. , W. T. Silkworth , M. L. Roppolo , and M. S. Whittingham . 2010. Cytotoxicity of nanostructured vanadium oxide on human cells in vitro . Toxicol In Vitro 24(1):292296. doi: 10.1016/j.tiv.2009.08.010 Sharma, L. R. , A. Subedi , and B. K. Shah . 2014. Anaphylaxis to pegylated liposomal Doxorubicin: A case report. West Indian Med J 63(4):376377. doi: 10.7727/wimj.2013.270 Shimizu, M. , H. Tainaka , T. Oba , K. Mizuo , M. Umezawa , and K. Takeda . 2009. Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters235 gene expression related to brain development in the mouse. Part Fibre Toxicol 6(1):1. Shvedova, A. A. , V. Castranova , E. R. Kisin , D. Schwegler-Berry , A. R. Murray , V. Z. Gandelsman , A. Maynard , and P. Baron . 2003. Exposure to carbon nanotube material: Assessment of nanotube cytotoxicity using human keratinocyte cells. J Toxicol Environ Health A 66(20):19091926. doi: 10.1080/713853956 Shvedova, A. A. , E. R. Kisin , N. Yanamala , A. V. Tkach , D. W. Gutkin , A. Star , G. V. Shurin , V. E. Kagan , and M. R. Shurin . 2015. MDSC and TGF are required for facilitation of tumor growth in the lungs of mice exposed to carbon nanotubes. Cancer Res 75(8):16151623. Simate, G. S. , S. E. Iyuke , S. Ndlovu , M. Heydenrych , and L. F. Walubita . 2012. Human health effects of residual carbon nanotubes and traditional water treatment chemicals in drinking water. Environ Int 39(1):3849. Skaper, S. D. , M. Floreani , M Ceccon , L. Facci , and P. Giusti . 1999. Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin. Ann NY Acad Sci 890(1):107118. Smulders, S. , J.-P. Kaiser , S. Zuin , K. L. Van Landuyt , L. Golanski , J. Vanoirbeek , P. Wick , and P. H. M. Hoet . 2012. Contamination of nanoparticles by endotoxin: Evaluation of different test methods. Part Fibre Toxicol 9(1):1.

Song, B. , Y. L. Zhang , J. Liu , X. L. Feng , T. Zhou , and L. Q. Shao . 2016. Is Neurotoxicity of metallic nanoparticles the cascades of oxidative stress? Nanoscale Res Lett 11(1):291. Stone, V. , H. Johnston , and M. J. Clift . 2007. Air pollution, ultrafine and nanoparticle toxicology: Cellular and molecular interactions. IEEE Trans Nanobioscience 6(4):331340. Sun, J. , Q. Zhang , Z. Wang , and B. Yan . 2013. Effects of nanotoxicity on female reproductivity and fetal development in animal models. Int J Mol Sci 14(5):93199337. Thubagere, A. , and B. M. Reinhard . 2010. Nanoparticle-induced apoptosis propagates through hydrogen-peroxide-mediated bystander killing: Insights from a human intestinal epithelium in vitro model. ACS Nano 4(7):36113622. doi: 10.1021/nn100389a Tkachenko, A. G. , H. Xie , D. Coleman , W. Glomm , J. Ryan , M. F. Anderson , S. Franzen , and D. L. Feldheim . 2003. Multifunctional gold nanoparticle-peptide complexes for nuclear targeting. J Am Chem Soc 125(16):47004701. van Zijverden, M. , and B. Granum . 2000. Adjuvant activity of particulate pollutants in different mouse models. Toxicology 152(1):6977. Vellayappan, M. V. , A. Balaji , A. P. Subramanian , A. A. John , S. K. Jaganathan , S. Murugesan , E. Supriyanto , and M. Yusof . 2015. Multifaceted prospects of nanocomposites for cardiovascular grafts and stents. Int J Nanomedicine 10:2785. Vetten, M. A. , C. S. Yah , T. Singh , and M. Gulumian . 2014. Challenges facing sterilization and depyrogenation of nanoparticles: Effects on structural stability and biomedical applications. Nanomed Nanotech Biol Med 10(7):13911399. Wang, L. , D. C. Davidson , V. Castranova , and Y. Rojanasakul . 2016a. Pulmonary effects of carbon nanomaterials. In Biomedical Applications and Toxicology of Carbon Nanomaterials, eds. C. Chen and H. Wang . Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, pp. 163193. Wang, Y.-J. , M. Larsson , W.-T. Huang , S.-H. Chiou , S. J. Nicholls , J.-I. Chao , and D.-M. Liu . 2016b. The use of polymer-based nanoparticles and nanostructured materials in treatment and diagnosis of cardiovascular diseases: Recent advances and emerging designs. Prog Polym Sci 57:153178.236 Warheit, D. B. , T. R. Webb , V. L. Colvin , K. L. Reed , and C. M. Sayes . 2007. Pulmonary bioassay studies with nanoscale and fine-quartz particles in rats: Toxicity is not dependent upon particle size but on surface characteristics. Toxicol Sci 95(1):270280. Wells, P. G. , Y. Bhuller , C. S. Chen , W. Jeng , S. Kasapinovic , J. C. Kennedy , P. M. Kim , R. R. Laposa , G. P. McCallum , and C. J. Nicol . 2005. Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicol Appl Pharmacol 207(2):354366. Wick, P. , A. Malek , P. Manser , D. Meili , X. Maeder-Althaus , L. Diener , P.-A. Diener , A. Zisch , H. F. Krug , and U. von Mandach . 2010. Barrier capacity of human placenta for nanosized materials. Environ Health Perspect(Online) 118(3):432. Williams, K. M. , K. Gokulan , C. E. Cerniglia , and S. Khare . 2016. Size and dose dependent effects of silver nanoparticle exposure on intestinal permeability in an in vitro model of the human gut epithelium. J Nanobiotechnology 14(1):62. doi: 10.1186/s12951-016-0214-9 Working, IARC Monograph . 2014. Carcinogenicity of fluoro-edenite, silicon carbide fibres and whiskers, and carbon nanotubes. Ann Ist Super Sanita 50:111118. Wright, C. , A. K. V. Iyer , L. Wang , N. Wu , J. S. Yakisich , Y. Rojanasakul , and N. Azad . 2017. Effects of titanium dioxide nanoparticles on human keratinocytes. Drug Chem Toxicol 40(1):90100. Xiang, S. D. , A. Scholzen , G. Minigo , C. David , V. Apostolopoulos , P. L. Mottram , and M. Plebanski . 2006. Pathogen recognition and development of particulate vaccines: Does size matter? Methods 40(1):19. Xu, J. , D. B. Alexander , M. Futakuchi , T. Numano , K. Fukamachi , M. Suzui , T. Omori , J. Kanno , A. Hirose , and H. Tsuda . 2014. Size- and shape-dependent pleural translocation, deposition, fibrogenesis, and mesothelial proliferation by multiwalled carbon nanotubes. Cancer Sci 105(7):763769. doi: 10.1111/cas.12437 Yamashita, K. , Y. Yoshioka , K. Higashisaka , K. Mimura , Y. Morishita , M. Nozaki , T. Yoshida , T. Ogura , H. Nabeshi , and K. Naga . 2011. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol 6(5):321328. Yang, K.-C. , J.-H. Zheng , Y.-L. Chen , K.-C. Lee , and E.-C. Cho . 2016a. Carboxyfullerene decorated titanium dioxide nanomaterials for reactive oxygen species scavenging activities. RSC Adv 6(58):5302553033. Yang, Y. , J. J. Faust , J. Schoepf , K. Hristovski , D. G. Capco , P. Herckes , and P. Westerhoff . 2016b. Survey of food-grade silica dioxide nanomaterial occurrence, characterization, human gut impacts and fate across its lifecycle. Sci Total Environ 565:902912. Yu, X. , F. Hong , and Y.-Q. Zhang . 2016. Bio-effect of nanoparticles in the cardiovascular system. J Biomed Mater Res A 104(11):28812897.

Zhang, R. , Y. Dai , X. Zhang , Y. Niu , T. Meng , Y. Li , H. Duan , P. Bin , M. Ye , and X. Jia . 2014. Reduced pulmonary function and increased pro-inflammatory cytokines in nanoscale carbon black-exposed workers. Part Fibre Toxicol 11(1):1. Zhang, T. , M. Xu , L. He , K. Xi , M. Gu , and Z. Jiang . 2008. Synthesis, characterization and cytotoxicity of phosphoryl choline-grafted water-soluble carbon nanotubes. Carbon 46(13):17821791.

Mechanisms of Nanotoxicity to Cells, Animals, and Humans Afeseh Ngwa, H. , A. Kanthasamy , Y. Gu , N. Fang , V. Anantharam , and A. G. Kanthasamy . 2011. Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells. Toxicol Appl Pharmacol 256(3):227240. Ahamed, M. , R. Posgai , T. J. Gorey , M. Nielsen , S. M. Hussain , and J. J. Rowe . 2010. Silver nanoparticles induced heat shock protein 70, oxidative stress and apoptosis in Drosophila melanogaster. Toxicol Appl Pharmacol 242(3):263269. Akhtar, M. J. , M. Ahamed , S. Kumar , M. M. Khan , J. Ahmad , and S. A. Alrokayan . 2012. Zinc oxide nanoparticles selectively induce apoptosis in human cancer cells through reactive oxygen species. Int J Nanomedicine 7:845857. Allegri, M. , M. G. Bianchi , M. Chiu , J. Varet , A. L. Costa , S. Ortelli , M. Blosi , O. Bussolati , C. A. Poland , and E. Bergamaschi . 2016. Shape-related toxicity of titanium dioxide nanofibres. PloS one 11(3):e0151365. Amaral, J. D. , J. M. Xavier , C. J. Steer , and C. M. Rodrigues . 2010. The role of p53 in apoptosis. Discov Med 9(45):145152. Arthur, J. S. , and S. C. Ley . 2013. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13(9):679692. AshaRani, P. V. , G. Low Kah Mun , M. P. Hande , and S. Valiyaveettil . 2009. Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano 3(2):279290. Avalos, A. , A. I. Haza , D. Mateo , and P. Morales . 2014. Cytotoxicity and ROS production of manufactured silver nanoparticles of different sizes in hepatoma and leukemia cells. J Appl Toxicol 34(4):413423. Baktur, R. , H. Patel , and S. Kwon . 2011. Effect of exposure conditions on SWCNT-induced inflammatory response in human alveolar epithelial cells. Toxicol In Vitro 25(5):11531160. Barillet, S. , M. L. Jugan , M. Laye , Y. Leconte , N. Herlin-Boime , C. Reynaud , and M. Carriere . 2010. In vitro evaluation of SiC nanoparticles impact on A549 pulmonary cells: Cyto-, genotoxicity and oxidative stress. Toxicol Lett 198(3):324330. Baweja, L. , D. Gurbani , R. Shanker , A. K. Pandey , V. Subramanian , and A. Dhawan . 2011. C60-fullerene binds with the ATP binding domain of human DNA topoiosmerase II alpha. J Biomed Nanotechnol 7(1):177178. Beer, C. , R. Foldbjerg , Y. Hayashi , D. S. Sutherland , and H. Autrup . 2012. Toxicity of silver nanoparticlesnanoparticle or silver ion? Toxicol Lett 208(3):286292. Berndt, C. , T. Kurz , M. Selenius , A. P. Fernandes , M. R. Edgren , and U. T. Brunk . 2010. Chelation of lysosomal iron protects against ionizing radiation. Biochem J 432(2):295301. Blanco, J. , D. Lafuente , M. Gomez , T. Garcia , J. L. Domingo , and D. J. Sanchez . 2016. Polyvinyl pyrrolidone-coated silver nanoparticles in a human lung cancer cells: Time- and dosedependent influence over p53 and caspase-3 protein expression and epigenetic effects. Arch Toxicol 91(2):651666. Bulavin, D. V. , S. Saito , M. C. Hollander , K. Sakaguchi , C. W. Anderson , E. Appella , and A. J. Fornace, Jr. 1999. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J 18(23):68456854.273 Capasso, L. , M. Camatini , and M. Gualtieri . 2014. Nickel oxide nanoparticles induce inflammation and genotoxic effect in lung epithelial cells. Toxicol Lett 226(1):2834. Caracciolo, G. , O. C. Farokhzad , and M. Mahmoudi . 2016. Biological identity of nanoparticles in vivo: Clinical implications of the protein corona. Trends Biotechnol 35(3):257264. Carroll, M. V. and R. B. Sim . 2011. Complement in health and disease. Adv Drug Deliv Rev 63(12):965975. Chang, Y. Y. and T. P. Neufeld . 2009. An Atg1/Atg13 complex with multiple roles in TORmediated autophagy regulation. Mol Biol Cell 20(7):20042014. doi: 10.1091/mbc.E0812-1250 Chen, L. B. 1988. Mitochondrial membrane potential in living cells. Annu Rev Cell Dev Biol 4(1):155181. Choi, A. O. , S. E. Brown , M. Szyf , and D. Maysinger . 2008. Quantum dot-induced epigenetic and genotoxic changes in human breast cancer cells. J Mol Med(Berl) 86(3):291302.

Choi, A. O. , S. J. Cho , J. Desbarats , J. Lovric , and D. Maysinger . 2007. Quantum dotinduced cell death involves Fas upregulation and lipid peroxidation in human neuroblastoma cells. J Nanobiotechnology 5:1. Choi, J. E. , S. Kim , J. H. Ahn , P. Youn , J. S. Kang , K. Park , J. Yi , and D. Y. Ryu . 2010. Induction of oxidative stress and apoptosis by silver nanoparticles in the liver of adult zebrafish. Aquat Toxicol 100(2):151159. Choi, S. J. , H. J. Paek , and J. Yu . 2015. Oxidative stress by layered double hydroxide nanoparticles via an SFK-JNK and p38-NF-kappaB signaling pathway mediates induction of interleukin-6 and interleukin-8 in human lung epithelial cells. Int J Nanomedicine 10:32173229. Cohen, G. M. 1997. Caspases: The executioners of apoptosis. Biochem J 326(Pt 1):116. Corbo, C. , R. Molinaro , A. Parodi , N. E. Toledano Furman , F. Salvatore , and E. Tasciotti . 2016. The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery. Nanomedicine(Lond) 11(1):81100. Cory, S. and J. M. Adams . 2002. The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647656. Couto, D. , M. Freitas , G. Porto , M. A. Lopez-Quintela , J. Rivas , P. Freitas , F. Carvalho , and E. Fernandes . 2015. Polyacrylic acid-coated and non-coated iron oxide nanoparticles induce cytokine activation in human blood cells through TAK1, p38 MAPK and JNK pro-inflammatory pathways. Arch Toxicol 89(10):17591769. Czabotar, P. E. , G. Lessene , A. Strasser , and J. M. Adams . 2014. Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat Rev Mol Cell Biol 15(1):4963. Dalle-Donne, I. , R. Rossi , D. Giustarini , A. Milzani , and R. Colombo . 2003. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329(12):2338. De Simone, U. , D. Lonati , A. Ronchi , and T. Coccini . 2016. Brief exposure to nanosized and bulk titanium dioxide forms induces subtle changes in human D384 astrocytes. Toxicol Lett 254:821. Deng, Z. J. , M. Liang , M. Monteiro , I. Toth , and R. F. Minchin . 2011. Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nat Nanotechnol 6(1):3944.274 Dowhan, W. 1997. Molecular basis for membrane phospholipid diversity: Why are there so many lipids? Annu Rev Biochem 66:199232. Driessen, M. D. , S. Mues , A. Vennemann 2015. Proteomic analysis of protein carbonylation: A useful tool to unravel nanoparticle toxicity mechanisms. Part Fibre Toxicol 12:36. Duan, J. , Y. Yu , Y. Yu , Y. Li , J. Wang , W. Geng , L. Jiang , Q. Li , X. Zhou , and Z. Sun . 2014. Silica nanoparticles induce autophagy and endothelial dysfunction via the PI3K/Akt/mTOR signaling pathway. Int J Nanomedicine 9:51315141. Duyckaerts, C. , B. Delatour , and M. C. Potier . 2009. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118(1):536. Elmore, S. 2007. Apoptosis: A review of programmed cell death. Toxicol Pathol 35(4):495516. Eom, H. J. , and J. Choi . 2010. p38 MAPK activation, DNA damage, cell cycle arrest and apoptosis as mechanisms of toxicity of silver nanoparticles in Jurkat T cells. Environ Sci Technol 44(21):83378342. Ershova, E. S. , V. A. Sergeeva , A. I. Chausheva 2016. Toxic and DNA damaging effects of a functionalized fullerene in human embryonic lung fibroblasts. Mutat Res Genet Toxicol Environ Mutagen 805:4657. Fadok, V. A. , A. de Cathelineau , D. L. Daleke , P. M. Henson , and D. L. Bratton . 2001. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J Biol Chem 276(2):10711077. Favaloro, B. , N. Allocati , V. Graziano , C. Di Ilio , and V. De Laurenzi . 2012. Role of apoptosis in disease. Aging(Albany NY) 4(5):330349. Fu, P. P. , Q. Xia , H.-M. Hwang , P. C. Ray , and H. Yu . 2014. Mechanisms of nanotoxicity: Generation of reactive oxygen species. J Food Drug Anal 22(1):6475. Fubini, B. and A. Hubbard . 2003. Reactive oxygen species(ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic Biol Med 34(12):15071516. Gheshlaghi, Z. N. , G. H. Riazi , S. Ahmadian , M. Ghafari , and R. Mahinpour . 2008. Toxicity and interaction of titanium dioxide nanoparticles with microtubule protein. Acta Biochim Biophys Sin (Shanghai) 40(9):777782. Gilardino, A. , F. Catalano , F. A. Ruffinatti , G. Alberto , B. Nilius , S. Antoniotti , G. Martra , and D. Lovisolo . 2015. Interaction of SiO2 nanoparticles with neuronal cells: Ionic mechanisms involved in the perturbation of calcium homeostasis. Int J Biochem Cell Biol 66:101111. Giovanni, M. , J. Yue , L. Zhang , J. Xie , C. N. Ong , and D. T. Leong . 2015. Pro-inflammatory responses of RAW264.7 macrophages when treated with ultralow concentrations of silver, titanium dioxide, and zinc oxide nanoparticles. J Hazard Mater 297:146152.

Greenhalgh, D. G. 1998. The role of apoptosis in wound healing. Int J Biochem Cell Biol 30(9):10191030. Gudmann, N. S. , N. U. Hansen , A. C. Jensen , M. A. Karsdal , and A. S. Siebuhr . 2015. Biological relevance of citrullinations: Diagnostic, prognostic and therapeutic options. Autoimmunity 48(2):7379. Guo, C. , Y. Xia , P. Niu , L. Jiang , J. Duan , Y. Yu , X. Zhou , Y. Li , and Z. Sun . 2015. Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-kappaB signaling. Int J Nanomedicine 10:14631477.275 Gyorgy, B. , E. Toth , E. Tarcsa , A. Falus , and E. I. Buzas . 2006. Citrullination: A posttranslational modification in health and disease. Int J Biochem Cell Biol 38(10):16621677. Hackenberg, S. , A. Scherzed , M. Kessler , S. Hummel , A. Technau , K. Froelich , C. Ginzkey , C. Koehler , R. Hagen , and N. Kleinsasser . 2011a. Silver nanoparticles: Evaluation of DNA damage, toxicity and functional impairment in human mesenchymal stem cells. Toxicol Lett 201(1):2733. Hackenberg, S. , A. Scherzed , A. Technau , M. Kessler , K. Froelich , C. Ginzkey , C. Koehler , M. Burghartz , R. Hagen , and N. Kleinsasser . 2011b. Cytotoxic, genotoxic and proinflammatory effects of zinc oxide nanoparticles in human nasal mucosa cells in vitro . Toxicol In Vitro 25(3):657663. Hadrup, N. , K. Loeschner , A. Mortensen , A. K. Sharma , K. Qvortrup , E. H. Larsen , and H. R. Lam . 2012. The similar neurotoxic effects of nanoparticulate and ionic silver in vivo and in vitro . Neurotoxicology 33(3):416423. Halamoda Kenzaoui, B. , C. Chapuis Bernasconi , S. Guney-Ayra , and L. Juillerat-Jeanneret . 2012. Induction of oxidative stress, lysosome activation and autophagy by nanoparticles in human brain-derived endothelial cells. Biochem J 441(3):813821. Hanot-Roy, M. , E. Tubeuf , A. Guilbert , A. Bado-Nilles , P. Vigneron , B. Trouiller , A. Braun , and G. Lacroix . 2016. Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro . Toxicol In Vitro 33:125135. He, C. and D. J. Klionsky . 2009. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:6793. He, X. , S. H. Young , D. Schwegler-Berry , W. P. Chisholm , J. E. Fernback , and Q. Ma . 2011. Multiwalled carbon nanotubes induce a fibrogenic response by stimulating reactive oxygen species production, activating NF-kappaB signaling, and promoting fibroblast-to-myofibroblast transformation. Chem Res Toxicol 24(12):22372248. Hsu, H. , J. Xiong , and D. V. Goeddel . 1995. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 81(4):495504. Huang, C. C. , R. S. Aronstam , D. R. Chen , and Y. W. Huang . 2010. Oxidative stress, calcium homeostasis, and altered gene expression in human lung epithelial cells exposed to ZnO nanoparticles. Toxicol In Vitro 24(1):4555. Huang, J. and B. D. Manning . 2008. The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. Biochem J 412(2):179190. Huang, S. , P. J. Chueh , Y. W. Lin , T. S. Shih , and S. M. Chuang . 2009. Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nanoTiO2 long-term exposure. Toxicol Appl Pharmacol 241(2):182194. Hussain, S. , L. C. Thomassen , I. Ferecatu , M. C. Borot , K. Andreau , J. A. Martens , J. Fleury , A. Baeza-Squiban , F. Marano , and S. Boland . 2010. Carbon black and titanium dioxide nanoparticles elicit distinct apoptotic pathways in bronchial epithelial cells. Part Fibre Toxicol 7:10. Inoki, K. , T. Zhu , and K. L. Guan . 2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577590. Inoue, K. , H. Takano , R. Yanagisawa , S. Hirano , M. Sakurai , A. Shimada , and T. Yoshikawa . 2006. Effects of airway exposure to nanoparticles on lung inflammation induced by bacterial endotoxin in mice. Environ Health Perspect 114(9):13251330.276 Jain, A. , S. Ranjan , N. Dasgupta , and C. Ramalingam . 2017. Nanomaterials in food and agriculture: An overview on their safety concerns and regulatory issues. Crit Rev Food Sci Nutr. In Press. doi: 10.1080/10408398.2016.1160363. Janeway, C. A., Jr , P. Travers , and M. Walport . 2012. Immunobiology. (8th Ed). New York: Garland Science. Johnson-Lyles, D. N. , K. Peifley , S. Lockett , B. W. Neun , M. Hansen , J. Clogston , S. T. Stern , and S. E. McNeil . 2010. Fullerenol cytotoxicity in kidney cells is associated with cytoskeleton disruption, autophagic vacuole accumulation, and mitochondrial dysfunction. Toxicol Appl Pharmacol 248(3):249258.

Kabeya, Y. , Y. Kamada , M. Baba , H. Takikawa , M. Sasaki , and Y. Ohsumi . 2005. Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 16(5):25442553. Kang, S. J. , B. M. Kim , Y. J. Lee , and H. W. Chung . 2008. Titanium dioxide nanoparticles trigger p53-mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen 49(5):399405. Kang, S. J. , B. M. Kim , Y. J. Lee , S. H. Hong , and H. W. Chung . 2009. Titanium dioxide nanoparticles induce apoptosis through the JNK/p38-caspase-8-Bid pathway in phytohemagglutinin-stimulated human lymphocytes. Biochem Biophys Res Commun 386(4):682687. Karlsson, H. L. , P. Cronholm , J. Gustafsson , and L. Moller . 2008. Copper oxide nanoparticles are highly toxic: A comparison between metal oxide nanoparticles and carbon nanotubes. Chem Res Toxicol 21(9):17261732. Kermanizadeh, A. , S. Vranic , S. Boland , K. Moreau , A. Baeza-Squiban , B. K. Gaiser , L. A. Andrzejczuk , and V. Stone . 2013. An in vitro assessment of panel of engineered nanomaterials using a human renal cell line: Cytotoxicity, pro-inflammatory response, oxidative stress and genotoxicity. BMC Nephrol 14:96. doi: 10.1186/1471-2369-14-96 Khan, M. I. , A. Mohammad , G. Patil , S. A. Naqvi , L. K. Chauhan , and I. Ahmad . 2012. Induction of ROS, mitochondrial damage and autophagy in lung epithelial cancer cells by iron oxide nanoparticles. Biomaterials 33(5):14771488. Kim, E. , P. Goraksha-Hicks , L. Li , T. P. Neufeld , and K. L. Guan . 2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10(8):935945. doi: 10.1038/ncb1753 Kothakota, S. , T. Azuma , C. Reinhard 1997. Caspase-3-generated fragment of gelsolin: Effector of morphological change in apoptosis. Science 278(5336):294298. Lane, D. P. 1992. Cancer. p53, guardian of the genome. Nature 358(6381):1516. Lee, J. H. , K. E. Cha , M. S. Kim , H. W. Hong , D. J. Chung , G. Ryu , and H. Myung . 2009. Nanosized polyamidoamine (PAMAM) dendrimer-induced apoptosis mediated by mitochondrial dysfunction. Toxicol Lett 190(2):202207. Lee, Y. H. , F. Y. Cheng , H. W. Chiu , J. C. Tsai , C. Y. Fang , C. W. Chen , and Y. J. Wang . 2014. Cytotoxicity, oxidative stress, apoptosis and the autophagic effects of silver nanoparticles in mouse embryonic fibroblasts. Biomaterials 35(16):47064715. Lee, Y. K. , E. J. Choi , T. J. Webster , S. H. Kim , and D. Khang . 2015. Effect of the protein corona on nanoparticles for modulating cytotoxicity and immunotoxicity. Int J Nanomedicine 10:97113. doi: 10.2147/IJN.S72998 Lesniak, A. , F. Fenaroli , M. P. Monopoli , C. Aberg , K. A. Dawson , and A. Salvati . 2012. Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells. ACS Nano 6(7):58455857. doi: 10.1021/nn300223w 277 Li, C. , H. Liu , Y. Sun 2009. PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway. J Mol Cell Biol 1(1):3745. doi: 10.1093/jmcb/mjp002 Li, H. , H. Zhu , C. J. Xu , and J. Yuan . 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94(4):491501. Li, J. J. , D. Hartono , C. N. Ong , B. H. Bay , and L. Y. Yung . 2010. Autophagy and oxidative stress associated with gold nanoparticles. Biomaterials 31(23):59966003. Li, Y. , H. Zhu , S. Wang , X. Qian , J. Fan , Z. Wang , P. Song , X. Zhang , W. Lu , and D. Ju . 2015. Interplay of oxidative stress and autophagy in PAMAM dendrimers-induced neuronal cell death. Theranostics 5(12):13631377. doi: 10.7150/thno.13181 Liang, S. , K. Sun , Y. Wang , S. Dong , C. Wang , L. Liu , and Y. Wu . 2016. Role of CytC/caspases-9,3, Bax/Bcl-2 and the FAS death receptor pathway in apoptosis induced by zinc oxide nanoparticles in human aortic endothelial cells and the protective effect by alpha-lipoic acid. Chem Biol Interact 258:4051. doi: 10.1016/j.cbi.2016.08.013 Liang, X. H. , S. Jackson , M. Seaman , K. Brown , B. Kempkes , H. Hibshoosh , and B. Levine . 1999. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672676. Lim, D. , J. Y. Roh , H. J. Eom , J. Y. Choi , J. Hyun , and J. Choi . 2012. Oxidative stressrelated PMK-1 P38 MAPK activation as a mechanism for toxicity of silver nanoparticles to reproduction in the nematode Caenorhabditis elegans. Environ Toxicol Chem 31(3):585592. Lin, W. , Y. W. Huang , X. D. Zhou , and Y. Ma . 2006. Toxicity of cerium oxide nanoparticles in human lung cancer cells. Int J Toxicol 25(6):451457. doi: 10.1080/10915810600959543 Liu, H. L. , Y. L. Zhang , N. Yang 2011. A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt-TSC2-mTOR signaling. Cell Death Dis 2:e159. doi: 10.1038/cddis.2011.27 Liu, L. Z. , M. Ding , J. Z. Zheng , Y. Zhu , B. A. Fenderson , B. Li , J. J. Yu , and B. H. Jiang . 2015. Tungsten carbide-cobalt nanoparticles induce reactive oxygen species, AKT, ERK, AP-1,

NF-kappaB, VEGF, and angiogenesis. Biol Trace Elem Res 166(1):5765. Long, X. , Y. Lin , S. Ortiz-Vega , K. Yonezawa , and J. Avruch . 2005. Rheb binds and regulates the mTOR kinase. Curr Biol 15(8):702713. doi: 10.1016/j.cub.2005.02.053 Loza, K. , J. Diendorf , C. Sengstock , L. Ruiz-Gonzalez , J. M. Gonzalez-Calbet , M. ValletRegi , M. Kller , and M. Epple . 2014. The dissolution and biological effects of silver nanoparticles in biological media. Journal of Materials Chemistry B 2(12):16341643. Lu, X. , J. Qian , H. Zhou , Q. Gan , W. Tang , J. Lu , Y. Yuan , and C. Liu . 2011. In vitro cytotoxicity and induction of apoptosis by silica nanoparticles in human HepG2 hepatoma cells. Int J Nanomedicine 6:18891901. doi: 10.2147/IJN.S24005 Lucarelli, M. , A. M. Gatti , G. Savarino , P. Quattroni , L. Martinelli , E. Monari , and D. Boraschi . 2004. Innate defence functions of macrophages can be biased by nano-sized ceramic and metallic particles. Eur Cytokine Netw 15(4):339346. Lund, L. R. , J. Romer , N. Thomasset , H. Solberg , C. Pyke , M. J. Bissell , K. Dano , and Z. Werb . 1996. Two distinct phases of apoptosis in mammary gland involution: Proteinaseindependent and -dependent pathways. Development 122(1):181193.278 Ma, X. , Y. Wu , S. Jin , Y. Tian , X. Zhang , Y. Zhao , L. Yu , and X. J. Liang . 2011. Gold nanoparticles induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment. ACS Nano 5(11):86298639. doi: 10.1021/nn202155y Manke, A. , L. Wang , and Y. Rojanasakul . 2013. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int 2013:942916. doi: 10.1155/2013/942916 Manning, B. D. , A. R. Tee , M. N. Logsdon , J. Blenis , and L. C. Cantley . 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10(1):151162. Mao, B.-H. , J.-C. Tsai , C.-W. Chen , S.-J. Yan , and Y.-J. Wang . 2016. Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy. Nanotoxicology 10(8):10211040. Meena, R. , M. Rani , R. Pal , and P. Rajamani . 2012. Nano-TiO2-induced apoptosis by oxidative stress-mediated DNA damage and activation of p53 in human embryonic kidney cells. Appl Biochem Biotechnol 167(4):791808. doi: 10.1007/s12010-012-9699-3 Mendoza, A. , J. A. Torres-Hernandez , J. G. Ault , J. H. Pedersen-Lane , D. Gao , and D. A. Lawrence . 2014. Silica nanoparticles induce oxidative stress and inflammation of human peripheral blood mononuclear cells. Cell Stress Chaperones 19(6):777790. Meyer, K. , P. Rajanahalli , M. Ahamed , J. J. Rowe , and Y. Hong . 2011. ZnO nanoparticles induce apoptosis in human dermal fibroblasts via p53 and p38 pathways. Toxicol In Vitro 25(8):17211726. Mohamed, B. M. , N. K. Verma , A. M. Davies 2012. Citrullination of proteins: A common posttranslational modification pathway induced by different nanoparticles in vitro and in vivo . Nanomedicine (Lond) 7(8):11811195. Monick, M. M. , L. S. Powers , K. Walters , N. Lovan , M. Zhang , A. Gerke , S. Hansdottir , and G. W. Hunninghake . 2010. Identification of an autophagy defect in smokers alveolar macrophages. J Immunol 185(9):54255435. Montgomery, R. R. , P. Webster , and I. Mellman . 1991. Accumulation of indigestible substances reduces fusion competence of macrophage lysosomes. J Immunol 147(9):30873095. Mytych, J. , A. Lewinska , J. Zebrowski , and M. Wnuk . 2015. Gold nanoparticles promote oxidant-mediated activation of NF-kappaB and 53BP1 recruitment-based adaptive response in human astrocytes. Biomed Res Int 2015:304575. Nel, A. E. , L. Madler , D. Velegol , T. Xia , E. M. Hoek , P. Somasundaran , F. Klaessig , V. Castranova , and M. Thompson . 2009. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8(7):543557. Nezis, I. P. , A. Simonsen , A. P. Sagona , K. Finley , S. Gaumer , D. Contamine , T. E. Rusten , H. Stenmark , and A. Brech . 2008. Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol 180(6):10651071. Nobukuni, T. , M. Joaquin , M. Roccio 2005. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A 102(40):1423814243. Noda, T. , and Y. Ohsumi . 1998. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273(7):39633966.279 Oberdrster, G. , E. Oberdrster , and J. Oberdrster . 2005. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823839. Orazizadeh, M. , E. Daneshi , M. Hashemitmar , F. Absalan , and L. Khorsandi . 2015. Protective effect of beta-carotene against titanium dioxide nanoparticles induced apoptosis in mouse testicular tissue. Andrologia 47(7):816825. doi: 10.1111/and.12336

Orrenius, S. , M. J. McCabe, Jr. , and P. Nicotera . 1992. Ca(2+)-dependent mechanisms of cytotoxicity and programmed cell death. Toxicol Lett 6465:357364. Pacurari, M. , X. J. Yin , J. Zhao , M. Ding , S. S. Leonard , D. Schwegler-Berry , B. S. Ducatman , D. Sbarra , M. D. Hoover , V. Castranova , and V. Vallyathan . 2008. Raw singlewall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells. Environ Health Perspect 116(9):12111217. Pankiv, S. , T. H. Clausen , T. Lamark , A. Brech , J. A. Bruun , H. Outzen , A. Overvatn , G. Bjorkoy , and T. Johansen . 2007. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):2413124145. Park, E. J. , and K. Park . 2009. Oxidative stress and pro-inflammatory responses induced by silica nanoparticles in vivo and in vitro . Toxicol Lett 184(1):1825. Park, E. J. , J. Yi , K. H. Chung , D. Y. Ryu , J. Choi , and K. Park . 2008. Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. Toxicol Lett 180(3):222229. doi: 10.1016/j.toxlet.2008.06.869 Park, J. W. , I. C. Lee , N. R. Shin , C. M. Jeon , O. K. Kwon , J. W. Ko , J. C. Kim , S. R. Oh , I. S. Shin , and K. S. Ahn . 2016. Copper oxide nanoparticles aggravate airway inflammation and mucus production in asthmatic mice via MAPK signaling. Nanotoxicology 10(4):445452. Parveen, A. , S. H. Rizvi , S. F. Mahdi , I. Ahmad , P. P. Singh , and A. A. Mahdi . 2015. Intranasal exposure to silica nanoparticles induce alterations in pro-inflammatory environment of rat brain: Involvement of oxidative stress. Toxicol Ind Health 33(2):119132. doi: 10.1177/0748233715602985 Petrache Voicu, S. N. , D. Dinu , C. Sima , A. Hermenean , A. Ardelean , E. Codrici , M. S. Stan , O. Zarnescu , and A. Dinischiotu . 2015. Silica nanoparticles induce oxidative stress and autophagy but not apoptosis in the MRC-5 cell line. Int J Mol Sci 16(12):2939829416. Piao, M. J. , K. A. Kang , I. K. Lee , H. S. Kim , S. Kim , J. Y. Choi , J. Choi , and J. W. Hyun . 2011. Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis. Toxicol Lett 201(1):92100. doi: 10.1016/j.toxlet.2010.12.010 Priault, M. , B. Salin , J. Schaeffer , F. M. Vallette , J. P. di Rago , and J. C. Martinou . 2005. Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ 12(12):16131621. Qu, C. , L. Wang , J. He , J. Tan , W. Liu , S. Zhang , C. Zhang , Z. Wang , S. Jiao , S. Liu , and G. Jiang . 2012. Carbon nanotubes provoke inflammation by inducing the pro-inflammatory genes IL-1beta and IL-6. Gene 493(1):912. doi: 10.1016/j.gene.2011.11.046 Radu, M. , M. C. Munteanu , S. Petrache , A. I. Serban , D. Dinu , A. Hermenean , C. Sima , and A. Dinischiotu . 2010. Depletion of intracellular glutathione and increased lipid peroxidation mediate cytotoxicity of hematite nanoparticles in MRC-5 cells. Acta Biochim Pol 57(3):355360.280 Rahman, I. , S. K. Biswas , L. A. Jimenez , M. Torres , and H. J. Forman . 2005. Glutathione, stress responses, and redox signaling in lung inflammation. Antioxid Redox Signal 7(12):4259. Ranjan, S. , N. Dasgupta , B. Rajendran , G. S. Avadhani , and C. Ramalingam . 2016. Microwave-irradiation-assisted hybrid chemical approach for titanium dioxide nanoparticle synthesis: Microbial and cytotoxicological evaluation. Environ Sci Poll Res 23(12):1228712302. doi: doi.org/10.1007/s11356-016-6440-8 Renehan, A. G. , C. Booth , and C. S. Potten . 2001. What is apoptosis, and why is it important? BMJ 322(7301):1536. Rice, K. M. , S. K. Nalabotu , N. D. Manne , M. B. Kolli , G. Nandyala , R. Arvapalli , J. Y. Ma , and E. R. Blough . 2015. Exposure to cerium oxide nanoparticles is associated with activation of mitogen-activated protein kinases signaling and apoptosis in rat lungs. J Prev Med Public Health 48(3):132141. doi: 10.3961/jpmph.15.006 Ritz, S. , S. Schottler , N. Kotman 2015. Protein corona of nanoparticles: Distinct proteins regulate the cellular uptake. Biomacromolecules 16(4):13111321. Roy, R. , S. K. Singh , L. K. Chauhan , M. Das , A. Tripathi , and P. D. Dwivedi . 2014a. Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition. Toxicol Lett 227(1):2940. doi: 10.1016/j.toxlet.2014.02.024 Roy, R. , S. K. Singh , M. Das , A. Tripathi , and P. D. Dwivedi . 2014b. Toll-like receptor 6 mediated inflammatory and functional responses of zinc oxide nanoparticles primed macrophages. Immunology 142(3):453464. Saelens, X. , N. Festjens , L. Vande Walle , M. van Gurp , G. van Loo , and P. Vandenabeele . 2004. Toxic proteins released from mitochondria in cell death. Oncogene 23(16):28612874. Sakahira, H. , M. Enari , and S. Nagata . 1998. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391(6662):9699.

Salvador-Morales, C. , E. Flahaut , E. Sim , J. Sloan , M. L. Green , and R. B. Sim . 2006. Complement activation and protein adsorption by carbon nanotubes. Mol Immunol 43(3):193201. Sarkar, A. , J. Das , P. Manna , and P. C. Sil . 2011. Nano-copper induces oxidative stress and apoptosis in kidney via both extrinsic and intrinsic pathways. Toxicology 290(23):208217. Sarkar, A. , M. Ghosh , and P. C. Sil . 2014. Nanotoxicity: Oxidative stress mediated toxicity of metal and metal oxide nanoparticles. J Nanosci Nanotechnol 14(1):730743. Sayes, C. M. , A. M. Gobin , K. D. Ausman , J. Mendez , J. L. West , and V. L. Colvin . 2005. Nano-C60 cytotoxicity is due to lipid peroxidation. Biomaterials 26(36):75877595. Scherz-Shouval, R. , E. Shvets , E. Fass , H. Shorer , L. Gil , and Z. Elazar . 2007. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26(7):17491760. Selim, M. E. , and A. A. Hendi . 2012. Gold nanoparticles induce apoptosis in MCF-7 human breast cancer cells. Asian Pac J Cancer Prev 13(4):16171620. Sharma, V. , R. K. Shukla , N. Saxena , D. Parmar , M. Das , and A. Dhawan . 2009. DNA damaging potential of zinc oxide nanoparticles in human epidermal cells. Toxicol Lett 185(3):211218. Sheng, L. , Y. Ze , L. Wang 2015. Mechanisms of TiO2 nanoparticle-induced neuronal apoptosis in rat primary cultured hippocampal neurons. J Biomed Mater Res A 103(3):11411149.281 Shi, J. , X. Sun , Y. Lin , X. Zou , Z. Li , Y. Liao , M. Du , and H. Zhang . 2014. Endothelial cell injury and dysfunction induced by silver nanoparticles through oxidative stress via IKK/NFkappaB pathways. Biomaterials 35(24):66576666. doi: 10.1016/j.biomaterials.2014.04.093 Shukla, R. K. , V. Sharma , A. K. Pandey , S. Singh , S. Sultana , and A. Dhawan . 2011. ROSmediated genotoxicity induced by titanium dioxide nanoparticles in human epidermal cells. Toxicol In Vitro 25(1):231241. Siddiqui, M. A. , M. Ahamed , J. Ahmad , M. A. Majeed Khan , J. Musarrat , A. A. Al-Khedhairy , and S. A. Alrokayan . 2012. Nickel oxide nanoparticles induce cytotoxicity, oxidative stress and apoptosis in cultured human cells that is abrogated by the dietary antioxidant curcumin. Food Chem Toxicol 50(34):641647. doi: 10.1016/j.fct.2012.01.017 Simon, M. , P. Barberet , M. H. Delville , P. Moretto , and H. Seznec . 2011. Titanium dioxide nanoparticles induced intracellular calcium homeostasis modification in primary human keratinocytes. Towards an in vitro explanation of titanium dioxide nanoparticles toxicity. Nanotoxicology 5(2):125139. doi: 10.3109/17435390.2010.502979 Singh, N. , B. Manshian , G. J. Jenkins , S. M. Griffiths , P. M. Williams , T. G. Maffeis , C. J. Wright , and S. H. Doak . 2009. NanoGenotoxicology: The DNA damaging potential of engineered nanomaterials. Biomaterials 30(2324):38913914. Stern, S. T. , P. P. Adiseshaiah , and R. M. Crist . 2012. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part Fibre Toxicol 9:20. doi: 10.1186/17438977-9-20 Stern, S. T. and D. N. Johnson . 2008. Role for nanomaterial-autophagy interaction in neurodegenerative disease. Autophagy 4(8):10971100. Stokoe, D. , L. R. Stephens , T. Copeland , P. R. Gaffney , C. B. Reese , G. F. Painter , A. B. Holmes , F. McCormick , and P. T. Hawkins . 1997. Dual role of phosphatidylinositol-3,4,5trisphosphate in the activation of protein kinase B. Science 277(5325):567570. Tilly, J. L. , K. I. Kowalski , A. L. Johnson , and A. J. Hsueh . 1991. Involvement of apoptosis in ovarian follicular atresia and postovulatory regression. Endocrinology 129(5):27992801. Trickler, W. J. , S. M. Lantz , R. C. Murdock 2010. Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells. Toxicol Sci 118(1):160170. Trouiller, B. , R. Reliene , A. Westbrook , P. Solaimani , and R. H. Schiestl . 2009. Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res 69(22):87848789. Turabekova, M. , B. Rasulev , M. Theodore , J. Jackman , D. Leszczynska , and J. Leszczynski . 2014. Immunotoxicity of nanoparticles: A computational study suggests that CNTs and C60 fullerenes might be recognized as pathogens by Toll-like receptors. Nanoscale 6(7):34883495. Valko, M. , D. Leibfritz , J. Moncol , M. T. D. Cronin , M. Mazur , and J. Telser . 2007. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):4484. Valko, M. , C. J. Rhodes , J. Moncol , M. Izakovic , and M. Mazur . 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160(1):140. van Meer, G. , D. R. Voelker , and G. W. Feigenson . 2008. Membrane lipids: Where they are and how they behave. Nat Rev Mol Cell Biol 9(2):112124. doi: 10.1038/nrm2330 282

Vossenaar, E. R. , and W. H. Robinson . 2005. Citrullination and autoimmune disease: 8th Bertine Koperberg meeting. Ann Rheum Dis 64(10):15131515. doi: 10.1136/ard.2005.045716 Wajant, H. 2002. The Fas signaling pathway: More than a paradigm. Science 296(5573):16351636. Wan, B. , Z. X. Wang , Q. Y. Lv , P. X. Dong , L. X. Zhao , Y. Yang , and L. H. Guo . 2013. Single-walled carbon nanotubes and graphene oxides induce autophagosome accumulation and lysosome impairment in primarily cultured murine peritoneal macrophages. Toxicol Lett 221(2):118127. Wan, J. , J. H. Wang , T. Liu , Z. Xie , X. F. Yu , and W. Li . 2015. Surface chemistry but not aspect ratio mediates the biological toxicity of gold nanorods in vitro and in vivo . Sci Rep 5:11398. Wang, J. , P. Sun , Y. Bao , J. Liu , and L. An . 2011. Cytotoxicity of single-walled carbon nanotubes on PC12 cells. Toxicol In Vitro 25(1):242250. doi: 10.1016/j.tiv.2010.11.010 Wang, J. J. , B. J. Sanderson , and H. Wang . 2007. Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. Mutat Res 628(2):99106. Wangoo, N. , C. Raman Suri , and G. Shekhawat . 2008. Interaction of gold nanoparticles with protein: A spectroscopic study to monitor protein conformational changes. Appl Phys Lett 92(13):133104. Wilson, C. L. , V. Natarajan , S. L. Hayward , O. Khalimonchuk , and S. Kidambi . 2015. Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles. Nanoscale 7(44):1847718488. doi: 10.1039/c5nr03646a Xi, C. , J. Zhou , S. Du , and S. Peng . 2016. Autophagy upregulation promotes macrophages to escape mesoporous silica nanoparticle (MSN)-induced NF-kappaB-dependent inflammation. Inflamm Res 65(4):325341. doi: 10.1007/s00011-016-0919-0 Xia, T. , M. Kovochich , J. Brant , M. Hotze , J. Sempf , T. Oberley , C. Sioutas , J. I. Yeh , M. R. Wiesner , and A. E. Nel . 2006. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6(8):17941807. doi: 10.1021/nl061025k Xia, T. , M. Kovochich , M. Liong , L. Madler , B. Gilbert , H. Shi , J. I. Yeh , J. I. Zink , and A. E. Nel . 2008. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano 2(10):21212134. Ye, Y. , J. Liu , J. Xu , L. Sun , M. Chen , and M. Lan . 2010. Nano-SiO2 induces apoptosis via activation of p53 and Bax mediated by oxidative stress in human hepatic cell line. Toxicol In Vitro 24(3):751758. doi: 10.1016/j.tiv.2010.01.001 Yu, J. X. , and T. H. Li . 2011. Distinct biological effects of different nanoparticles commonly used in cosmetics and medicine coatings. Cell Biosci 1(1):19. Yu, K.-N. , S.-H. Chang , S. J. Park , J. Lim , J. Lee , T.-J. Yoon , J.-S. Kim , and M.-H. Cho . 2015a. Titanium dioxide nanoparticles induce endoplasmic reticulum stress-mediated autophagic cell death via mitochondria-associated endoplasmic reticulum membrane disruption in normal lung cells. PloS one 10(6):e0131208. Yu, K. N. , J. H. Sung , S. Lee 2015b. Inhalation of titanium dioxide induces endoplasmic reticulum stress-mediated autophagy and inflammation in mice. Food Chem Toxicol 85:106113. doi: 10.1016/j.fct.2015.08.001 283 Yu, Y. , J. Duan , Y. Yu , Y. Li , X. Liu , X. Zhou , K. F. Ho , L. Tian , and Z. Sun . 2014. Silica nanoparticles induce autophagy and autophagic cell death in HepG2 cells triggered by reactive oxygen species. J Hazard Mater 270:176186. doi: 10.1016/j.jhazmat.2014.01.028 Ze, Y. , L. Sheng , X. Zhao 2014. TiO2 nanoparticles induced hippocampal neuroinflammation in mice. PLoS One 9(3):e92230. doi: 10.1371/journal.pone.0092230 Zhang, T. , Y. Hu , M. Tang , L. Kong , J. Ying , T. Wu , Y. Xue , and Y. Pu . 2015a. Liver Toxicity of cadmium telluride quantum dots (CdTe QDs) due to oxidative stress in vitro and in vivo. Int J Mol Sci 16(10):2327923299. doi: 10.3390/ijms161023279 Zhang, X. F. , Y. J. Choi , J. W. Han , E. Kim , J. H. Park , S. Gurunathan , and J. H. Kim . 2015b. Differential nanoreprotoxicity of silver nanoparticles in male somatic cells and spermatogonial stem cells. Int J Nanomedicine 10:13351357. doi: 10.2147/IJN.S76062 Zhang, X. , H. Yin , Z. Li , T. Zhang , and Z. Yang . 2016a. Nano-TiO2 induces autophagy to protect against cell death through antioxidative mechanism in podocytes. Cell Biol Toxicol 32(6):513527. doi: 10.1007/s10565016-9352-y Zhang, X. , H. Zhang , X. Liang , J. Zhang , W. Tao , X. Zhu , D. Chang , X. Zeng , G. Liu , and L. Mei . 2016b. Iron oxide nanoparticles induce autophagosome accumulation through multiple mechanisms: Lysosome impairment, mitochondrial damage, and ER stress. Mol Pharm 13(7):25782587. doi: 10.1021/acs.molpharmaceut.6b00405 Zhang, X. J. , S. Chen , K. X. Huang , and W. D. Le . 2013. Why should autophagic flux be assessed? Acta Pharmacol Sin 34(5):595599. doi: 10.1038/aps.2012.184

Zhang, Y. , X. Gao , L. J. Saucedo , B. Ru , B. A. Edgar , and D. Pan . 2003. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5(6):578581. Zhao, J. , L. Bowman , X. Zhang , X. Shi , B. Jiang , V. Castranova , and M. Ding . 2009a. Metallic nickel nano- and fine particles induce JB6 cell apoptosis through a caspase-8/AIF mediated cytochrome c-independent pathway. J Nanobiotechnology 7:2. Zhao, J. , L. Bowman , X. Zhang , V. Vallyathan , S. H. Young , V. Castranova , and M. Ding . 2009b. Titanium dioxide (TiO2) nanoparticles induce JB6 cell apoptosis through activation of the caspase-8/Bid and mitochondrial pathways. J Toxicol Environ Health A 72(19):11411149. Zhao, X. , X. Ren , R. Zhu , Z. Luo , and B. Ren . 2016. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria-mediated apoptosis in zebrafish embryos. Aquat Toxicol 180:5670. Zhdanov, V. P. , and N. J. Cho . 2016. Kinetics of the formation of a protein corona around nanoparticles. Math Biosci 282:8290. doi: 10.1016/j.mbs.2016.09.018 Zuo, G. , S. G. Kang , P. Xiu , Y. Zhao , and R. Zhou . 2013. Interactions between proteins and carbon-based nanoparticles: Exploring the origin of nanotoxicity at the molecular level. Small 9(910):15461556. doi: 10.1002/smll.201201381

Methods and Protocols for In Vitro Animal Nanotoxicity Evaluation: A Detailed Review Aardema, M. J. , B. C. Barnett , Z. Khambatta , K. Reisinger , G. Ouedraogo-Arras , B. Faquet , A. C. Ginestet 2010. International Prevalidation Studies of the EpiDerm 3D Human Reconstructed Skin Micronucleus (RSMN) Assay: Transferability and Reproducibility. Mutation Research - Genetic Toxicology and Environmental Mutagenesis 701(2):123131. https://doi.org/10.1016/j.mrgentox.2010.05.017 Agemy, L. , K. N. Sugahara , V. R. Kotamraju , K. Gujraty , O. M. Girard , Y. Kono , R. F. Mattrey 2010. Nanoparticle-Induced Vascular Blockade in Human Prostate Cancer. Blood 116(15):28472856. https://doi.org/10.1182/blood-2010-03-274258 315 Astashkina, A. and D. W. Grainger . 2014. Critical Analysis of 3-D Organoid In Vitro Cell Culture Models for High-Throughput Drug Candidate Toxicity Assessments. Advanced Drug Delivery Reviews 6970(April):118. http://dx.doi.org/10.1016/j.addr.2014.02.008 Baxter, A. , S. Thain , A. Banerjee , L. Haswell , A. Parmar , G. Phillips , and E. Minet . 2015. Targeted Omics Analyses, and Metabolic Enzyme Activity Assays Demonstrate Maintenance of Key Mucociliary Characteristics in Long Term Cultures of Reconstituted Human Airway Epithelia. Toxicology In Vitro: An International Journal Published in Association with BIBRA 29(5):864875. England. https://doi.org/10.1016/j.tiv.2015.03.004 Becker, H. , F. Herzberg , A. Schulte , and M. Kolossa-Gehring . 2011. The Carcinogenic Potential of Nanomaterials, Their Release from Products and Options for Regulating Them. International Journal of Hygiene and Environmental Health 214(3):231238. https://doi.org/10.1016/j.ijheh.2010.11.004 Bhatia, S. N. and D. E. Ingber . 2014. Microfluidic Organs-on-Chips. Nature Biotechnology 32(8):760772. https://doi.org/10.1038/nbt.2989 Bissell, M. J. , V. M. Weaver , S. A. Lelievre , F. Wang , O. W. Petersen , and K. L. Schmeichel . 1999. Tissue Structure, Nuclear Organization, and Gene Expression in Normal and Malignant Breast. Cancer Research 59(7 Suppl):17571763s. Braydich-Stolle, L. K. , N. M. Schaeublin , R. C. Murdock , J. Jiang , P. Biswas , J. J. Schlager , and S. M. Hussain . 2009. Crystal Structure Mediates Mode of Cell Death in TiO2 Nanotoxicity. Journal of Nanoparticle Research 11(6):13611374. https://doi.org/10.1007/s11051-008-9523-8 Cancino, J. , I. M. M. Paino , K. C. Micocci , H. S. Selistre-de-Araujo , and V. Zucolotto . 2013. In Vitro Nanotoxicity of Single-Walled Carbon Nanotubedendrimer Nanocomplexes against Murine Myoblast Cells. Toxicology Letters 219(1):1825. http://dx.doi.org/10.1016/j.toxlet.2013.02.009 Choi, C. K. , M. T. Breckenridge , and C. S. Chen . 2010. Engineered Materials and the Cellular Microenvironment: A Strengthening Interface between Cell Biology and Bioengineering. Trends in Cell Biology 20(12):705714. http://dx.doi.org/10.1016/j.tcb.2010.09.007 Correia Carreira, S. , L. Walker , K. Paul , and M. Saunders . 2015. The Toxicity, Transport and Uptake of Nanoparticles in the In Vitro BeWo b30 Placental Cell Barrier Model Used within NanoTEST. Nanotoxicology 9(suppl):6678. Taylor & Francis. https://doi.org/10.3109/17435390.2013.833317 Davoren, M. , E. Herzog , A. Casey , B. Cottineau , G. Chambers , H. J. Byrne , and F. M. Lyng . 2007. In Vitro Toxicity Evaluation of Single Walled Carbon Nanotubes on Human A549 Lung

Cells. Toxicology In Vitro 21(3):438448. https://doi.org/10.1016/j.tiv.2006.10.007 De Graaf, I. M. , P. Olinga , M. H. de Jager , M. T. Merema , R. de Kanter , E. G. van de Kerkhof , and G. M. M. Groothuis . 2010. Preparation and Incubation of Precision-Cut Liver and Intestinal Slices for Application in Drug Metabolism and Toxicity Studies. Nature Protocols 5(9):15401551. https://doi.org/10.1038/nprot.2010.111 Dragoni, S. , G. Franco , M. Regoli , M. Bracciali , V. Morandi , G. Sgaragli , E. Bertelli , and M. Valoti . 2012. Gold Nanoparticles Uptake and Cytotoxicity Assessed on Rat Liver Precision-Cut Slices. Toxicological Sciences 128(1):186197. https://doi.org/10.1093/toxsci/kfs150 Esch, E. W. , A. Bahinski , and D. Huh . 2015. Organs-on-Chips at the Frontiers of Drug Discovery. Nature Reviews Drug Discovery 14(4):248260. Nature Publishing Group.316 Eustaquio, T. and J. F. Leary . 2012. Single-Cell Nanotoxicity Assays of Superparamagnetic Iron Oxide Nanoparticles. Methods in Molecular Biology 926:6985. https://doi.org/10.1007/9781-62703-002-1_5 Faulkner-Jones, A. , S. Greenhough , J. A. King , J. Gardner , A. Courtney , and W. Shu . 2013. Development of a Valve-Based Cell Printer for the Formation of Human Embryonic Stem Cell Spheroid Aggregates. Biofabrication 5(1):15013. England. https://doi.org/10.1088/17585082/5/1/015013 Ferdowsian, H. R. and N. Beck . 2011. Ethical and Scientific Considerations Regarding Animal Testing and Research. PLoS ONE 6(9). https://doi.org/10.1371/journal.pone.0024059 Foty, R. 2011. A Simple Hanging Drop Cell Culture Protocol for Generation of 3D Spheroids. Journal of Visualized Experiments 20(51):47. https://doi.org/10.3791/2720 Fowler, P. , K. Smith , J. Young , L. Jeffrey , D. Kirkland , S. Pfuhler , and P. Carmichael . 2012. Reduction of Misleading (false) Positive Results in Mammalian Cell Genotoxicity Assays. I. Choice of Cell Type. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 742(12):1125. https://doi.org/10.1016/j.mrgentox.2011.10.014 Friedman, L. 1987. Teratological Research Using In Vitro Systems. II. Rodent Limb Bud Culture System. Environ Health Perspect 72:211219. Frohlich, E. 2013. Cellular targets and mechanisms in the cytotoxic action of non-biodegradable engineered nanoparticles. Current Drug Metabolism 14(9):976988. Ghaemmaghami, A. M. , M. J. Hancock , H. Harrington , H. Kaji , and A. Khademhosseini . 2012. Biomimetic Tissues on a Chip for Drug Discovery. Drug Discovery Today 17(3):173181. https://doi.org/10.1016/j.drudis.2011.10.029 Ghosh, M. , J. Manivannan , S. Sinha , A. Chakraborty , S. Kumar , M. Bandyopadhyay , and A. Mukherjee . 2012. Mutation Research/Genetic Toxicology and Environmental Mutagenesis In Vitro and In Vivo Genotoxicity of Silver. Nanoparticles 749:6069. Guo, X. and T. Chen . 2015. Progress in Genotoxicity Evaluation of Engineered Nanomaterials. NanomaterialsToxicity and Risk Assesment 142160. https://doi.org/dx.doi.org/10.5772/61013 Hendriks, G. , M. Atallah , B. Morolli , F. Callja , N. Ras-Verloop , I. Huijskens , M. Raamsman , B. van de Water , and H. Vrieling . 2012. The ToxTracker assay: Novel GFP reporter systems that provide mechanistic insight into the genotoxic properties of chemicals. Toxicological Sciences 125(1):285298. https://doi.org/10.1093/toxsci/kfr281 Hill, C. , A. Jain , H. Takemoto , M. D. Silver , S. V. S. Nagesh , C. N. Ionita , D. R. Bednarek , and S. Rudin . 2015. Imaging interactions of metal oxide nanoparticles with macrophage cells by ultra-high resolution scanning electron microscopy techniques. Proceedings of SPIEthe International Society for Optical Engineering 73(4):389400. https://doi.org/10.1530/ERC-140411.Persistent Hillegass, J. M. and M. B. Macpherson . 2010. NIH Public Access, 117. https://doi.org/10.1002/wnan.54.Assessing Hondroulis, E. , C. Liu , and C. Z. Li . 2010. Whole cell based electrical impedance sensing approach for a rapid nanotoxicity assay. Nanotechnology 21(31):315103. https://doi.org/10.1088/0957-4484/21/31/315103 Huang, C. Y. , T. R. Ger , Z. H. Wei , and M. F. Lai . 2014. Compare analysis for the nanotoxicity effects of different amounts of endocytic iron oxide nanoparticles at single cell level. In: ed Xu B. PLoS ONE vol. 9, no. 5. San Francisco, USA: Public Library of Science, p. e96550. https://doi.org/10.1371/journal.pone.0096550 317 Huang, S. , L. Wiszniewski , S. Constant , and E. Roggen . 2013. Potential of in vitro reconstituted 3D Human Airway Epithelia (MucilAir) to assess respiratory sensitizers. Toxicology In Vitro: An International Journal Published in Association with BIBRA 27(3):11511156. England. https://doi.org/10.1016/j.tiv.2012.10.010 Huh, D. , B. D. Matthews , A. Mammoto , M. Montoya-Zavala , H. Y. Hsin , and D. E. Ingber . 2010. Reconstituting organ-level lung functions on a chip. Science 328(5986):16621668. https://doi.org/10.1126/science.1188302 Hussain, S. M. , D. B. Warheit , S. P. Ng , K. K. Comfort , C. M. Grabinski , and L. K. BraydichStolle . 2015. At the crossroads of nanotoxicology in vitro: Past achievements and current

challenges. Toxicological Sciences 147(1):516. https://doi.org/10.1093/toxsci/kfv106 Iannitti, T. , S. Capone , A. Gatti , F. Capitani , F. Cetta , and B. Palmieri . 2010. Intracellular heavy metal nanoparticle storage: Progressive accumulation within lymph nodes with transformation from chronic inflammation to malignancy. International Journal of Nanomedicine 5(1):955960. https://doi.org/10.2147/IJN.S14363 Kang, J. L. , C. Moon , H. S. Lee , H. W. Lee , E.-M. Park , H. S. Kim , and V. Castranova . 2008. Comparison of the biological activity between ultrafine and fine titanium dioxide particles in RAW 264.7 cells associated with oxidative stress. Journal of Toxicology and Environmental Health, Part A 71(8):478485. https://doi.org/10.1080/15287390801906675 Karlsson, H. L. , A. R. Gliga , F. M. G. R. Callja , C. S. A. G. Gonalves , I. O. Wallinder , H. Vrieling , B. Fadeel , and G. Hendriks . 2014. Mechanism-based genotoxicity screening of metal oxide nanoparticles using the ToxTracker panel of reporter cell lines. Particle and Fibre Toxicology 11:41. https://doi.org/10.1186/s12989-014-0041-9 Khanna, P. , C. Ong , B. Bay , and G. Baeg . 2015. Nanotoxicity: An interplay of oxidative stress, inflammation and cell death. Nanomaterials 5(3):11631180. https://doi.org/10.3390/nano5031163 Kim, J.-H. , J. Sanetuntikul , S. Shanmugam , and E. Kim . 2015. Necrotic cell death caused by exposure to graphitic carbon-coated magnetic nanoparticles. Journal of Biomedical Materials Research Part A 103(9):28752887. https://doi.org/10.1002/jbm.a.35418 Kirkland, D. , S. Pfuhler , D. Tweats , M. Aardema , R. Corvi , F. Darroudi , A. Elhajouji 2007. How to Reduce False Positive Results When Undertaking In Vitro Genotoxicity Testing and Thus Avoid Unnecessary Follow-up Animal Tests: Report of an ECVAM Workshop. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 628(1):3155. https://doi.org/10.1016/j.mrgentox.2006.11.008 Klaper, R. , D. Arndt , J. Bozich , and G. Dominguez . 2014. Molecular Interactions of Nanomaterials and Organisms: Defining Biomarkers for Toxicity and High-Throughput Screening Using Traditional and next-Generation Sequencing Approaches. Analyst 139(5):882895. https://doi.org/10.1039/c3an01644g Kochhar, D. M. 1983. Embryonic Organs in Culture BTTeratogenesis and Reproductive Toxicology. In: eds Marshall Johnson, E. and D. M. Kochhar . Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 301314. https://doi.org/10.1007/978-3-642-81919-3_15 Krewski, D. , D. Acosta , M. Andersen , H. Anderson , J. C. Bailar , K. Boekelheide , R. Brent 2010. Toxicity Testing in the 21st Century: A Vision and a Strategy. Journal of Toxicology and Environmental Health. Part B, Critical Reviews 13(24):51138. https://doi.org/10.1080/10937404.2010.483176 318 Lauenstein, L. , S. Switalla , F. Prenzler , S. Seehase , O. Pfennig , C. Forster , H. Fieguth , A. Braun , and K. Sewald . 2014. Assessment of Immunotoxicity Induced by Chemicals in Human Precision-Cut Lung Slices (PCLS). Toxicology In Vitro: An International Journal Published in Association with BIBRA 28(4):588599. England. https://doi.org/10.1016/j.tiv.2013.12.016 Lee, M. Y. , R. Anand Kumar , S. M. Sukumaran , M. G. Hogg , D. S. Clark , and J. S. Dordick . 2008. Three-Dimensional Cellular Microarray for High-Throughput Toxicology Assays. Proceedings of the National Academy of Sciences of the United States of America 105(1):5963. United States. https://doi.org/10.1073/pnas.0708756105 Lee, P. J. , P. J. Hung , and L. P. Lee . 2007. An Artificial Liver Sinusoid with a Microfluidic Endothelial-like Barrier for Primary Hepatocyte Culture. Biotechnology and Bioengineering 97(5):13401346. https://doi.org/10.1002/bit.21360 Li, H. , B. van Ravenzwaay , I. M. C. M. Rietjens , and J. Louisse . 2013. Assessment of an In Vitro Transport Model Using BeWo b30 Cells to Predict Placental Transfer of Compounds. Archives of Toxicology 87(9):16611669. Germany. https://doi.org/10.1007/s00204-013-1074-9 Li, N. , M. Hao , R. F. Phalen , W. C. Hinds , and A. E. Nel . 2003. Particulate Air Pollutants and Asthma: A Paradigm for the Role of Oxidative Stress in PM-Induced Adverse Health Effects. Clinical Immunology 109(3):250265. https://doi.org/10.1016/j.clim.2003.08.006 Liao, K. H. , Y. S. Lin , C. W. MacOsko , and C. L. Haynes . 2011. Cytotoxicity of Graphene Oxide and Graphene in Human Erythrocytes and Skin Fibroblasts. ACS Applied Materials and Interfaces 3(7):26072615. https://doi.org/10.1021/am200428v Liberati, T. A. , M. R. Randle , and L. A. Toth . 2010. In Vitro Lung Slices: A Powerful Approach for Assessment of Lung Pathophysiology. Expert Review of Molecular Diagnostics 10(4):501508. https://doi.org/10.1586/erm.10.21 Liu, Y. , Zhao, Y. , Sun, B. , and Chen, C. 2013. Understanding the toxicity of carbon nanotubes. Accounts of Chemical Research 46(3):702713. https://doi.org/10.1021/ar300028m Love, S. A. , M. A. Maurer-Jones , J. W. Thompson , Y.-S. Lin , and C. L. Haynes . 2012. Assessing Nanoparticle Toxicity. Annual Review of Analytical Chemistry 5(1):181205. https://doi.org/10.1146/annurev-anchem-062011-143134 Magdolenova, Z. , A. Collins , A. Kumar , A. Dhawan , V. Stone , and M. Dusinska . 2014. Mechanisms of Genotoxicity. A Review of In Vitro and In Vivo Studies with Engineered

Nanoparticles. Nanotoxicology 8(July 2016):233278. https://doi.org/10.3109/17435390.2013.773464 Manickam, V. , R. Kumar , R. Lochana , Amiti , B. Rajendran , M. Kumar , and T. Ramasamy . 2017. Genotoxicity of Nanomaterials in Food. Nanoscience in Food and Agriculture 4:141180. https://doi.org/10.1007/978-3-319-53112-0 Marx, U. , H. Walles , S. Hoffmann , G. Lindner , R. Horland , F. Sonntag , U. Klotzbach , D. Sakharov , A. Tonevitsky , and R. Lauster . 2012. Human-on-a-Chip' Developments: A Translational Cuttingedge Alternative to Systemic Safety Assessment and Efficiency Evaluation of Substances in Laboratory Animals and Man?. ATLA Alternatives to Laboratory Animals 40(5):235257. Maurer-Jones, M. A. and C. L. Haynes . 2012. Toward Correlation in In Vivo and In Vitro Nanotoxicology Studies. Journal of Law, Medicine and Ethics 40(4):795801. https://doi.org/10.1111/j.1748-720X.2012.00707.x 319 Mohanan, R. N. S. and P. Valappil . 2015. Stem Cells, a New Generation Model for Predictive Nano Toxicological Assessment. Current Drug Metabolism. http://dx.doi.org/10.2174/1389200216666151015113720 Muller, J. , F. Huaux , N. Moreau , P. Misson , J. F. Heilier , M. Delos , M. Arras , A. Fonseca , J. B. Nagy , and D. Lison . 2005. Respiratory Toxicity of Multi-Wall Carbon Nanotubes. Toxicology and Applied Pharmacology 207(3):221231. https://doi.org/10.1016/j.taap.2005.01.008 Muoth, C. , A. Wichser , M. Monopoli , M. Correia , N. Ehrlich , K. Loeschner , A. Gallud 2016. A 3D Co-Culture Microtissue Model of the Human Placenta for Nanotoxicity Assessment. Nanoscale 8(39):1732217332. Royal Society of Chemistry. https://doi.org/10.1039/C6NR06749B Nau, K. and H. F. Krug . 2009. The NanoCare Project: A German Initiative on Health Aspects of Synthetic Nanoparticles. Journal of Physics: Conference Series 170:012038. https://doi.org/10.1088/1742-6596/170/1/012038 OECD . 2016. The economic consequences of outdoor air pollution Organisation for Economic Cooperation and Development (OECD). http://www.oecd-ilibrary.org/environment/theeconomic-consequences-of-outdoor-air-pollution_9789264257474-en OECD Guidelines for the Testing of Chemicals . 2014. Test No. 487: In Vitro Mammalian Cell Micronucleus Test. OECD Publishing. https://doi.org/10.1787/9789264224438-en Oh, J. H. , M. Y. Son , M. S. Choi , S. Kim , A. Young Choi , H. A. Lee , K. S. Kim , J. Kim , C. W. Song , and S. Yoon . 2016. Integrative Analysis of Genes and miRNA Alterations in Human Embryonic Stem Cells-Derived Neural Cells after Exposure to Silver Nanoparticles. Toxicology and Applied Pharmacology 299(May):823. http://dx.doi.org/10.1016/j.taap.2015.11.004 Ong, T. , M. Mukhtar , C. R. Wolf , and E. Zeiger . 1980. Differential Effects of Cytochrome P450-Inducers on Promutagen Activation Capabilities and Enzymatic Activities of S-9 from Rat Liver. Journal of Environmental Pathology and Toxicology 4(1):5565. United States. Paradis, F.-H. , C. Huang , and B. F. Hales . 2012. The Murine Limb Bud in Culture as an In Vitro Teratogenicity Test System. In Developmental Toxicology: Methods and Protocols, eds Harris, C. and M. Jason Hansen . Totowa, NJ: Humana Press, pp. 197213. https://doi.org/10.1007/978-1-61779-867-2_12 Polacheck, W. J. , R. Li , S. G. M. Uzel , and R. D. Kamm . 2013. Microfluidic Platforms for Mechanobiology. Lab on a Chip 13(12):22522267. https://doi.org/10.1039/c3lc41393d Portes, P. , M. H. Grandidier , C. Cohen , and R. Roguet . 2002. Refinement of the Episkin Protocol for the Assessment of Acute Skin Irritation of Chemicals: Follow-up to the ECVAM Prevalidation Study. Toxicol In Vitro 16(6):765770. https://doi.org/10.1016/S08872333(02)00090-5 Reisetter, A. C. , L. V. Stebounova , J. Baltrusaitis , L. Powers , A. Gupta , V. H. Grassian , and M. M. Monick . 2011. Induction of Inflammasome-Dependent Pyroptosis by Carbon Black Nanoparticles. The Journal of Biological Chemistry 286(24):2184421852. 9650 Rockville Pike, Bethesda, MD 20814, U.S.A.: American Society for Biochemistry and Molecular Biology. https://doi.org/10.1074/jbc.M111.238519 Rizzo, L. Y. , S. K. Golombek , M. E. Mertens , and Y. Pan . 2013. Europe PMC Funders Group In Vivo Nanotoxicity Testing Using the Zebrafish Embryo Assay, 113. Rossini, G. P. and T. Hartung . 2012. Food for Thought towards Tailored Assays for Cell-Based Approaches to Toxicity Testing. Altex 29(4):359372.320 Rothen-Rutishauser, B. M. , S. G. Kiama , and P. Gehr . 2005. A Three-Dimensional Cellular Model of the Human Respiratory Tract to Study the Interaction with Particles. American Journal of Respiratory Cell and Molecular Biology 32(4):281289. https://doi.org/10.1165/rcmb.20040187OC Rujanapun, N. , S. Aueviriyavit , S. Boonrungsiman , A. Rosena , D. Phummiratch , S. Riolueang , N. Chalaow , V. Viprakasit , and R. Maniratanachote . 2015. Human Primary Erythroid Cells as a More Sensitive Alternative In Vitro Hematological Model for Nanotoxicity

Studies: Toxicological Effects of Silver Nanoparticles. Toxicology In Vitro 29(8):19821992. http://dx.doi.org/10.1016/j.tiv.2015.08.005 Sanyal, S. 2014. Culture and Assay Systems Used for 3D Cell Culture. Corning. Sauer, U. G. , S. Vogel , A. Aumann , A. Hess , S. N. Kolle , L. Ma-Hock , W. Wohlleben 2014. Applicability of Rat Precision-Cut Lung Slices in Evaluating Nanomaterial Cytotoxicity, Apoptosis, Oxidative Stress, and Inflammation. Toxicology and Applied Pharmacology 276(1):120. https://doi.org/10.1016/j.taap.2013.12.017 Seabra, A. B. , A. J. Paula , R. De Lima , O. L. Alves , and N. Durn . 2014. Nanotoxicity of Graphene and Graphene Oxide. Chemical Research in Toxicology. https://doi.org/10.1021/tx400385x Semenzin, E. , E. Lanzellotto , D. Hristozov , A. Critto , A. Zabeo , E. Giubilato , and A. Marcomini . 2015. Species Sensitivity Weighted Distribution for Ecological Risk Assessment of Engineered Nanomaterials: The N-TiO2 Case Study. Environmental Toxicology and Chemistry 34(11):26442659. https://doi.org/10.1002/etc.3103 Semmler-Behnke, M. , W. G. Kreyling , J. Lipka , S. Fertsch , A. Wenk , S. Takenaka , G. Schmid , and W. Brandau . 2008. Biodistribution of 1.4- and 18-Nm Gold Particles in Rats. Small 4(12):21082111. WILEY-VCH Verlag. https://doi.org/10.1002/smll.200800922 Sha, B. , W. Gao , S. Wang , X. Gou , W. Li , X. Liang , Z. Qu , F. Xu , and T. J. Lu . 2014. Oxidative Stress Increased Hepatotoxicity Induced by Nano-Titanium Dioxide in BRL-3A Cells and Sprague-Dawley Rats. Journal of Applied Toxicology 34(4):345356. https://doi.org/10.1002/jat.2900 Shah, P. , X. Zhu , X. Zhang , J. He , and C.-Z. Li . 2016. Microelectromechanical SystemBased Sensing Arrays for Comparative In Vitro Nanotoxicity Assessment at Single Cell and Small Cell-Population Using Electrochemical Impedance Spectroscopy. ACS Applied Materials & Interfaces 8(9):58045812. American Chemical Society. https://doi.org/10.1021/acsami.5b11409 Sharma, V. , S. K. Singh , D. Anderson , D. J. Tobin , and A. Dhawan . 2011. Zinc Oxide Nanoparticle Induced Genotoxicity in Primary Human Epidermal Keratinocytes. Journal of Nanoscience and Nanotechnology 11(January 2016): 37823788. https://doi.org/10.1166/jnn.2011.4250 Shelley, M. L. , A. J. Wagner , S. M. Hussain , and C. Bleckmann . 2008. Modeling the In Vivo Case with In Vitro Nanotoxicity Data. International Journal of Toxicology 27(5):359367. United States. https://doi.org/10.1080/10915810802503487 Shubayev, V. I. , T. R. Pisanic , and S. Jin . 2009. Magnetic Nanoparticles for Theragnostics. Advanced Drug Delivery Reviews. https://doi.org/10.1016/j.addr.2009.03.007 Toh, Y.-C. , T. C. Lim , D. Tai , G. Xiao , D. van Noort , and H. Yu . 2009. A Microfluidic 3D Hepatocyte Chip for Drug Toxicity Testing. Lab on a Chip 9(14):20262035. England. https://doi.org/10.1039/b900912d Trnqvist, E. , A. Annas , B. Granath , E. Jalkesten , I. Cotgreave , and M. berg . 2014. Strategic Focus on 3R Principles Reveals Major Reductions in the Use of Animals in Pharmaceutical Toxicity Testing. PLoS ONE 9(7):e101638. Public Library of Science. http://dx.doi.org/10.1371%2Fjournal.pone.0101638 321 Umair, M. , I. Javed , M. Rehman , A. Madni , A. Javeed , and A. Ghafoor . 2016. Nanotoxicity of Inert Materials: The Case of Gold, Silver and Iron. Journal of Pharmacy and Pharmaceutical Science 19(2):161180. Van der Worp, H. B. , D. W. Howells , E. S. Sena , M. J. Porritt , S. Rewell , V. O'Collins , and M. R. Macleod . 2010. Can Animal Models of Disease Reliably Inform Human Studies?. PLoS Medicine 7(3):e1000245. United States. https://doi.org/10.1371/journal.pmed.1000245 Wang, Y. , G. Kaur , A. Zysk , V. Liapis , S. Hay , A. Santos , D. Losic , and A. Evdokiou . 2015. Systematic Invitro Nanotoxicity Study on Anodic Alumina Nanotubes with Engineered Aspect Ratio: Understanding Nanotoxicity by a Nanomaterial Model. Biomaterials 46:117130. Elsevier Ltd. https://doi.org/10.1016/j.biomaterials.2014.12.008 Wick, P. , S. Chortarea , O. T. Guenat , M. Roesslein , J. D. Stucki , S. Hirn , A. Petri-Fink , and B. Rothen-Rutishauser . 2015. In Vitro-Ex Vivo Model Systems for Nanosafety Assessment. European Journal of Nanomedicine 7(3):169179. https://doi.org/10.1515/ejnm-2014-0049 Wills, J. W. , N. Hondow , A. D. Thomas , K. E. Chapman , D. Fish , T. G. Maffeis , M. W. Penny 2016. Genetic Toxicity Assessment of Engineered Nanoparticles Using a 3D In Vitro Skin Model (EpiDermTM). Particle and Fibre Toxicology 13(1):50. https://doi.org/10.1186/s12989-016-0161-5 Winter, M. , H.-D. Beer , V. Hornung , U. Krmer , R. P. F. Schins , and I. Frster . 2011. Activation of the Inflammasome by Amorphous Silica and TiO2 Nanoparticles in Murine Dendritic Cells. Nanotoxicology 5(3):326340. Taylor & Francis. https://doi.org/10.3109/17435390.2010.506957 Xiao, G. G. , M. Wang , N. Li , J. A. Loo , and A. E. Nel . 2003. Use of Proteomics to Demonstrate a Hierarchical Oxidative Stress Response to Diesel Exhaust Particle Chemicals in

a Macrophage Cell Line. Journal of Biological Chemistry 278(50):5078150790. https://doi.org/10.1074/jbc.M306423200 Xin, L. , J. Wang , Y. Wu , S. Guo , and J. Tong . 2014. Increased Oxidative Stress and Activated Heat Shock Proteins in Human Cell Lines by Silver Nanoparticles. Human & Experimental Toxicology 34(3):315323. SAGE Publications. https://doi.org/10.1177/0960327114538988 Young, E. W. K. and D. J. Beebe . 2010. Fundamentals of Microfluidic Cell Culture in Controlled Microenvironments. Chemical Society Reviews 39(3):10361048. https://doi.org/10.1039/b909900j Zervantonakis, I. K. , C. R. Kothapalli , S. Chung , R. Sudo , and R. D. Kamm . 2011. Microfluidic Devices for Studying Heterotypic Cell-Cell Interactions and Tissue Specimen Cultures under Controlled Microenvironments. Biomicrofluidics 5(1):114. https://doi.org/10.1063/1.3553237 Zhang, L. W. , W. W. Yu , V. L. Colvin , and N. A. Monteiro-Riviere . 2008. Biological Interactions of Quantum Dot Nanoparticles in Skin and in Human Epidermal Keratinocytes. Toxicology and Applied Pharmacology 228(2):200211. https://doi.org/10.1016/j.taap.2007.12.022 Zou, J. , X. Wang , L. Zhang , and J. Wang . 2015. Iron Nanoparticles Significantly Affect the In Vitro and In Vivo Expression of Id Genes. Chemical Research in Toxicology 28(3):373383. https://doi.org/10.1021/tx500333q

Methods and Protocols for In Vivo Animal Nanotoxicity Evaluation: A Detailed Review Adamcakova-Dodd, A. , L. V. Stebounova , J. S. Kim , S. U. Vorrink , A. P. Ault , P. T. O'Shaughnessy , V. H. Grassian , and P. S. Thorne . 2014. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murineinhalation models. Part Fibre Toxicol 11:15. doi: 10.1186/1743-8977-11-15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994238/ Adams, L. , D. Lyon , A. McIntosh , and P. Alvarez . 2006a. Comparative toxicity of nano-scale TiO2, SiO2 and ZnO water suspensions. Water Sci Technol 54:327334. Adams, L. K. , D. Y. Lyon , and P. J. J. Alvarez . 2006b. Comparative eco-toxicity of nanoscale TiO2, SiO2, and ZnO water suspensions. Water Res 40:35273532. Alestrm, P. , J. L. Holter , and R. Nourizadeh-Lillabadi . 2006. Zebrafish in functional genomics and aquatic biomedicine. Trends Biotechnol 24:1521. Ambalavanan, N. , A. Stanishevsky , A. Bulger , B. Halloran , C. Steele , Y. Vohra , and S. Matalon . 2013. Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice. Am J Physiol Lung Cell Mol Physiol 304(3):L152161. doi: 10.1152/ajplung.00013.2012. https://ajplung.physiology.org/content/304/3/L152 Ames, B. , J. McCann , and E. Yamasaki . 1975. Methods for detecting carcinogens and mutagens with the salmonella/mammalian-microsome mutagenicity test. Mutat Res 31:347364. Asare, N. , N. Duale , H. H. Slagsvold 2015 Genotoxicity and gene expression modulation of silver and titanium dioxide nanoparticles in mice. Nanotoxicology 10(3):312321. https://doi.org/10.3109/17435390.2015.1071443 Asare, N. , C. Instanes , W. Sandberg 2012. Cytotoxic and genotoxic effects of silver nanoparticles in testicular cells. Toxicology 291:6572.374 Azad, N. , A. Iyer , V. Vallyathan , L. Wang , V. Castranova , C. Stehlik , and Y. Rojanasakul . 2010. Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation. Ann N Y Acad Sci 1203:16. doi: 10.1111/j.1749-6632.2010.05608.x. Azevedo, S. , F. Ribeiro , K. Jurkschat 2016. Co-exposure of ZnO nanoparticles and UV radiation to Daphnia magna and Danio rerio: Combined effects rather than protection. Environ Toxicol Chem 35:458467. Azqueta, A. , J. Slyskova , S. A. Langie , G. I. O'Neill , and A. Collins . 2014. Comet assay to measure DNA repair: Approach and applications. Front Genet 5:288. Review. file:///C:/Users/farmacologia/Downloads/fgene-05-00288.pdf Baird D. , A. Soares , A. Girling 1989a. The long-term maintenance of Daphnia magna Straus for use in ecotoxicity tests: Problems and prospects. In Proceedings of the First European Conference on Ecotoxicology, Lyngby, 1719 October, eds. Lokke, H. , H. Tyle , and F. BroRasmussen , pp. 144148. Baird, J. , I. Barber , M. Bradley 1989b. The Daphnia bioassay: A critique. Hydrobiology 188/189:403406.

Baisch, B. L. , N. M. Corson , P. Wade-Mercer , R. Gelein , A. J. Kennell , G. Oberdrster , and A. Elder . 2014. Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: The effect of dose rate on acute respiratory tract inflammation. Part Fibre Toxicol 11:5. doi: 10.1186/1743-8977-11-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905288/ Baky, N. , L. Faddah , N. Al-Rashid , N. Al-Rasheed , and A. Fatani . 2013. Induction of inflammation, DNA damage and apoptosis in rat heart after oral exposure to zinc oxide nanoparticles and the cardioprotective role of -lipoic acid and vitamin E. Drug Res (Stuttg) 63(5):228236. Barnes, C. , A. Elsaesser , J. Arkusz 2008. Reproducible comet assay of amorphous silica nanoparticles detects no genotoxicity. Nano Lett 8:30693074. Baun, A. , N. B. Hartmann , K. Grieger , and K. O. Kusk . 2008. Ecotoxicity of engineered nanoparticles to aquatic invertebrates: A brief review and recommendations for future toxicity testing. Ecotoxicology 17(5):387395. Review. PMID: 18425578. https://sci-hub.io Belyanskaya, L. , P. Manser , P. Spohn 2007. Carbon 45:26432648. Blinova I. , L. Kanarbik , N. Irha , and A. Kahru . 2015. Ecotoxicity of nanosized magnetite to crustacean Daphnia magna and duckweed Lemna minor. Hydrobiologia. doi:10.1007/s10750015-2540-6 Bopp, S. , M. Minuzzo , and T. Lettieri . 2006. The Zebrafish (Danio rerio): An Emerging Model Organism in the Environmental Field. Scientific and Technical Research Series 24. Borm, P. , F. Klaessig , T. Landry 2006. Research strategies for safety evaluation of nanomaterials, part V: Role of dissolution in biological fate and effects of nanoscale particles. Toxicol Sci 90:2332. Bowen, D. 2011. Evaluation of a multi-endpoint assay in rats, combining the bone-marrow micronucleus test, the Comet assay and the flow-cytometric peripheral blood micronucleus test. Mutation Res 722:719. Brookes, P. , E. Salinas , K. Darley-Usmar 2000. Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release. J Biol Chem 275:2047420479. Brown, D. , K. Donaldson , and V. Stone 2004. Effects of PM10 in human peripheral blood monocytes and J774 macrophages. Respir Res 5:29.375 Brown, G. and V. Borutaite . 2007. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 75:283290. Buford, M. , R. Hamilton , and A. Holian . 2007. A comparison of dispersing media for various engineered carbon nanoparticles. Part Fibre Toxicol 4:6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950524/pdf/1743-8977-4-6.pdf Bundschuh, M. , F. Seitz , R. Rosenfeldt 2012. Titanium dioxide nanoparticles increase sensitivity in the next generation of the water flea Daphnia magna. PLoS One 7(11):e48956. Calleja, M. and G. Persoone . 1992. Cyst-based toxicity tests. IV. The potential of ecotoxicological tests for the prediction of acute toxicity in man as evaluated on the first ten chemicals of the MEIC program. ALTA 20:396405. Cattaneo, A. , R. Gornati , M. Chiriva-Internati , and G. Bernardini . 2009. Ecotoxicology of nanomaterials: The role of invertebrate testing. Invertebrate Surv J 6:7897. Cel, P. , B. Vesel , E. Matalov , Z. Veea , and M. Buchtov . 2014. Embryonic toxicity of nanoparticles. Cells Tissues Organs 199(1):123. http://sci-hub.io/10.1159/000362163 Chakraborty, C. , A. R. Sharma , G. Sharma , and S. S. Lee . 2016. Zebrafish: A complete animal model to enumerate the nanoparticle toxicity. J Nanobiotechnology 14(1):65. https://jnanobiotechnology.biomedcentral.com/track/pdf/10.1186/s12951-016-02176?site=jnanobiotechnology.biomedcentral.com Chakraborty, C. , A. R. Sharma , G. Sharma , and S.-S. Lee . 2017. Zebrafish: A complete animal model to enumerate the nanoparticle toxicity. J Nanobiotechnol 14:65. doi: 10.1186/s12951-016-0217-6 Chen, H. , A. Dorrigan , S. Saad , D. J. Hare , M. B. Cortie , and S. M. Valenzuela . 2013. In vivo study of spherical gold nanoparticles: Inflammatory effects and distribution in mice. PLoS ONE 8(2):e58208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585265/ Chen, T. , J. Yan , and Y. Li . 2014. Genotoxicity of titanium dioxide nanoparticles. J Food Drug Anal 22(1):95104. Chen, T. H. , C. Y. Lin , and M. C. Tseng . 2011. Behavioral effects of titanium dioxide nanoparticles on larval zebrafish (Danio rerio). Mar Pollut Bull 63:303308. Chen, Y. , X. Hu , J. Sun , and Q. Zhou . 2016. Specific nanotoxicity of graphene oxide during zebrafish embryogenesis. Nanotoxicology 10(1):4252. doi: 10.3109/17435390.2015.1005032. https://academic.oup.com/toxsci/article/1639278 Cheng, J. , E. Flahaut , and S. H. Cheng . 2007. Effect of carbon nanotubes on developing zebrafish (Danio rerio) embryos. Environ Toxicol Chem 26(4):708716. PMID:17447555.

Choi, J. E. , S. Kim , J. H. Ahn , P. Youn , J. S. Kang , K. Park , J. Yi , and D. Y. Ryu . 2010. Induction of oxidative stress and apoptosis by silver nanoparticles in the liver of adult zebrafish. Aquat Toxicol 100(2):151159. http://sci-hub.io/10.1016/j.aquatox.2009.12.012 Circu, M. and T. Aw . 2010. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48:749762. Clemente, Z. , V. L. Castro , L. O. Feitosa , R. Lima , C. M. Jonsson , A. H. Maia , and L. F. Fraceto . 2013. Fish exposure to nano-TiO2 under different experimental conditions: Methodological aspects for nanoecotoxicology investigations. Sci Total Environ 463464:647656. Clemente, Z. , V. L. Castro , M. A. Moura , C. M. Jonsson , and L. F. Fraceto . 2014. Toxicity assessment of TiO2 nanoparticles in zebrafish embryos under different exposure conditions. Aquat Toxicol 147:129139. https://www.researchgate.net/profile/Vera_Castro/publication/25971985 Collins, A. 2004. The Comet assay for DNA damage and repair: Principles, applications, and limitations. Mol Biotechno 26:249261. Collins, A. , M. Dusinska , M. Franklin 1997. Comet Assay in human biomonitoring studies: Reliability, validation, and applications. Environ Mol Mutagen 30:139146.376 Collins, A. , M. Dusinsk , and A. Horsk . 2001. Detection of alkylation damage in human lymphocyte DNA with the comet assay. Acta Biochim Pol 48:611614. Crist, R. , J. Grossman , A. Patri 2013. Common pitfalls in nanotechnology: Lessons learned from NCI's nanotechnology characterization laboratory. Intgr Biol 5:6673. Cui, D. , F. Tian , C. S. Ozkan , M. Wang , and H. Gao . 2005. Effect of single wall carbon nanotubes on human HEK293 cells. Toxicol Lett 155:7385. Dahl, A. 1989. Metabolic characteristics of the respiratory tract. In: Concepts in Inhalation Toxicology, eds. McClellan, R. O. and R. F. Henderson . New York: Hemisphere, pp. 141160. D'Costa, A. and I. T. Shepherd . 2009. Zebrafish development and genetics: Introducing undergraduates to developmental biology and genetics in a large introductory laboratory class. Zebrafish 6(2):169177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774836/ DeGeorge J. J. , C. H. Ahn , P. A. Andrews 1997. Considerations for toxicology studies of respiratory drug products. Regul Toxicol Pharmacol 252:189193. Dehghani, N. , A. Noori , and M. Modaresi . 2014. Investigating the effect of titanium dioxide nanoparticles on the growth and sexual maturation of male rats. Inter J Basic Scien Appl Res 3(11):772776. http://www.isicenter.org/fulltext/paper-324.pdf Demokritou, P. , S. Gass , G. Pyrgiotakis 2013. An in vivo and in vitro toxicological characterisation of realistic nanoscale CeO2 inhalation exposures. Nanotoxicology 7(8):13381350. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438163/ Dhawan, A. and V. Sharma . 2010. Toxicity assessment of nanomaterials: Methods and challenges. Anal Bioanal Chem 398(2):589605. doi: 10.1007/s00216-010-3996-x Doak, S. , S. Griffiths , B. Manshian 2009. Confounding experimental considerations in nanogenotoxicology. Mutagenesis 24:285293. Dominguez, G. , S. Lohse , M. Torelli 2015. Effects of charge and surface ligand properties of nanoparticles on oxidative stress and gene expression within the gut of Daphnia magna. Aquat Toxicol 162:19. Downs, T. , M. Crosby , T. Hu 2012. Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not. Mutat Res 745(12):3850. Driscoll, K. E. , D. L. Costa , G. Hatch , R. Henderson , G. Oberdrster , H. Salem , and R.B. Schlesinger . 2000. Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: Uses and limitations, Toxicol Sci 55:2435. Drge, W. 2002. Free radicals in the physiological control of cell function. Physiol Rev 82:4795. Dunnick, K. M. , A. M. Morris , M. A. Badding 2016. Evaluation of the effect of valence state on cerium oxide nanoparticle toxicity following intratracheal instillation in rats. Nanotoxicology 10(7):9921000. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889510/ 377 Ema, M. , J. Tanaka , N. Kobayashi 2012a. Genotoxicity evaluation of fullerene C60 nanoparticles in a comet assay using lung cells of intratracheally instilled rats. Regul Toxicol Pharmacol 62(3):419424. Ema, M. , T. Imamura , H. Suzuki , N. Kobayashi , M. Naya , and J. Nakanishi . 2012b. Evaluation of genotoxicity of multi-walled carbon nanotubes in a battery of in vitro and in vivo assays. Regul Toxicol Pharmacol 63(2):188195. Erdmann, K. , B. Cheung , S. Immenschuh 2008. Heme oxygenase-1 is a novel target and antioxidant mediator of S-adenosylmethionine. Biochem Biophys Res Commun 368:937941. Erusalimsky, J. and S. Moncada . 2007. Nitric oxide and mitochondrial signaling: From physiology to pathophysiology. Arterioscler Thromb Vasc Biol 27:25242531.

Fabrega, J. , S. N. Luoma , C. R. Tyler , T. S. Galloway , and J. R. Lead . 2011. Silver nanoparticles: Behaviour and effects in the aquatic environment. Environ Int 37(2):517531. https://www.researchgate.net/profile/Samuel_Luoma/publication/49684482 Fahmy, B. and S. Cormier . 2009. Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. Toxicol In Vitro 23:13651371. Fenech, M. 2000. The in vitro micronucleus technique. Mutat Res 455:8195. Fenech, M. and A. Morley . 1985a. Solutions to the kinetic problem in the micronucleus assay. Cytobios 43:233246. Fenech, M. and A. Morley . 1985b. Measurement of micronuclei in lymphocytes. Mutat Res 147:2936. Filho J. de S. , E. Y. Matsubara , L. P. Franchi , I. P. Martins , L. M. Rivera , J. M. Rosolen , and C. K. Grisolia . 2014. Evaluation of carbon nanotubes network toxicity in zebrafish (Danio rerio) model. Environ Res 134:916. https://www.researchgate.net/profile/Jose_De_Souza_Filho3/publication/264085282 Fischer, H. C. and W. C. Chan . 2007. Nanotoxicity: The growing need for in vivo study. Curr Opin Biotechnol 18(6):565571. Epub 2007 Dec 21. Forbe, T. , M. Garca , and E. Gonzalez . 2011. Potencial risks of nanoparticles. Cinc Tecnol Aliment Campinas 31(4):835842. http://www.scielo.br/pdf/cta/v31n4/02.pdf Freshney, R. I. 2005. Culture of Animal Cells: A Manual of Basic Techniques. USA: John Wiley. Fujiwara, R. , Y. Luo , T. Sasaki 2015. Cancer therapeutic effects of titanium dioxide nanoparticles are associated with oxidative stress and cytokine induction. Pathobiology 82(6):243251. https://doi.org/10.1159/000439404 Garca-Corvillo, M. P. 2016. Nanopartculas polimricas de administracin intranasal para la liberacin de activos en el sistema nervioso central. Ars Pharm 57(1):2735. Gatti, A. 2004. Biocompatibility of micro- and nano-particles in the colon. Part II. Biomaterials 25(3):385392. George, S. , H. Gardner , E. K. Seng , H. Chang , C. Wang , C. H. Fang Yu , M. Richards , S. Valiyaveettil , and W. K. Chan . 2014. Differential effect of solar light in increasing the toxicity of silver and titanium dioxide nanoparticles to a fish cell line and zebrafish embryos. Environ Sci Technol 48(11):63746382. Gillespie, P. A. , G. S. Kang , A. Elder , R. Gelein , L. Chen , A. L. Moreira , J. Koberstein , K. M. Tchou-Wong , T. Gordon , and L. C. Chen . 2010. Pulmonary response after exposure to inhaled nickel hydroxide nanoparticles: Short and long-term studies in mice. Nanotoxicology 4(1):106119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922767/ Glei, M. , T. Schneider , and W. Schlrmann . 2016. Comet assay: An essential tool in toxicological research. Arch Toxicol 90(10):23152336.378 Gmez-Gaete, C. 2014. Nanopartculas polimricas: Tecnologa y aplicaciones farmacuticas. Rev Farmacol Chile 7(2):716. Gonzalez, L. , J. Sanderson , and M. Kirsch-Volders . 2011. Adaptations of the in vitro MN assay for the genotoxicity assessment of nanomaterials. Mutagenesis 26:185191. https://academic.oup.com/mutage/article/26/1/185/1066742 Graham, U. M. , M. T. Tseng , J. B. W. Jasinski 2014. In vivo processing of ceria nanoparticles inside liver: Impact on free-radical scavenging activity and oxidative stress. Chempluschem 79(8):10831088. http://sci-hub.io/10.1002/cplu.201402080 Guo, X. , Y. Li , J. Yan 2016. Size- and coating-dependent cytotoxicity and genotoxicity of silver nanoparticles evaluated using in vitro standard assays. Nanotoxicology 10:13731384. Guttenberg, M. , L. Bezerra , N. M. Neu-Baker 2016. Biodistribution of inhaled metal oxide nanoparticles mimicking occupational exposure: A preliminary investigation using enhanced darkfield microscopy. J Biophotonics 9(10):987993. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291524/ Gutteridge, J. M. 1986. Aspects to consider when detecting and measuring lipid peroxidation. Free Radic Res Commun 1:173184. Gutteridge, J. M. and B. Halliwell . 2000. Free radicals and antioxidants in the year 2000. A historical look to the future. Ann N Y Acad Sci 899:136147. https://www.ncbi.nlm.nih.gov/pubmed/10863535 Hail, N. Jr and R. Lotan . 2009. Cancer chemoprevention and mitochondria: Targeting apoptosis in transformed cells via the disruption of mitochondrial bioenergetics/redox state. Mol Nutr Food Res 53(1):4967. Hayashi M. , T. Morita , Y. Kodama 1990. The micronucleus assay with mouse peripheral blood reticulocytes using acridine orange-coated slides. Mutat Res 245:245249. He, J. H. , J. M. Gao , C. J. Huang , and C. Q. Li . 2014. Zebrafish models for assessing developmental and reproductive toxicity. Neurotoxicol Teratol 42:3542. doi: 10.1016/j.ntt.2014.01.006

Heddle, J. , M. Hite , B. Kirkhart 1983. The induction of micronuclei as a measure of genotoxicity. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res 123:61118. Heddle, M. 1973. A rapid in vivo test for chromosomal damage. Mutat Res 18:187190. Hennes, C. , M. Batke , W. Bomann 2014 Incorporating potency into EU classification for carcinogenicity and reproductive toxicity. Regul Toxicol Pharmacol 70:457467. Hickey, L. and L. Garcia-Contreras . 2001. Immunological and toxicological implications for short-term studies in animals of pharmaceutical aerosol delivery to the lungs: Relevance to humans. Crit Rev Therap Drug Carrier Systems 184:387431. Hill, A. , H. Teraoka , W. Heidemann , and R. Peterson . 2005. Zebrafish as model vertebrate for investigating chemical toxicity. Toxicol Sci 86:619. PubMed: 15703261 Hosseini, A. , A. M. Sharifi , and M. Abdollahi . 2015. Cerium and yttrium oxide nanoparticles against lead-induced oxidative stress and apoptosis in rat hippocampus. Biol Trace Elem Res 164(1):8089. https://doi.org/10.1007/s12011-014-0197-z Hou, W. C. , P. Westerhoff , and J. D. Posner . 2013. Biological accumulation of engineered nanomaterials: A review of current knowledge. Environ Sci Process Impacts 15(1):103122. http://pubs.rsc.org/en/content/articlehtml/2013/em/c2em30686g 379 Jackson, P. , N. Jacobsen , A. Baun 2013. Bioaccumulation and ecotoxicity of carbon nanotubes. Chem Cent J 7:154. Jensen, F. 2009. The role of nitrite in nitric oxide homeostasis: A comparative perspective. Biochim Biophys Acta 1787:841848. Juang, Y. M. , B. H. Lai , H. J. Chien 2014. Changes in protein expression in rat broncho alveolar lavage fluid after exposure to zinc oxide nanoparticles: An iTRAQ proteomic approach. Rapid Commun Mass Spectrom 28(8):974980. https://doi.org/10.1002/rcm.6866 Karlsson, H. 2010. The comet assay in nanotoxicology research. Anal Bioanal Chem 398:651666. Khangarot, B. , P. Ray , and H. Chandra . 1987. Daphnia magna as a model to assess heavy metal toxicity: Comparative assessment with mouse system. Acta Hydrochem Hydrobiol 15:427432. Khanna, P. , C. Ong , B. B. Huat , and B. G. Hun . 2015. Nanotoxicity: An interplay of oxidative stress, Inflammation and cell death. Nanomaterials 5:11631180. Kimmel, B. , W. Ballard , S. Kimmel , B. Ullmann , and T. Schilling . 1995. Stages of embryonic development of the zebrafish. Dev Dyn 203:253310. Kirkland, D. , L. Reeve , D. Gatehouse , and P. Vanparys . 2011. A core in vitro genotoxicty battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins. Mutat Res 721:2773. Knaapen, A. , P. Borm , C. Albrecht , and R. Schins . 2004. Inhaled particles and lung cancer. Part A: Mechanisms. Int J Cancer 109:799809. Knaapen, A. M. , F. Seiler , P. A. Schilderman 1999. Neutrophils cause oxidative DNA damage in alveolar epithelial cells. Free Radical Biol Med 27:234240. Kolamunne, R. , M. Clare , and H. R. Griffiths . 2011. Mitochondrial superoxide anion radicals mediate induction of apoptosis in cardiac myoblasts exposed to chronic hypoxia. Arch Biochem Biophys 505:256265. Kovrinych, J. A. , R. Sotnkov , D. Zeljenkov , E. Rollerov , and E. Szabov . 2014. Long-term (30 days) toxicity of NiO nanoparticles for adult zebrafish Danio rerio . Interdiscip Toxicol 7(1):2326. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427711/ Kruman, I. , T. Kumaravel , A. Lohani 2002. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci 22:17521762. Kumaravel, T. and R. Bristow . 2005. Detection of genetic instability at HER-2/neu and p53 loci in breast cancer cells using Comet-FISH. Breast Cancer Res Treat 91:8993. Kumari, M. , S. I. Kumari , P. Grover . 2014. Genotoxicity analysis of cerium oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral administration. Mutagenesis 29(6):467479. https://academic.oup.com/mutage/article/29/6/467/2883270 Kwon, J.Y. , H. L. Kim , J. Y. Lee 2014. Undetectable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests. Int J Nanomedicine. 9(Suppl 2):173181. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279720/ 380 Landsiedel, R. , L. Ma-Hock , B. Van Ravenzwaay , M. Schulz , K. Wiench , S. Champ , S. Schulte , W. Wohlleben , and F. Oesch . 2010a. Gene toxicity studies on titanium dioxide and zinc oxide nanomaterials used for UV-protection in cosmetic formulations. Nanotoxicol 4:364381. Landsiedel, R. , L. Ma-Hock , A. Kroll , D. Hahn , J. Schnekenburger , K. Wiench , and W. Wohlleben . 2010b. Testing metal-oxide nanomaterials for human safety. Adv Mater 22:26012627. doi: 10.1002/adma.200902658.

Langenheinrich, U. 2003 Zebrafish: A new model on the pharmaceutical catwalk. BioEssays 25:904912. Lee, J. F. , S. P. Tung , D. Wang , D. Y. Yeh , Y. Fong , Y. C. Young , and F. J. Leu . 2014. Lipoxygenase pathway mediates increases of airway resistance and lung inflation induced by exposure to nanotitanium dioxide in rats. Oxid Med Cell Longev. 2014 (February):485604. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945789/ Lee, S. W. , S. M. Kim , and J. Choi . 2009. Genotoxicity and ecotoxicity assays using the freshwater crustacean Daphnia magna and the larva of the aquatic midge Chironomus riparius to screen the ecological risks of nanoparticle exposure. Environ Toxicol Pharmacol 28(1):8691. http://linkinghub.elsevier.com./retrieve/pii/S1382-6689(09)00038-6 Li, N. , C. Sioutas , A. Cho 2003. Ultrafine particulate pollutants Induce oxidative stress and mitochondrial damage environ. Health Persp 111:455460. Li, Y. , D. Chen , J. Yan 2011. Genotoxicity of silver nanoparticles evaluated using the Ames test and in vitro micronucleus assay. Mutat Res. 745:410. Lin, S. , Y. Zhao , Z. Ji 2013. Zebrafish high-throughput screening to study the impact of dissolvable metal oxide nanoparticles on the hatching enzyme, ZHE1. Small 9(910):17761785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034474/ Lin, W. , I. Stayton , Y. Huang , X. Zhou , and Y. Ma . 2008. Cytotoxicity and cell membrane depolarization induced by aluminum oxide nanoparticles in human lung epithelial cells A549. Toxicol Environ Chem 90:983996. Linder, J. and S. I. Rennard . 1988. Bronchoalveolar Lavage. Chicago, IL: ASCP Press, p. 179. Linderholm, A. L. , L. M. Franzi , K. J. Bein 2015. A quantitative comparison of intranasal and intratracheal administration of coarse PM in the mouse. Integr Pharm Toxicol Genotoxicol 1(1):510. https://oatext.com/pdf/IPTG-1-103.pdf Lockman, P. R. , R. J. Mumper , M. A. Khan , and D. D. Allen . 2002. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm Journal 28:113. Long, H. , T. Shi , P. Borm 2004. ROS mediated TNF- and MIP-2 gene expression in alveolar macrophages exposed to pine dust. Part Fibre Toxicol 1:3. Lopes, S. , F. Ribeiro , J. Wojnarowicz 2014. Zinc oxide nanoparticles toxicity to Daphnia magna: Size-dependent effects and dissolution. Environ Toxicol Chem 33(1):190198. Lpez-Serrano, A. , R. Muoz-Olivas , J. Sanz-Landaluze , M. Olasagasti , S. Rainieri , and C. Cmara . 2014. Comparison of bioconcentration of ionic silver and silver nanoparticles in zebrafish eleutheroembryos. Environ Pollut 191:207214. https://www.researchgate.net/profile/Ana_Lopez-Serrano/publication/262607736 Lovern, S. and R. Klaper . 2006. Daphnia magna mortality when exposed to titanium dioxide and fullerene (C60) nanoparticles. Environ Toxicol Chem 25:11321137. Lovern, S. , J. Strickler , and R. Klaper . 2007. Behavioral and physiological changes in Daphnia magna when exposed to nanoparticle suspensions (titanium dioxide, nano-C60, and C60HxC70Hx). Environ Sci Technol 41:44654470.381 Lu, M. and X. Gong . 2009. Upstream reactive oxidative species (ROS) signals in exogenous oxidative stress-induced mitochondrial dysfunction. Cell Biol Int 33:658664. Ma, J. , H. Zhao , R. Mercer , M. Barger , M. Rao , T. Meighan , D. Schwegler-Berry , V. Castranova and J. Ma . 2011. Cerium oxide nanoparticle-induced pulmonary inflammation and alveolar macrophage functional change in rats. Nanotoxicol 5(3):312325. Ma, S. and D. Lin . 2013. The biophysicochemical interactions at the interfaces between nanoparticles and aquatic organisms: Adsorption and internalization. Environ Sci Processes Impact 15:145160. MacGregor, J. , J. Heddle , M. Hite 1987. Guidelines for the conduct of micronucleus assays in mammalian bone marrow erythrocytes. Mutat Res 189:103112. MacGregor, J. , R. Schlegel , W. Choy , and C. Wehr . 1983. Micronuclei in circulating erythrocytes: A rapid screen for chromosomal damage during routine toxicity testing in mice. Dev Toxicol Environ Sci 11:555558. MacGregor, J. , C. Wehr , P. Henika , and M. Shelby . 1990. The in vivo erythrocyte micronucleus test: Measurement at steady state increases assay efficiency and permits integration with toxicity studies. Fundam Appl Toxicol 14:513522. Madl, A. , L. Plummer , C. Carosino , and K. Pinkerton . 2014. Nanoparticles, lung injury, and the role of oxidant stress. Annu Rev Physiol 76:447465. Magdolenova, Z. , Y. Lorenzo , A. Collins , and M. Maria Dusinska . 2012. Can standard genotoxicity tests be applied to nanoparticles? J Toxicol Environmen Health A 75:800806. Mahdieh, Y. , S. Sajad , G. Mahmoudreza 2015. The effects of titanium dioxide nanoparticles on pituitary-gonad axis in male mice. J Chem Pharma Res 7(10):720772. http://www.jocpr.com/articles/the-effects-of-titanium-dioxide-nanoparticles-on-pituitarygonadaxis-in-male-mice.pdf

Manke, A. , L. Wang , and Y. Rojanasakul . 2013. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762079/pdf/BMRI2013-942916.pdf Maron, D. and B. Ames . 1983. Revised methods for the Salmonella mutagenicity test. Mutat Res 113:173215. Mavournin, K. , D. Blakey , M. Cimino , M. Salamone , and J. Heddle . 1990. The in vivo micronucleus assay in mammalian bone marrow and peripheral blood. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res 239:2980. McKelvey-Martin, V. , E. Ho , S. McKeown 1998 Emerging applications of the single cell gel electrophoresis (Comet) assay. I. Management of invasive transitional cell human bladder carcinoma. II. Fluorescent in situ hybridization Comets for the identification of damaged and repaired DNA sequences in individual cells. Mutagenesis 13:18. McKenna, D. , B. Doherty , C. Downes , S. McKeown , and V. McKelvey-Martin . 2012. Use of the Comet-FISH assay to compare DNA damage and repair in p53 and hTERT genes following ionizing radiation. PLoS One 7:e49364. Mills, N. , N. Amin , S. Robinson 2006. Do inhaled carbon nanoparticles translocate directly into the circulation in humans? Am J Resp Criti Care 173:426431. Minetto, D. , G. Libralato , and A. V. Ghirardini . 2014. Ecotoxicity of engineered TiO2 nanoparticles to saltwater organisms: An overview. Environ Int 66:1827.382 Mitchelmore, C. L. and J. K. Chipman . 1998. DNA strand breakage in aquatic organisms and the potential value of the comet assay in environmental monitoring. Mutation Res 399:135147. Monteiro-Riviere, N. A. and Inman, A. O. 2006. Challenges for assessing carbon nanomaterial toxicity to the skin. Carbon. 44:10701078. https://www.researchgate.net/publication/233802042_MonteiroRiviere_NA_AO_Inman_2006_Challenges_for_assessing_carbon_nanomaterial_toxicity_to_th e_skin_Carbon_44610701078. Morimoto, Y. , H. Izumi , Y. Yoshiura 2016. Evaluation of pulmonary toxicity of zinc oxide nanoparticles following inhalation and intratracheal instillation. Int J Mol Sci 17(8):116. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000639/ Murdock, R. C. , L. Braydich-Stolle , A. M. Schrand , J. J. Schlager , and S. M. Hussain . 2008. Characterization of nanomaterial dispersion in solution prior to in vitro exposure using dynamic light scattering technique. Toxicol Sci 101(2):239253. https://academic.oup.com/toxsci/article/1639278 Murray, A. , E. Kisin , S. Leonard 2009. Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubes. Toxicology 257:161171. Mwaanga, P. , E. Carraway , and P. van den Hurk . 2014. The induction of biochemical changes in Daphnia magna by CuO and ZnO nanoparticles. Aquat Toxicol 150:201209. Navarro, E. , F. Piccapietra , B. Wagner , F. Marconi , R. Kaegi , N. Odzak , L. Sigg , and R. Behra . 2008. Toxicity of silver nanoparticles to Chlamydomonas reinhardtii. Environ Sci Technol 42(23):89598964. Nel, A. , T. Xia , L. Madler , and N. Li . 2006. Toxic potential of materials at the nanolevel. Science 311:622627. http://www.oecd.org/chemicalsafety/risk-assessment/1948418.pdf, consultada octubre 01/2016. Nemmar, A. , S. Beegam , P. Yuvaraju 2016a. Ultrasmall superparamagnetic iron oxide nanoparticles acutely promote thrombosis and cardiac oxidative stress and DNA damage in mice. Particle Fibre Toxicol 13:22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852430/ Nemmar, A. , P. Yuvaraju , S. Beegam , J. Yasin , E. E. Kazzam , and B. H. Ali . 2016b. Oxidative stress, inflammation, and DNA damage in multiple organs of mice acutely exposed to morphous silica nanoparticles. Inter J Nanomedicine 11:919928. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788369/ Oberdrster, E. 2004. Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain of juvinile largemouth bass. Environ Health Perspect 112:10581062. Oberdrster, E. , S. Zhu , M. Blickley , P. Mcclellan-Green , and M. Haasch . 2006. Ecotoxicology of carbon-based engineered nanoparticles: Effects of fullerene (C60) on aquatic organisms. Carbon 44:11121120.383 Oberdrster, G. , A., Maynard , K. Donaldson 2005a. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part Fibre Toxicol 2:8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1260029/ Oberdrster, G. , E. Oberdrster , and J. Oberdrster . 2005b. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles Environ Health Perspect 113:823839. Oberdrster, G. , Z. Sharp , V. Atudorei , A. Elder , R. Gelein , W. Kreyling , and C. Cox . 2004. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16:437445. O'Donovan, M. and B. Burlinson . 2013. Maximum dose levels for the rodent comet assay to examine damage at the site of contact or to the gastrointestinal tract. Mutagenesis 28:621623.

OECD . 2002. Test No. 423: Acute Oral toxicityAcute Toxic Class Method. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264071001-en OECD . 2004. Test No. 202. Dapnia sp. Acute Immobilisation test. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264069947-en OECD . 2004. Test No. 434. Acute Dermal ToxicityFixed Dose Procedure. Paris: OECD Publishing. http://www.oecd.org/chemicalsafety/testing/32037747.pdf OECD . 2009. Test No. 405: Acute Eye Irritation/Corrosion. Paris: OECD Publishing. https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-tg405-2012-508.pdf OECD . 2009. Test No. 412: Subacute Inhalation Toxicity: 28-Day Study. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264070806-en OECD . 2009. Test No 413. Subchronic Inhalation Toxicity: 90-Day Study. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264070806-en OECD . 2009. Test No. 436. Acute Inhalation ToxicityAcute Toxic Class Method. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264076037-en OECD . 2009. Test No. 453. Combined Chronic Toxicity/Carcinogenicity Studies. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264071223-en OECD . 2012. Test 305. Bioaccumulation in Fish: Aqueous and Dietary Exposure. Paris: OECD Publishing. http://www.oecd.org/chemicalsafety/testing/49190738.pdf OECD . 2012. Test No. 40. Guidance on Sample Preparation and Dosimetry for the Safety Testing of Manufactured Nanomaterials. Paris: OECD Publishing. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2012) 40&docLanguage=En OECD . 2012. Test No. 211. Dapnia Magna Reproduction Test. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264185203-en OECD . 2014. Test No. 203: Fish, Acute Toxicity Test. Paris: OECD Publishing. https://www.oecd.org/chemicalsafety/testing/Draft-Update-TG-203-for-commenting.pdf OECD . 2014. Test No. 474: Mammalian Erythrocyte Micronucleus Test. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264224292-en OECD . 2014. Test 489. Assays Comet In Vivo. Paris: OECD Publishing. https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-tg489-2014.pdf OECD . 2015. Test No. 215: Fish Juvenile Growth Test. Paris: OECD Publishing. http://enfo.agt.bme.hu/drupal/sites/default/files/C14web2001.pdf OECD . 2015. Test No. 404: Acute Dermal Irritation/Corrosion. Paris: OECD Publishing. http://dx.doi.org/10.1787/9789264242678-en Olive, P. , Banath, J. , and Durand, R. 1990. Heterogeneity in radiation-induced DNAdamage and repair in tumor and normal cells using the comet assay. Radiat Res 122:8694. Ostling, O. and K. J. Johanson . 1984. Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. Biochem Biophys Res Commun 123:291298.384 Owens, D. E. III and N. A. Peppas . 2006. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307(1):93102. Epub 2005 Nov 21. http://s3.amazonaws.com/academia.edu.documents/6550334/intjourpharm_307_93102_2006_.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1501198114&Signat ure=6%2BIP5YgVmccE3g%2FvWbc%2Bci2xXGg%3D&response-contentdisposition=inline%3B%20filename%3DOpsonization_biodistribution_and_pharmac.pdf Pati, R. , I. Das , R. Mehta , R. Sahu , and A. Sonawane . 2016. Zinc-Oxide nanoparticles exhibit genotoxic, clastogenic, cytotoxic and actin depolymerization effects by inducing oxidative stress responses in macrophages and adult mice. Toxicol Scien 150(2):454472. http://sci-hub.io/10.1093/toxsci/kfw010 Patlolla, A. K. , D. Hackett , and P. B. Tchounwou . 2015 Silver nanoparticle induced oxidative stress-dependent toxicity in Sprague-Dawley rats. Mol Cell Biochem 399(January):257268. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268425/pdf/nihms639114.pdf Pauluhn, J. 2003. Overview of testing methods used in inhalation toxicity: From facts to artifacts. Toxicol Lett 140141:183193. Pauluhn, J. and U. Mohr . 2000. Inhalation studies in laboratory animalscurrent concepts and alternatives. Toxicol Pathol 28(5):734753. http://sci-hub.io/10.1177/019262330002800514 Petersen, E. J. , J. Akkanen , J. V. Kukkonen , and W. J. Weber, Jr . 2009. Biological uptake and depuration of carbon nanotubes by Daphnia magna . Environ Sci Technol 43(8):29692975. https://www.ncbi.nlm.nih.gov/pubmed/19475979 Petersen, E. J. and B. C. Nelson . 2010. Mechanisms and measurements of nanomaterialinduced oxidative damage to DNA. Anal Bioanal Chem 398:613650. Petersen, E. J. , R. Pinto , D. Mai , P. Landrum , and W. Weber, Jr . 2011. Influence of polyethyleneimine graftings of multi-walled carbon nanotubes on their accumulation and elimination by and toxicity to Daphnia magna. Environ Sci Technol 45(3):11331138.

Pirela, S. V. , X. Lu , I. Miousse 2016. Effects of intratracheally instilled laser printer-emitted engineered nanoparticles in a mouse model: A case study of toxicological implications from nanomaterials released during consumer use. NanoImpact 1:18. http://scihub.io/10.1016/j.impact.2015.12.001 Poderoso, J. 2009. The formation of peroxynitrite in the applied physiology of mitochondrial nitric oxide. Arch Biochem Biophys 484:214220. Porter, D. , K. Sriram , M. Wolfarth , A. Jefferson , D. Schwegler-Berry , M. Andrew , and V. Castranova . 2008. A biocompatible medium for nanoparticle dispersion. Nanotoxicology 2(3):144154. http://sci-hub.io/http://dx.doi.org/10.1080/17435390802318349 Poynton, H. , J. Lazorchak , C. Impellitteri 2011. Differential gene expression in Daphnia magna suggests distinct modes of action and bioavailability for ZnO nanoparticles and Zn ions. Environ Sci Technol 45:762768. Rapp, A. , C. Bock , H. Dittmar , and K. Greulich . 1999 Comet-fish used to detect UV-A sensitive regions in the whole human genome and on chromosome 8. Neoplasma 46(suppl_1):90101. Ray, P. , B. Huang , and Y. Tsuji . 2012. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981990. Recio, L. , C. Hobbs , W. Caspary , and K. Witt . 2010. Dose-response assessment of four genotoxic chemicals in a combined mouse and rat micronucleus (MN) and Comet assay protocol. J Toxicol Sci 35(2):149162.385 Recordati, C. , M. De Maglie , S. Bianchessi 2016. Tissue distribution and acute toxicity of silver after single intravenous administration in mice: Nano-specific and size-dependent effects. Part Fibre Toxicol 13(12). https://dx.doi.org/10.1186%2Fs12989-016-0124-x Reddy, U. A. , P. V. Prabhakar , and M. Mahboob . 2015. Biomarkers of oxidative stress for in vivo assessment of toxicological effects of iron oxide nanoparticles. Saudi J Biological Sci. http://dx.doi.org/10.1016/j.sjbs.2015.09.029 Ren, L. , J. Zhang , Y. Zou , L. Zhang , J. Wei , Z. Shi , Y. Li , C. Guo , Z. Sun , and X. Zhou . 2016. Silica nanoparticles induce reversible damage of spermatogenic cells via RIPK1 signal pathways in C57 mice. Int J Nanomedicine 11:22512264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887058/ Richmond, J. 2002 Refinement, reduction, and replacement of animal use for regulatory testing: Future improvements and implementation within the regulatory framework. ILAR J. 43(Suppl_1):S63S68. doi: 10.1093/ilar.43.Suppl_1.S63 Risom, L. , P. Mller , and S. Loft . 2005. Oxidative stress-induced DNA damage by particulate air pollution. Mutat Res 592:119137. Rizzo, L. Y. , S. K. Golombek , M. E. Mertens 2013. In vivo nanotoxicity testing using the Zebrafish embryo assay. J Mater Chem 1:39183925. Roberts, J. R. , R. R. Mercer , A. B. Stefaniak 2016. Evaluation of pulmonary and systemic toxicity following lung exposure to graphite nanoplates: A member of the grapheme based nanomaterial family. Particle Fibre Toxicol 13:34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915050/ Rocha, A. , S. Ruiz , A. Estep , and J. M. Coll . 2001. Biologa molecular de los peces: Inters y aplicaciones. Revista Acuatic 15:110. Rojas-Muoz, A. , A. Bernard , and J. C. Izpisa . 2007. El pez cebra, versatilidad al servicio de la biomedicina. Investig Cienc 366:6669. Rossetto, A. , S. Melegari , L. Ouriques , and W. Matias . 2014. Comparative evaluation of acute and chronic toxicities of CuO nanoparticles and bulk using Daphnia magna and Vibrio fischeri. Sci Total Environ 490:807814. Rothfuss, A. , M. Honma , A. Czich 2011. Improvement of in vivo genotoxicity assessment: Combination of acute tests and integration into standard toxicity testing. Mutat Res 723:108120. Rothfuss, A. , M. O'Donovan , M. De Boeck 2010. Collaborative study on fifteen compounds in the rat-liver Comet assay integrated into 2- and 4-week repeat-dose studies. Mutat Res 702:4069. Rubinstein, A. 2006 Zebrafish assays for drug toxicity screening. Expert Opin Drug Metab Toxicol 2:231240. Ryman-Rasmussen, J. P. , J. E. Riviere , N. A. Monteiro-Riviere . 2007. Variables influencing interactions of untargeted quantum dot nanoparticles with skin cells and identification of biochemical modulators. Nano Lett 7:13441348. doi: 10.1021/nl070375j. Sager, T. M. , Porter, D. M. , Robinson, V. A. , Lindsley, W. G. , Schwegler-Berry, D. E. , and Castranova, V. 2007. Improved method to disperse nanoparticles for in vitro and in vivo investigation of toxicity. Nanotoxicology 1(2):118129. http://scihub.io/http://dx.doi.org/10.1080/17435390701381596 Santos, S. , N. Singh , and A. Natarajan . 1997. Fluorescence in situ hybridization with comets. Exp Cell Res 232:407411.

Sarkar, A. , M. Ghosh , and P. C. Sil . 2014. Nanotoxicity: Oxidative stress mediated toxicity of metal and metal oxide nanoparticles. J Nanosci Nanotechnol 14:730743. Schmid, W. 1975. The micronucleus test. Mutat Res 31:915.386 Sharma, V. , P. Singh , A. Pandey , and A. Dhawan . 2012. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res 745(12):8491. Shrivastava, R. , S. Raza , A. Yadav , A. Kushwaha , and J. S. Swaran . 2013. Effects of subacute exposure to TiO2, ZnO and Al2O3 nanoparticles on oxidative stress and histological changes in mouse liver and brain. Drug Chem Toxicol, Early Online: 112. http://scihub.io/10.3109/01480545.2013.866134 Singh, N. , R. Tice , R. Stephens , and E. Schneider . 1991. A microgel electrophoresis technique for the direct quantitation of DNA damage and repair in individual fibroblasts cultured on microscope slides. Mutat Res 252:289296. Singh, N. P. , M. T. McCoy , R. R. Tice , and E. L. Schneider . 1988. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184191. Sioutas, C. , R. Delfino , and M. Singh . 2005 Exposure assessment for atmospheric ultrafine particles (UFPs) and Implications in epidemiologic research. Environ Health Res 113:947955. Smith, C. , B. Shaw , and R. Handy . 2007. Toxicity of single walled carbon nanotubes to rainbow trout, (Oncorhynchus mykiss): Respiratory toxicity, organ pathologies, and other physiological effects. Aquat Toxicol 82:94109. Smith, M. A. , R. Michael , R. G. Aravindan , S. Dash , S. I. Shah , D. S. Galileo , and P. A. Martin-DeLeon . 2015. Anatase titanium dioxide nanoparticles in mice: Evidence for induced structural and functional sperm defects after short-, but not long-, term exposure. Asian J Androl 17(2):261268. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650460/pdf/AJA-17-261.pdf Soetaert, A. , L. N. Moens , K. Van der Ven , K. Van Leemput , B. Naudts , R. Blust , and W. M. De Coen . 2006. Molecular impact of propiconazole on Daphnia magna using a reproductionrelated cDNA array. Comp Biochem Physiol C Toxicol Pharmacol 142(12):6676. https://scihub.io/10.1016/j.cbpc.2005.10.009 Spitsbergen, J. and M. Kent . 2003 The state of the art of the zebrafish model for toxicology and toxicologic pathology research Advantages and current limitations. Toxicol Pathol 31(suppl.):6287. Stone, V. , H. Johnston , and R. Schins . 2009. Development of in vitro systems for nanotoxicology: Methodological considerations. Crit Rev Toxicol 39:613626. Stone, V. , J. Shaw , D. Brown , W. MacNee , S. Faux , and K. Donaldson . 1998 The role of oxidative stress in the prolonged inhibitory effect of ultrafine carbon black on epithelial cell function. Toxicol In Vitro 12:649659. Stone, V. , H. Johnston , and R. P. F. Schins . 2009. Development of in vitro systems for nanotoxicology: methodological considerations. Crit Rev Toxicol 39(7): 613626. https://www.researchgate.net/profile/Vicki_Stone/publication/26713070_Development_of_in_vitr o_systems_for_nanotoxicology_Methodological_considerations/links/0deec51641cf047523000 000/Development-of-in-vitro-systems-for-nanotoxicology-Methodological-considerations.pdf Tang, H. Q. , M. Xu , Q. Rong , R. W. Jin , Q. J. Liu , and Y. L. Li . 2016. The effect of ZnO nanoparticles on liver function in rats. Int J Nanomedicine 11:42754285. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012617/ Truong, L. , I. S. Moody , D. P. Stankus , J. A. Nason , M. C. Lonergan , and R. L. Tanguay . 2011. Differential stability of lead sulfide nanoparticles influences biological responses in embryoniczebrafish. Arch Toxicol 85(7):787798. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148102/ 387 Valenzuela, P. and J. A. Simon . 2012. Nanoparticle delivery for transdermal HRT. Maturitas 73(1):7480. http://sci-hub.io/10.1016/j.maturitas.2011.12.019 Valko, M. , D. Leibfritz , J. Moncol , M. Cronin , M. Mazur , and J. Telser . 2007. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:4484. Vasquez, M. 2010. Combining the in vivo Comet and micronucleus assays: A practical approach to genotoxicity testing and data interpretation. Mutagenesis 25:187199. Vicario-Pars, U. , L. Castaaga , J. M. Lacave , M. Oron , P. Reip , D. Berhanu , E. ValsamiJones , P. Miren , M. P. Cajaraville , and A. Amaia Orbea . 2014. Comparative toxicity of metal oxide nanoparticles (CuO, ZnO and TiO2) to developing zebrafish embryos. J Nanopart Res 16:2550. http://sci-hub.io/10.1007/s11051-014-2550-8 Wang, J. J. , B. J. Sanderson , and H. Wang . 2007. Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. Mutat Res 628:99106. Warheit, D. B. and E. M. Donner . 2015. Risk assessment strategies for nanoscale and finesized titanium dioxide particles: Recognizing hazard and exposure issues. Food Chem Toxicol 85:138147. http://sci-hub.io/10.1016/j.fct.2015.07.001

Watson, C. Y. , R. M. Molina , A. Louzada , K. M. Murdaugh , T. C. Donaghey , and J. D. Brain . 2015. Effects of zinc oxide nanoparticles on Kupffer cell phagosomal motility, bacterial clearance, and liver function. Int J Nanomedicine 10:41734184. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492628/pdf/ijn-10-4173.pdf Wells, M. A. , A. Abid , I. M. Kennedy , and A. I. Barakat . 2012. Serum proteins prevent aggregation of Fe2O3 and ZnO nanoparticles. Nanotoxicology 6:837846. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963816/pdf/nihms-540014.pdf Wick, P. , P. Manser , L. K. Limbach , U. Dettlaff-Weglikowska , F. Krumeich , S. Roth , W. J. Stark , and A. Bruinink . 2007. The degree and kind of agglomeration affect carbon nanotube cytotoxicity. Toxicol Lett 168(2):121131. PMID: 17169512 Wiench, K. , W. Wohlleben , V. Hisgen 2009. Acute and chronic effects of nano- and non-nanoscale TiO(2) and ZnO particles on mobility and reproduction of the freshwater invertebrate Daphnia magna. Chemosphere 76(10):13561365. Wilson, M. , J. Lightbody , K. Donaldson , J. Sales , and V. Stone . 2002. Interactions between ultrafine particles and transition metals in vivo and in vitro Toxicol. Appl Pharmacol 184:172179. Wrle-Knirsch, J. M. , K. Pulskamp , and H. F. Krug . 2006. Oops they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Lett 6(6):12611268. doi: 10.1021/nl060177c Xia, T. , M. Kovochich , J. Brant 2006 Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6:17941807. Xia, Q. , H. Li , Y. Liu , and K. Xiao . 2016. The effect of particle size on the genotoxicity of gold nanoparticles. J Biomed Mater Res A 105(3):710719. doi: 10.1002/jbm.a.35944. Xiao, Y. , M. Vijver , G. Chen , and W. Peijnenburg 2015. Toxicity and accumulation of Cu and ZnO nanoparticles in Daphnia magna. Environ Sci Technol. 49:46574664. Xu, Y. , N. Wang , Y. Yu , Y. Li , Y.B. Li , Y.B. Yu , X. Q. Zhou , and Z. W. Sun . 2014. Exposure to silica nanoparticles causes reversible damage of the spermatogenic process in mice. PLoS One. 9(7):e101572. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086902/ 388 Yokota, S. , H. Hiroshi Hori , M. Umezawa 2013. Gene expression changes in the olfactory bulb of mice induced by exposure to diesel exhaust are dependent on animal rearing environment. PLoS One 8(8):e70145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734019/ Yu, B. P. 1994. Cellular defenses against damage from reactive oxygen species. Physiol Rev 74:139162. http://physrev.physiology.org/content/74/1/139.full-text.pdf+html Zhu, M. , G. Nie , H. Meng , T. Xia , A. Nel , and Y. Zhao . 2013. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate. Acc Chem Res 46(3):622631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414238/pdf/nihms682129.pdf Zhu, S. , E. Oberdrster , and M. L. Haasch . 2006. Toxicity of an engineered nanoparticle (fullerene, C60) in two aquatic species, Daphnia and fathead minnow. Mar Environ Res 62(Suppl):S59. https://doi.org/10.1016/j.marenvres.2006.04.059 Zhu, X. , Y. Chang , and Y. Chen . 2010. Toxicity and bioaccumulation of TiO2 nanoparticle aggregates in Daphnia magna. Chemosphere 78:209215. Zhu, X. , S. Tian , and Z. Cai . 2012. Toxicity assessment of iron oxide nanoparticles in Zebrafish (Danio rerio) early life stages. PLoS One 7(9):e46286. doi: 10.1371/journal.pone.0046286 Zhu, X. , L. Zhu , Y. Chen , and S. Tian . 2009. Acute toxicities of six manufactured nanomaterial suspensions to Daphnia manga. J Nanopart Res 11:6775.

Nanotoxicity Evaluation Using Experimental Animals: A Detailed Review Amorim, M. J. and J. J. Scott-Fordsmand . 2012. Toxicity of copper nanoparticles and CuCl2 salt to Enchytraeus albidus worms: survival, reproduction and avoidance responses. Environ Pollut 164:164168. Aruoja, V. , H. C. Dubourguier , K. Kasemets , and A. Kahru . 2009. Toxicity of nanoparticles of CuO, ZnO and TiO2 to microalgae Pseudokirchneriella subcapitata . Sci Total Environ 407:14611468. Asharani, P. V. , Y. Lianwu , Z. Gong 2011. Comparison of the toxicity of silver, gold and platinum nanoparticles in developing zebrafish embryos. Nanotoxicology 5:4354. Baker, T. J. , C. R. Tyler , and T. S. Galloway . 2014. Impacts of metal and metal oxide nanoparticles on marine organisms. Environ Pollut 186:257271. Bar-Ilan, O. , R. M. Albrecht , V. E. Fako 2009. Toxicity assessments of multisized gold and silver nanoparticles in zebrafish embryos. Small 5:8971910.

BCC Research . 2012. Global markets and technologies for carbon nanotubes, BCC Research, Wellesley, MA, USA, No. NAN024E, 1-408. https://www.bccresearch.com/marketresearch/nanotechnology/carbon-nantubes-markets-technologies-nan024e.html (accessed December 20, 2016). Blinova, I. , A. Ivask , M. Heinlaan 2010. Ecotoxicity of nanoparticles of CuO and ZnO in natural water. Environ Pollut 158:4147. Bondarenko, O. , K. Juganson , A. Ivask 2013. Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review. Arch Toxicol 87:11811200. Bondarenko, O. M. , M. Heinlaan , M. Sihtme 2016. Multilaboratory evaluation of 15 bioassays for (eco) toxicity screening and hazard ranking of engineered nanomaterials: FP7 project NANOVALID. Nanotoxicology 10:12291242. Buffet, P. E. , O. F. Tankoua , J. F. Pan 2011. Behavioural and biochemical responses of two marine invertebrates Scrobicularia plana and Hediste diversicolor to copper oxide nanoparticles. Chemosphere 84:166174. Canesi, L. and I. Corsi . 2016. Effects of nanomaterials on marine invertebrates. Sci Total Environ 565: 933940. Chernousova, S. and M. Epple . 2013. Silver as antibacterial agent: Ion, nanoparticle, and metal. Angewandte Chemie International Edition 52:16361653. Clemente, Z. , V. L. Castro , C. M. Jonsson , and L. F. Fraceto . 2012. Ecotoxicology of nanoTiO2 An evaluation of its toxicity to organisms of aquatic ecosystems. IJER 6:3350.412 Cong, Y. , G. T. Banta , H. Selck , D. Berhanu , E. Valsami-Jones , and V. E. Forbes . 2014. Toxicity and bioaccumulation of sediment-associated silver nanoparticles in the estuarine polychaete, Nereis (Hediste) diversicolor . Aquat Toxicol 156:106115. Dabrunz, A. , L. Duester , C. Prasse 2011. Biological surface coating and molting inhibition as mechanisms of TiO2 nanoparticle toxicity in Daphnia magna . PLoS One 6(5):e20112. David, C. A. , J. Galceran , C. Rey-Castro 2012. Dissolution kinetics and solubility of ZnO nanoparticles followed by AGNES. The Journal of Physical Chemistry C 116:11758. Dedeh, A. , A. Ciutat , M. Treguer-Delapierre , and J. P. Bourdineaud . 2015. Impact of gold nanoparticles on zebrafish exposed to a spiked sediment. Nanotoxicology 9:7180. Donaldson, K. , V. Stone , C. L. Tran , W. Kreyling , and P. J. Borm , 2004. Nanotoxicology. Occup Environ Med 61:727728. Drobne, D. and S. P. Hopkin . 1994. The toxicity of zinc to terrestrial isopods in a Standard Laboratory Test. Ecotoxicol Environ Saf 31:16. Drobne, D. and S. P. Hopkin . 1995. Ecotoxicological laboratory test for assessing the effects of chemicals on terrestrial isopods. Bull Environ Contam Toxicol 53:390397. Du, J. , S. Wang , H. You , and X. Zhao . 2013. Understanding the toxicity of carbon nanotubes in the environment is crucial to the control of nanomaterials in producing and processing and the assessment of health risk for human: A review. Environ Toxicol Pharmacol 36:451462. Duan, J. C. , Y. Yu , Y. Li 2013. Toxic effect of silica nanoparticles on endothelial Cells through DNA damage response via Chk1-Dependent G2/M checkpoint. PlosOne 8:62087. Elzey, S. and V. H. Grassian . 2010. Nanoparticle dissolution from the particle perspective: Insights from particle sizing measurements. Langmuir 26:1250512508. Fent, K. , C. J. Weisbrod , A. Wirth-Heller , and U. Pieles . 2010. Assessment of uptake and toxicity of fluorescent silica nanoparticles in zebrafish (Danio rerio) early life stages. Aquat Toxicol 100:218228. Future Markets Inc . 2013. The global market for carbon nanotubes to 2020, Future Markets Inc., Dublin, Ireland, No. 70, 1-229. Gambardella, C. , S. Ferrando , S. Morgana 2015. Exposure of Paracentrotus lividus male gametes to engineered nanoparticles affects skeletal bio-mineralization processes and larval plasticity. Aquat Toxicol 158:181191. Garca-Alonso, J. , N. Rodriguez-Sanchez , S. K. Misra 2014. Toxicity and accumulation of silver nanoparticles during development of the marine polychaete Platynereis dumerilii . Sci Total Environ 476477:688695. Garca-Cambero, J. P. , M. Nez Garca , G. D. Lpez 2013. Converging hazard assessment of gold nanoparticles to aquatic organisms. Chemosphere 93:11941200. Geffroy, B. , C. Ladhar , S. Cambier , Treguer-M. Delapierre , D. Brthes , and J. P. Bourdineaud . 2012. Impact of dietary gold nanoparticles in zebrafish at very low contamination pressure: The role of size, concentration and exposure time. Nanotoxicology 6:144160. Ghosh, M. , M. Bandyopadhyay , and A. Mukherjee . 2010. Genotoxicity of titanium dioxide TiO2 nanoparticles at two trophic levels: Plant and human lymphocytes. Chemosphere 81:12531262.413 Golobi, M. , A. Jemec , D. Drobne , T. Romih , K. Kasemets , and A. Kahru . 2012. Upon exposure to Cu nanoparticles, accumulation of copper in the isopod Porcellio scaber is due to

the dissolved Cu ions inside the digestive tract. Environ Sci Technol 46:1211212119. Gomes, S. I. , S. C. Novais , C. Gravato 2012. Effect of Cu-nanoparticles versus one Cu-salt: Analysis of stress biomarkers response in Enchytraeus albidus (Oligochaeta). Nanotoxicology 6:134143. Gomes, S. I. , A. M. Soares , J. J. Scott-Fordsmand , and M. J. Amorim . 2013. Mechanisms of response to silver nanoparticles on Enchytraeus albidus (Oligochaeta): Survival, reproduction and gene expression profile. J Hazard Mater 254255:336344. Han, X. , B. Geller , K. Moniz , P. Das , A. K. Chippindale , and V. K. Walker . 2014. Monitoring the developmental impact of copper and silver nanoparticle exposure in Drosophila and their microbiomes. Sci Total Environ 487:822829. Hanna, S. K. , R. J. Miller , D. Zhou , A. A. Keller , and H. S. Lenihan . 2013. Accumulation and toxicity of metal oxide nanoparticles in a soft-sediment estuarine amphipod. Aquat Toxicol 142143:441446. Harper, S. L. , J. L. Carriere , J. M. Miller 2011. Systematic evaluation of nanomaterial toxicity: Utility of standardized materials and rapid assays. ACS Nano 5:46884697. Hartmann, N. B. , F. Von der Kammer , T. Hofmann , M. Baalousha , S. Ottofuelling , and A. Baun . 2010. Algal testing of titanium dioxide nanoparticles testing considerations, inhibitory effects and modification of cadmium bioavailability. Toxicology 269:190197. Heckmann, L. H. , M. B. Hovgaard , D. S. Sutherland , H. Autrup , F. Besenbacher , and J. J. Scott-Fordsmand . 2011. Limit-test toxicity screening of selected inorganic nanoparticles to the earthworm Eisenia fetida . Ecotoxicology 20:226233. Heinlaan, M. , A. Ivask , I. Blinova , H. C. Dubourguier , and A. Kahru . 2008. Toxicity of nanosized and bulk ZnO, CuO and TiO2 to bacteria Vibrio fischeri and crustaceans Daphnia magna and Thamnocephalus platyurus . Chemosphere 71(7):13081316. Heinlaan, M. , A. Kahru , I. Kasemets , B. Arbeille , G. Prensier , and H. C. Dubourguier . 2011. Changes in the Daphnia magna midgut upon ingestion of copper oxide nanoparticles: A transmission electron microscopy study. Water Res 45:179190. Heinlaan, M. , M. Muna , M. Knbel 2016. Natural water as the test medium for Ag and CuO nanoparticle hazard evaluation: An interlaboratory case study. Environ Pollut 216:689699. Hristozov, D. and I. Malsch . 2009. Hazards and risks of engineered nanoparticles for the environment and human health. Sustainability 1:11611194. Hristozov, D. R. , A. Zabeo , C. Foran , P. Isigonis , A. Critto , A. Marcomini , and I. Linkov . 2014. A weight of evidence approach for hazard screening of engineered nanomaterials. Nanotoxicology 8:7287. Hu, C. W. , M. Li , Y. B. Cui , D. S. Li , J. Chen , and L. Y. Yang . 2010. Toxicological effects of TiO2 and ZnO nanoparticles in soil on earthworm Eisenia fetida . Soil Biology and Biochemistry 42:586591. Hund-Rinke, K. , A. Baun , D. Cupi 2016. Regulatory ecotoxicity testing of nanomaterialsproposed modifications of OECD test guidelines based on laboratory experience with silver and titanium dioxide nanoparticles. Nanotoxicology 10:14421447.414 Hund-Rinke, K. and M. Simon . 2006. Ecotoxic effect of photocatalytic active nanoparticles (TiO2) on algae and daphnids. Environmental Science and Pollution Research 13:18. ISO 6341 : 2014. Water quality Determination of the inhibition of the mobility of Daphnia magna Straus (Cladocera, Crustacea) Acute toxicity test. Brussels, Belgium. Ivask, A. , S. George , O. Bondarenko , and A. Kahru . 2012. Metal-containing nano antimicrobials: Differentiating the impact of solubilized metals and particles. In: NanoAntimicrobials: Progress and Prospects, eds. N. Cioffi , and M. Rai . Heidelberg: SpringerVerlag Berlin, pp. 253291. Ivask, A. , K. Juganson , O. Bondarenko 2014a. Mechanisms of toxic action of Ag, ZnO and CuO nanoparticles to selected ecotoxicological test organisms and mammalian cells in vitro: A comparative review. Nanotoxicology 8:5771. Ivask, A. , I. Kurvet , K. Kasemets 2014b. Size-dependent toxicity of silver nanoparticles to bacteria, yeast, algae, crustaceans and mammalian cells in vitro. PLOS ONE 9:p.e102108. Jackson, P. , N. R. Jacobsen , A. Baun 2013. Bioaccumulation and ecotoxicity of carbon nanotubes. Chemistry Central Journal 7:154. Jemec, A. , A. Kahru , A. Potthoff 2016. An interlaboratory comparison of nanosilver characterisation and hazard identification: Harmonising techniques for high quality data. Environ Int 87:2032. Kahru, A. and H. C. Dubourguier . 2010. From ecotoxicology to nanoecotoxicology. Toxicology 269:105119. Kahru, A. and A. Ivask . 2013. Mapping the dawn of nanoecotoxicological research. Acc Chem Res 46:823833. Khare, P. , M. Sonane , R. Pandey , S. Ali , K. C. Gupta , and A. Satish . 2011. Adverse effects of TiO2 and ZnO nanoparticles in soil nematode, Caenorhabditis elegans . J Biomed

Nanotechnol 7:116117. Kim, K. T. , T. Zaikova , J. E. Hutchison , and R. L. Tanguay . 2013. Gold nanoparticles disrupt zebrafish eye development and pigmentation. Toxicol Sci 133:275288. Kool, P. L. , M. D. Ortiz , and C. A. M. van Gestel . 2011. Chronic toxicity of ZnO nanoparticles, non-nano ZnO and ZnCl2 to Folsomia candida (Collembola) in relation to bioavailability in soil. Environ Pollut 159:27132719. Kos, M. , A. Kahru , D. Drobne 2016. A case study to optimise and validate the brine shrimp Artemia franciscana immobilisation assay with silver nanoparticles: The role of harmonisation. Environ Pollut 213:173183. Khnel, D. , C. Marquardt , K. Nau , H. F. Krug , B. Mathes , and C. Steinbach . 2014. Environmental impacts of nanomaterials: providing comprehensive information on exposure, transport and ecotoxicity-the project DaNa2.0. Environmental Sciences Europe 26:21. Khnel, D. and C. Nickel . 2014. The OECD expert meeting on ecotoxicology and environmental fate towards the development of improved OECD guidelines for the testing of nanomaterials. Sci Total Environ 472:347353. Lam, C. W. , J. T. James , R. McCluskey , S. Arepalli , and R. L. Hunter . 2006. A review of carbon nanotube toxicity and assessment of potential occupational and environmental health risks. Crit Rev Toxicol 36:189217. Lapied, E. , E. Moudilou , J. M. Exbrayat , D. H. Oughton , and E. J. Joner . 2010. Silver nanoparticle exposure causes apoptotic response in the earthworm Lumbricus terrestris (Oligochaeta). Nanomedicine (Lond) 5:975984.415 Lapresta-Fernandez, A. , A. Fernandez , and J. Blasco . 2012. Nanoecotoxicity effects of engineered silver and gold nanoparticles in aquatic organisms. Trends Anal Chem 32:4059. Lee, S. W. , S. M. Kim , and J. Choi . 2009. Genotoxicity and ecotoxicity assays using the freshwater crustacean Daphnia magna and the larva of the aquatic midge Chironomus riparius to screen the ecological risks of nanoparticle exposure. Environ Toxicol Pharmacol 28:8691. Li, L. Z. , D. M. Zhou , W. J. G. M. Peijnenburg , van C. A. M. Gestel , S. Y. Jin , Y. J. Wang , and P. Wang . 2011. Toxicity of zinc oxide nanoparticles in the earthworm, Eisenia fetida and subcellular fractionation of Zn. Environ Int 37:10981104. Li, S. , L. K. Wallis , H. Ma , and S. A. Diamond . 2014. Phototoxicity of TiO2 nanoparticles to a freshwater benthic amphipod: are benthic systems at risk? Sci Total Environ 466467:800808. Li, T. , B. Albee , M. Alemayehu , R. Diaz , L. Ingham , S. Kamal , M. Rodriguez , and S. Whaley . 2010. Comparative toxicity study of Ag, Au, and AgAu bimetallic nanoparticles on Daphnia magna . Anal Bioanal Chem 398:689700. Libralato, G. 2014. The case of Artemia spp. in nanoecotoxicology. Mar Environ Res 101:3843. Liu, J. , Z. Wang , F. D. Liu , A. B. Kane , and R. H. Hurt . 2012. Chemical transformations of nanosilver in biological environments. ACS Nano 6:98879899. Loureiro, S. , J. P. Sousa , A. J. A. Nogueira , and A. M. V. M. Soares . 2002. Assimilation efficiency and toxicokinetics of 14C-lindane in the terrestrial isopod Porcellionides pruinosus: The role of isopods in degradation of persistent soil pollutants. Ecotoxicology 11:481490. Lovern, S. B. and R. Klaper . 2006. Daphnia magna mortality when exposed to titanium dioxide and fullerene (C60) nanoparticles. Environ Toxicol Chem 25:11321137. Lovern, S. B. , H. A. Owen , and R. Klaper . 2008. Electron microscopy of gold nanoparticle intake in the gut of Daphnia magna . Nanotoxicology 2:4348. Ma, H. , P. M. Bertsch , T. C. Glenn , N. J. Kabengi , and P. L. Williams . 2009. Toxicity of manufactured zinc oxide nanoparticles in the nematode. Caenorhabditis elegans Environmental Toxicology and Chemistry 28:3241330. Ma, H. , A. Brennan , and S. A. Diamond . 2012. Phototoxicity of TiO2 nanoparticles under solar radiation to two aquatic species: Daphnia magna and Japanese medaka. Environ Toxicol Chem 31:16211629. Ma, H. , N. J. Kabengi , P. M. Bertsch , J. M. Unrine , T. C. Glenn , and P. L. Williams . 2011. Comparative phototoxicity of nanoparticulate and bulk ZnO to a free-living nematode Caenorhabditis elegans: the importance of illumination mode and primary particle size. Environ Pollut 159:14731480. Ma, H. , P. L. Williams , and S. A. Diamond . 2013. Ecotoxicity of manufactured ZnO nanoparticlesA review. Environ Pollut 172:7685. Magesky, A. and . Pelletier . 2015. Toxicity mechanisms of ionic silver and polymer-coated silver nanoparticles with interactions of functionalized carbon nanotubes on early development stages of sea urchin. Aquat Toxicol 167:106123. Manfra, L. , F. Savorelli , B. Di Lorenzo 2015. Intercalibration of ecotoxicity testing protocols with Artemia franciscana L. Ecol Indicators 57:4147. Manzo, S. , M. L. Miglietta , G. Rametta , S. Buono , and G. Di Francia . 2013. Toxic effects of ZnO nanoparticles towards marine algae Dunaliella tertiolecta . Sci Total Environ 445:371376.416

Manzo, S. , A. Rocco , R. Carotenuto 2011. Investigation of ZnO nanoparticles ecotoxicological effects towards different soil organisms. Environmental Science and Pollution Research 18:756763. Menard, A. , D. Drobne , and A. Jemec . 2011. Ecotoxicity of nanosized TiO2. Review of in vivo data. Environ Pollut 159: 677684. Mesari, T. , C. Gambardella , T. Milivojevi 2015. High surface adsorption properties of carbonbased nanomaterials are responsible for mortality, swimming inhibition, and biochemical responses in Artemia salina larvae. Aquat Toxicol 163:121129. Miller, R. J. , H. S. Lenihan , E. B. Mullerm , N. Tsengm , S. K. Hannam , and A. A. Kellerm . 2010. Impacts of metal oxide nanoparticles on marine phytoplankton. Environ Sci Technol 44:73297334. Minetto, D. , G. Libralato , and A. Volpi Ghirardini . 2014. Ecotoxicity of engineered TiO2 nanoparticles to saltwater organisms: An overview. Environ Int 66:1827. Nadrah, P. , U. Maver , A. Jemec 2013. Hindered disulfide bonds to regulate release rate of model drug from mesoporous silica. ACS Applied Materials & Interfaces 5:39083915. Nations, S. , M. Wages , J. E. Caas , J. Maul , C. Theodorakis , and G. P. Cobb . 2011a. Acute effects of Fe2O3, TiO2, ZnO and CuO nanomaterials on Xenopus laevis . Chemosphere 83(8):10531061. Nations, S. , M. Long , M. Wages , J. Canas , J. D. Maul , C. Theodorakis , and G. P. Cobb . 2011b. Effects of ZnO nanomaterials on Xenopus laevis growth and development. Ecotoxicol Environ Saf 74(2):203210. Novak, S. , D. Drobne , J. Valant , and P. Pelicon . 2012. Research Article: Internalization of consumed TiO2 nanoparticles by a model invertebrate organism. Journal of Nanomaterials 2012:18. OECD . 2004. No. 202: Daphnia sp., Acute Immobilization Test. http://www.oecdilibrary.org/environment/test-no-202-daphnia-sp-acute-immobilisation-test_9789264069947-en (accessed June 5, 2017). OECD . 2012. Guidance on sample preparation and dosimetry for the safety testing of manufactured nanomaterials; Series on the Safety of Manufactured Nanomaterials, No. 36; http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2012) 40&docLanguage=En (accessed June 5, 2017). Oomen, A. G. , P. M. Bos , T. F. Fernandes 2014. Concern-driven integrated approaches to nanomaterial testing and assessment report of the NanoSafety Cluster Working Group 10. Nanotoxicology 8:334348. Park, E. J. and K. Park . 2009. Oxidative stress and pro-inflammatory responses induced by silica nanoparticles in vivo and in vitro. Toxicol Lett 184:1825. Peng, X. , S. Palma , N. S. Fisher , and S. S. Wong . 2011. Effect of morphology of ZnO nanostructures on their toxicity to marine algae. Aquat Toxicol 102:186196. Persoone, G. , M. Van de Vel , M. Van Steertegem , and B. De Nayer . 1989. Predictive value of laboratory tests with aquatic invertebrates: Influence of experimental conditions. Aquat Toxicol 14:149166. Piccinno, F. , F. Gottschalk , S. Seeger , and B. Nowack . 2012. Industrial production quantities and uses of ten engineered nanomaterials in Europe and the world. J Nanoparticle Res 14:11091120. Pompa, P. , G. Vecchio , A. Galeone 2011. In vivo toxicity assessment of gold nanoparticles in Drosophila melanogaster . Nano Research 4:405413.417 Poynton, H. C. , J. M. Lazorchak , C. A. Impellitteri 2010. Differential gene expression in Daphnia magna suggests distinct modes of action and bioavailability for ZnO nanoparticles and Zn ions. Environ Sci Technol 45:762768. Project on Emerging Nanotechnologies . 2016. Consumer Products Inventory. http://www.nanotechproject.org/cpi (accessed December 22, 2016). Ramesh, R. , P. Kavitha , N. Kanipandian , S. Arun , R. Thirumurugan , and P. Subramanian . 2013. Alteration of antioxidant enzymes and impairment of DNA in the SiO2 nanoparticles exposed zebra fish (Danio rerio). Environ Monit Assess 185:58735881. Reed, R. B. , D. A. Ladner , C. P. Higgins , P. Westerhoff , and J. F. Ranville , 2012. Solubility of nano-zinc oxide in environmentally and biologically important matrices. Environ Toxicol Chem 31:9399. Renault, S. , M. Baudrimont , N. Mesmer-Dudons , P. Gonzalez , S. Mornet , and A. Brisson . 2008. Impacts of gold nanoparticle exposure on two freshwater species: A phytoplanktonic alga (Scenedesmus subspicatus) and a benthic bivalve (Corbicula fluminea). Gold Bull 41:116126. Roh, J. Y. , S. J. Sim , J. Yi , K. Park , K. H. Chung , D. Y. Ryu , and J. Choi . 2009. Ecotoxicity of silver nanoparticles on the soil nematode Caenorhabditis elegans using functional ecotoxicogenomics. Environ Sci Technol 43:39333940.

Romih, T. , A. Jemec , M. Kos , S. B. Hoevar , S. Kralj , D. Makovec , and D. Drobne . 2016a. The role of PVP in the bioavailability of Ag from the PVP-stabilized Ag nanoparticle suspension. Environ Pollut 218:957964. Romih, T. , A. Jemec , S. Novak 2016b. FTIR microscopy reveals distinct biomolecular profile of crustacean digestive glands upon subtoxic exposure to ZnO nanoparticles. Nanotoxicology 10:462470. Royal Society . 2004. Nanoscience and nanotechnologies: opportunities and uncertainties. https://royalsociety.org/topics-policy/publications/2004/nanoscience-nanotechnologies/ (accessed December 22, 2016). Scott-Fordsmand, J. J. , P. H. Krogh , M. Schaefer , and A. Johansen . 2008. The toxicity testing of double-walled nanotubes-contaminated food to Eisenia veneta earthworms. Ecotoxicol Environ Saf 71:616619. Sharif, F. , F. Porta , A. H. Meijer , A. Kros , and M. K. Richardson . 2012. Mesoporous silica nanoparticles as a compound delivery system in zebrafish embryos. Int J Nanomedicine 7:18751890. Sharma, V. K. , K. M. Siskova , R. Zboril , and J. L. Gardea-Torresdey . 2014. Organic-coated silver nanoparticles in biological and environmental conditions: Fate, stability and toxicity. Adv Colloid Interface Sci 204:1534. Shaw, B. J. , G. Al-Bairuty , and R. D. Handy . 2012. Effects of waterborne copper nanoparticles and copper sulphate on rainbow trout, (Oncorhynchus mykiss): Physiology and accumulation. Aquat Toxicol 116117:90101. Shi, H. , R. Magaye , V. Castranova , and J. Zhao . 2013. Titanium dioxide nanoparticles: A review of current toxicological data. Particle and Fibre Toxicology 10:15. Shoults-Wilson, W. A. , B. C. Reinsch , O. V. Tsyusko , P. M. Bertsch , G. V. Lowry , and J. M. Unrine . 2011. Effect of silver nanoparticle surface coating on bioaccumulation and reproductive toxicity in earthworms (Eisenia fetida). Nanotoxicology 5:432444. Swiss Re . 2004. Nanotechnology - Small matter, many unknowns. http://www.nanowerk.com/nanotechnology-report.php?reportid=93 (accessed December 22, 2016).418 Tourinho, P. S. , C. A. van Gestel , A. J. Morgan 2016. Toxicokinetics of Ag in the terrestrial isopod Porcellionides pruinosus exposed to Ag NPs and AgNO3 via soil and food. Ecotoxicology 25:267278. Truong, L. , S. C. Tilton , T. Zaikova , E. Richman , K. M. Waters , J. E. Hutchison , and R. L. Tanguay . 2013. Surface functionalities of gold nanoparticles impact embryonic gene expression responses. Nanotoxicology 7:192201. Unrine, J. M. , P. Bertsch , S. E. Hunyadi , H. B. Ma , L. A. Newman , and P. L. Williams . 2008. Spatial distribution and speciation of Au and Zn in terrestrial organisms exposed to Au and ZnO nanoparticles. In: Proceedings of the 235th ACS National Meeting. New Orleans, LA. Unrine, J. M. , S. E., Hunyadi , O. V., Tsyusko , W. Rao , W. A. Shoults-Wilson , and P. M. Bertsch . 2010a. Evidence for bioavailability of Au nanoparticles from soil and biodistribution within earthworms (Eisenia fetida). Environ Sci Technol 44:83088313. Unrine, J. M. , O. V. Tsyusko , S. E. Hunyadi , J. D. Judy , and P. M. Bertsch . 2010b. Effects of particle size on chemical speciation and bioavailability of copper to earthworms (Eisenia fetida) exposed to copper nanoparticles. J Environ Qual 39:19421953. US Environmental Protection Agency . 2009. Nanomaterial case studies: Nanoscale titanium dioxide in water treatment and in topical sunscreen. EPA/600/R-09/057. https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=230972 (accessed June 5, 2017). Van Brummelen, T. C. , R. A. Verweij , S. A. Wedzinga , and C. A. M. Van Gestel . 1996. Polycyclic aromatic hydrocarbons in earthworms and isopods from contaminated forest soils. Chemosphere 32:315341. Van Hoecke, K. , K. A. De Schamphelaere , Z. Ali 2013. Ecotoxicity and uptake of polymer coated gold nanoparticles. Nanotoxicology 7:3747. Vandebriel, R. J. and W. H. De Jong . 2012. A review of mammalian toxicity of ZnO nanoparticles. Nanotechnology, Science and Applications 5:6171. Wang, H. , R. L. Wick , and B. Xing . 2009. Toxicity of nanoparticulate and bulk ZnO, Al2O3 and TiO2 to the nematode Caenorhabditis elegans . Environ Pollut 157:11711177. Warheit, D. B. , R. A. Hoke , C. Finlay , E. M. Donner , K. L. Reed , C. M. Sayes , and C. Finlay . 2007. Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicol Lett 171:99110. Wei, C. , Y. Zhang , J. Guo , B. Han , X. Yang , and J. Yuan . 2010. Effects of silica nanoparticles on growth and photosynthetic pigment contents of Scenedesmus obliquus . J Environ Sci (China) 22:155160. Xiong, D. , T. Fang , L. Yu , X. Sima , and W. Zhu . 2011. Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrash: acute toxicity, oxidative stress and oxidative damage. Sci

Total Environ 409:14441452. Yang, X. , J. Liu , H. He 2010. SiO2 nanoparticles induce cytotoxicity and protein expression alteration in HaCaT cells. Particle and Fibre Toxicology 7:1. karkov, P. , T. Romih , T. Kos , S. Novak , V. Kononenko , A. Jemec , M. Vvrov , and D. Drobne . 2016. Gold nanoparticles do not induce adverse effects on terrestrial isopods Porcellio scaber after 14-day exposure. Acta Biol Slov 59: 3344.

Pharmacokinetics Approach for Nanotoxicity Evaluation Aggarwal, P. , J. B. Hall , C. B. McLeland 2009. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev 61:428437. Aitken, R. , M. Chaudhry , A. Boxall 2006. Manufacture and use of nanomaterials: current status in the UK and global trends. Occup Med 56:300306. Anderson, J. M. and M. S. Shive . 1997. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Delivery Rev 28:524. Arbab, A. S. , L. B. Wilson , P. Ashari 2005. A model of lysosomal metabolism of dextran coated superparamagnetic iron oxide (SPIO) nanomaterials: Implications for cellular magnetic resonance imaging. NMR Biomed 18:383389. Baek, M. , H. E. Chung , J. Yu 2012. Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanomaterials. Int J Nanomedicine 7:30813097. Ballou, B. , L. A. Ernst , S. Andreko 2007. Sentinel lymph node imaging using quantum dots in mouse tumor models. Bioconjugate Chem 18:389396. Ballou, B. , B. C. Lagerholm , L. A. Ernst 2004. Noninvasive imaging of quantum dots in mice. Bioconjug Chem 1:7986. Baroli, B. 2010. Penetration of nanomaterials and nanomaterials in the skin: Fiction OR reality? J Pharm Sci 99:2150.442 Bosman, S. J. , S. P. Nieto , W. C. Patton 2005. Development of mammalian embryos exposed to mixed size nanomaterials. Clin Exp Obstet Gynecol 4:222224. Boyes, W. K. , R. Chen , C. Chen 2012. The neurotoxic potential of engineered nanomaterials. Neurotoxicology 33:902910. Brannon-Peppas, L. and J. O. Blanchette . 2004. Nanoparticle and targeted systems for cancer therapy. Adv Drug Delivery Rev 56:16491659. Brigger, I. , C. Dubernet , and P. Couvreur . 2002. Nanomaterials in cancer therapy and diagnosis. Adv Drug Delivery Rev 54:631651. Cedervall, T. , I. Lynch , S. Lindman 2007. Understanding the nanoparticle protein corona using methods to quantify exchange rates and affinities of proteins for nanomaterials. Proc Natl Acad Sci USA 104:20502055. Chen, J. K. , M. H. Shih , J. J. Peir 2010. The use of radioactive zinc oxide nanomaterials in determination of their tissue concentrations following intravenous administration in mice. Analyst 135:17421746. Chiannilkulchai, N. , N. Ammoury , B. Caillou 1990. Hepatic tissue distribution of doxorubicinloaded nanomaterials after i.v. administration in reticulosarcoma m 5076 metastasis bearing mice. Cancer Chemother Pharmacol 26:122126. Cho, C. S. , A. Kobayashi , R. Takei 2001. Receptor mediated cell modulator delivery to hepatocyte using nanomaterials coated with carbohydrate-carrying polymers. Biomaterials 22:4551. Choi, H. S. , W. Liu , P. Misra 2007. Renal clearance of quantum dots. Nat Biotechnol 25:11651170. Corry, D. , P. Kulkarni , and M. F. Lipscomb . 1984. The migration of bronchoalveolar macrophages into hilar lymph nodes. Am J Pathol 115:321328. de Lorenzo, A. J. 1970. The olfactory neuron and the blood-brain barrier. In: Taste and Smell in Vertebrates, eds. G. Wolstenholme and J. Knight . London: Wiley Interscience, pp. 151176. Demoy, M. , J. P. Andreux , C. Weingarten 1999. In vitro evaluation of nanomaterials spleen capture. Life Sci 64(15):13291337. Demoy, M. , S. Gibaud , J. P. Andreux 1997. Splenic trapping of nanomaterials: Complementary approaches for in situ studies. Pharm Res 14:463468. Deng, X. , G. Jia , H. Wang 2007. Translocation and fate of multi-walled carbon nanotubes in vivo . Carbon 45:14191424. Desai, M. P. , V. Labhasetwar , G. L. Amidon 1996. Gastrointestinal uptake of biodegradable microparticles: Effect of particle size. Pharm Res 12:18381845.

Drobne, D. 2007. Nanotoxicology for safe and sustainable nanotechnology. Arh Hig Rada Toksikol 58:471478. Dutta, D. , S. K. Sundaram , J. G. Teeguarden 2007. Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials. Toxicol Sci 100:303315. Elder, A. , R. Gelein , J. N. Finkelstein , K. E. Driscoll , J. Harkema , and G. Oberdrster . 2005. Effects of subchronically inhaled carbon black in three species. I. Retention kinetics, lung inflammation, and histopathology. Toxicol Sci 2:614629. Fabian, E. , R. Landsiedel , L. Ma-Hock , K. Wiench , W. Wohlleben , and B. van Ravenzwaay . 2008. Tissue distribution and toxicity of intravenously administered titanium dioxide nanomaterials in rats. Arch Toxicol 82:151157. Ferin, J. , G. Oberdrster , and D. P. Penney . 1992. Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 6:535542. Fischer, H. C. and W. C. Chan . 2007. Nanotoxicity: The growing need for in vivo study. Curr Opin Biotechnol 18:565571.443 Florence, A. T. 2005. Nanoparticle uptake by the oral route: Fulfilling its potential? Drug Discov Today Technol 2:7581. Fujita, K. , M. Fukuda , S. Endoh 2015. Size effects of single-wall carbon nanotubes on in vivo and in vitro pulmonary toxicity. Inhal Toxicol 27:207223. Furumoto, K. , K. Ogawara , M. Yoshida 2001. Biliary excretion of polystyrene microspheres depends on the type of receptor-mediated uptake in rat liver. Biochim Biophys Acta 1526:221226. Gamer, A. O. , E. Leibold , and B. van Ravenzwaay . 2006. The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin. Toxicol In Vitro 20:301307. Geiser, M. 2002. Morphological aspects of particle uptake by lung phagocytes. Micr Res Tech 57:512522. Geiser, M. and W. G. Kreyling . 2010. Deposition and biokinetics of inhaled nanomaterials. Part Fibre Toxicol 7(2):117. Gopee, N. V. , D. W. Roberts , P. Webb 2007. Migration of intradermally injected quantum dots to sentinel organs in mice. Toxicol Sci 98:249257. Gopee, N. V. , D. W. Roberts , P. Webb 2009. Quantitative determination of skin penetration of PEG-coated CdSe quantum dots in dermabraded but not intact SKH-1 hairless mouse skin. Toxicol Sci 111:3748. Goppert, T. M. and R. H. Muller . 2005. Polysorbate-stabilized solid lipid nanomaterials as colloidal carriers for intravenous targeting of drugs to the brain: Comparison of plasma protein adsorption patterns. J Drug Target 13:179187. Hagens, W. I. , A. G. Oomen , W. H. de Jong , F. R. Cassee , and A. J. Sips . 2007. What do we (need to) know about the kinetic properties of nanomaterials in the body? Regul Toxicol Pharmacol 49:217229. Hamidi, M. , A. Azadi , P. Rafiei , and H. Ashrafi . 2013. A pharmacokinetic overview of nanotechnology-based drug delivery systems: An ADME-oriented approach. Crit Rev Ther Drug Carrier Syst 30:435467. Heckel, K. , R. Kiefmann , M. Dorger , M. Stoeckelhuber , and A. E. Goetz . 2004. Colloidal gold particles as a new in vivo marker of early acute lung injury. Am J Physiol Lung Cell Mol Physiol 287:L867L878. Hillyer, J. F. and R. M. Albrecht . 2001. Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanomaterials. J Pharm Sci 90:19271936. ICRP . 1994. Human respiratory tract model for radiological protection. ICRP Publication 66. Ann ICRP 24:231. http://www.icrp.org/publication.asp?id=ICRP Publication 66. Jain, R. K. 2005. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:5862. Jani, P. , G. W. Halbert , J. Langridge , and A. T. Florence . 1990. Nanoparticle uptake by the rat gastrointestinal mucosa: Quantitation and particle size dependency. J Pharm Pharmacol 42:821826. Joshi, M. D. and R. H. Muller . 2009. Lipid nanomaterials for parenteral delivery of actives. Eur J Pharm Biopharm 71:161172. Karmali, P. P. and D. Simberg . 2011. Interactions of nanomaterials with plasma proteins: Implication on clearance and toxicity of drug delivery systems. Expert Opi Drug Delivery 8:343357. Keelan, J. A. 2011. Nanotoxicology: Nanomaterials versus the placenta. Nat Nanotechnol 6:263264.444 Kim, S. , Y. T. Lim , E. G. Soltesz 2004. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol 22:9397. Kohli, A. K. and H. O. Alpar . 2004. Potential use of nanomaterials for transcutaneous vaccine delivery: Effect of particle size and charge. Int J Pharm 275:1317.

Kreuter, J. and Gelperina, S. 2008. Use of nanomaterials for cerebral cancer. Tumori 94:271277. Kreuter, J. , D. Shamenkov , V. Petrov 2002. Apolipoprotein-mediated transport of nanoparticlebound drugs across the blood-brain barrier. J Drug Target 10:317325. Kreyling, W. G. , M. Semmler , F. Erbe 2002. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J Toxicol Environ Health A 65:15131530. Lamanna, G. , M. Kueny-Stotz , H. Mamlouk-Chaouachi 2011. Dendronized iron oxide nanomaterials for multimodal imaging. Biomaterials 32:85628573. Landsiedel, R. , L. Ma-Hock , A. Kroll 2010. Testing metal-oxide nanomaterials for human safety. Adv Mater 25(22):26012627. Lartigue, L. , D. Alloyeau , J. Kolosnjaj-Tabi 2013. Biodegradation of iron oxide nanocubes: High-resolution in situ monitoring. ACS Nano 7:39393952. Lee, H. A. , T. L. Leavens , S. E. Mason , N. A. Monteiro-Riviere , and J. E. Riviere . 2009. Comparison of quantum dot biodistribution with a bloodflow-limited physiologically based pharmacokinetic model. Nano Lett 9:794799. Levchenko, T. S. , R. Rammohan , A. N. Lukyanov , K. R. Whiteman , and V. P. Torchilin . 2002. Liposome clearance in mice: The effect of a separate and combined presence of surface charge and polymer coating. Int J Pharm 240:95102. Levy, M. , N. Luciani , D. Alloyeau 2011. Long term in vivo biotransformation of iron oxide nanomaterials. Biomaterials 32:39883999. Li, S. D. and L. Huang . 2008. Pharmacokinetics and biodistribution of nanomaterials. Mol Pharmac 5:496504. Liang, X. , H. Wang , Y. Zhu 2016. Short- and long-term tracking of anionic ultrasmall nanomaterials in kidney. ACS Nano 10:387395. Lipinski, M. J. , J. C. Frias , V. Amirbekian 2009. Macrophage-specific lipid-based nanomaterials improve cardiac magnetic resonance detection and characterization of human atherosclerosis. J Am Coll Cardiol Imaging 2:637647. Liu, D. , A. Mori , and L. Huang . 1992. Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochim Biophys Acta 1104:95101. Lynch, I. and K. A. Dawson . 2008. Protein-nanoparticle interactions. Nano Today 3:4047. Ma-Hock, L. , A. Gamer , R. Landsiedel 2007. Generation and characterization of test atmospheres with nanomaterials. Inhal Toxicol 19:833848. Ma-Hock, L. , S. Burkhardt , V. Strauss 2009. Development of a short term inhalation test in the rat using nano-titanium dioxide as a model substance. Inhal Toxicol 21:102118. Meissner, T. , A. Potthoff , and V. Richter . 2009. Suspension characterization as important key for toxicological investigations. J Phys Conf Ser 170:16. Monteiro-Riviere, N. A. , K. Wiench , R. Landsiedel , S. Schulte , A. O. Inman , and J. E. Riviere . 2011. Safety evaluation of sunscreen formulations containing titanium dioxide and zinc oxide nanomaterials in UVB sun burned skin: An in vitro and in vivo study. Toxicol Sci 123:264280.445 Nagayama, S. , K. Ogawara , K. Minato 2007. Fetuin mediates hepatic uptake of negatively charged nanomaterials via scavenger receptor. Int J Pharm 329:192198. Nemmar, A. , H. Vanbilloen , M. F. Hoylaerts , P. H. Hoet , A. Verbruggen , and B. Nemery . 2001. Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster. Am J Respir Crit Care Med 164:16651668. Oberdrster, G. , E. Oberdrster , and J. Oberdrster . 2005. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823839. Ogawara, K. , M. Yoshida , K. Furumoto 1999. Uptake by hepatocytes and biliary excretion of intravenously administered polystyrene microspheres in rats. J Drug Target 7:213221. Otsuka, H. , Y. Nagasaki , and K. Kataoka . 2003. Pegylated nanomaterials for biological and pharmaceutical applications. Adv Drug Delivery Rev 55:403419. Owens, D. E. and N. A. Peppas . 2006. Opsonization, biodistribution, and pharmacokinetics of polymeric nanomaterials. Int J Pharm 307:93102. Paek, H. J. , Y. J. Lee , H. E. Chung 2013. Modulation of the pharmacokinetics of zinc oxide nanomaterials and their fates in vivo . Nanoscale 5:1141611427. Panagi, Z. , A. Beletsi , G. Evangelatos , E. Livaniou , D. S. Ithakissios , and K. Avgoustakis . 2001. Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGAmPEG nanomaterials. Int J Pharm 221:143152. Peira, E. , P. Marzola , V. Podio 2003. In vitro and in vivo study of solid lipid nanomaterials loaded with superparamagnetic iron oxide. J Drug Target 11:1924. Pflucker, F. , V. Wendel , H. Hohenberg 2001. The human stratum corneum layer: An effective barrier against dermal uptake of different forms of topically applied micronised titanium dioxide.

Skin Pharmacol Appl Skin Physiol 14:9297. Porter, C. J. H. , G. A. Edwards , and S. A. Charman . 2001. Lymphatic transport of proteins after s.c. injection: Implications of animal model selection. Adv Drug Deliv Rev 50:157171. Riviere, J. E. 2009. Pharmacokinetics of nanomaterials: An overview of carbon nanotubes, fullerenes and quantum dots. Wiley Interdiscip Rev Nanomed Nanobiotechnol 1:2634. Rodriguez-Fragoso, L. , I. Gutierrez-Sancha , J. Reyes-Esparza , and P. Rodriguez Fragoso . 2016. Pharmacokinetics of maltodextrin coated cadmium sulfide quantum dots in rats. J Nanomedicine & Biotherapeutic Discov 6:139. doi: 10.4172/2155-983X.1000139 Roser, M. , Fischer, D. , and Kissel, T. 1998. Surface-modified biodegradable albumin nanoand microspheres. II: Effect of surface charges on in vitro phagocytosis and biodistribution in rats. Eu J Pharm Biopharm 46:255263. Rothen-Rutishauser, B. M. , S. Schurch , B. Haenni , N. Kapp , and P. Gehr . 2006. Interaction of fine particles and nanomaterials with red blood cells visualized with advanced microscopic techniques. Environ Sci Technol 40:43534359. Rouse, J. G. , J. Yang , J. P. Ryman-Rasmussen , A. R. Barron , and N. A. Monteiro-Riviere . 2007. Effects of mechanical flexion on the penetration of fullerene amino acid-derivatized peptide nanomaterials through skin. Nano Lett 7:155160. Ryman-Rasmussen, J. P. , J. E. Riviere , and N. A. Monteiro-Riviere . 2006. Penetration of intact skin by quantum dots with diverse physicochemical properties. Toxicol Sci 91:159165.446 Sadauskas, E. , H. Wallin , M. Stoltenberg 2007. Kupffer cells are central in the removal of nanomaterials from the organism. Part Fibre Toxicol 4:10. doi: 10.1186/1743-8977-4-10 Sadrieh, N. , A. M. Wokovich , N. V. Gopee 2010. Lack of signicant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci 115:156166. Schulz, J. , H. Hohenberg , F. Pflucker 2002. Distribution of sunscreens on skin. Adv Drug Deliv Rev 54(1):S157S163. See, V. , P. Free , Y. Cesbron 2009. Cathepsin L digestion of nanobioconjugates upon endocytosis. ACS Nano 3:24612468. Singh, R. , D. Pantarotto , L. Lacerda 2006. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc Natl Acad Sci USA 103:33573362. Soltesz, E. T. , S. Kim , R. G. Laurence 2005. Intraoperative sentinel lymph node mapping of the lung using near-infrared fluorescent quantum dots. Ann Thorac Surg 79:269277. Sonavane, G. , K. Tomoda , and K. Makino . 2008. Biodistribution of colloidal gold nanomaterials after intravenous administration: Effect of particle size. Colloids Surf B Biointerfaces 66:274280. Su, J. , J. Zhang , L. Liu , Y. Huang , and R. P. Mason . 2008. Exploring feasibility of multicolored CdTe quantum dots for in vitro and in vivo fluorescent imaging. J Nanosci Nanotechno 8:11741177. Takeda, K. , K. Suzuki , A. Ishihara 2009. Nanomaterials transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 55:95102. Tan, W. B. , S. Jiang , and Y. Zhang . 2007. Quantum-dot based nanomaterials for targeted silencing of HER2/neu gene via RNA interference. Biomaterials 28:15651571. Umbreit, T. H. , S. Francke-Carroll , J. L. Weaver 2011. Tissue distribution and histopathological effects of titanium dioxide nanomaterials after intravenous or subcutaneous injection in mice. J Appl Toxicol 32:350357. Vibin, M. , R. Vinayakan , A. John , V. Raji , C. S. Rejiya , and A. Abraham . 2011. Biokinetics and in vivo distribution behaviours of silica-coated cadmium selenide quantum dots. Biol Trace Elem Res 142:213222. Videira, M. A. , M. F. Botelho , A. C. Santos , L. F. Gouveia , J. J. de Lima , and A. J. Almeida . 2002. Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanomaterials. J Drug Target 10:607613. Wahajuddin and S. Arora . 2012. Superparamagnetic iron oxide nanomaterials: Magnetic nanoplatforms as drug carriers. Int J Nanomed 7:34453471. Wang, J. , G. Zhou , C. Chen 2007. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176185. Wang, J. , C. Chen , Y. Liu 2008. Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183:7280. Wang, Z. , C. Tiruppathi , R. D. Minshall , and A. B. Malik . 2009. Size and dynamics of caveolae studied using nanomaterials in living endothelial cells. ACS Nano 3:41104116. Woodrow and Wilson Database . 2010. [http://www.nanotechproject.org].447 Wu, J. , W. Liu , C. Xue 2009. Toxicity and penetration of TiO2 nanomaterials in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett 191:18.

Xiaowen, L. , H. Wang , Y. Zhu 2016. Short- and long-term tracking of anionic ultrasmall nanomaterials in kidney. ACS Nano 10:387395. Xie, G. , J. Sun , G. Zhong , L. Shi , and D. Zhang . 2010. Biodistribution and toxicity of intravenously administered silica nanomaterials in mice. Arch Toxicol 84:183190. Xie, G. , C. Wang , J. Sun , and G. Zhong . 2011. Tissue distribution and excretion of intravenously administered titanium dioxide nanomaterials. Toxicol Lett 205:5561. Yamago, S. , H. Tokuyama , E. Nakamura 1995. In vivo biological behavior of a water-miscible fullerene: 14C labeling, absorption, distribution, excretion and acute toxicity. Chem Biol 2:385389. Yamashita, K. , Y. Yoshioka , K. Higashisaka 2011. Silica and titanium dioxide nanomaterials cause pregnancy complications in mice. Nat Nanotechnol 6:321328. Yang, R. S. H. , L. W. Chang , J. P. Wu 2007. Persistent tissue kinetics and redistribution of nanomaterials, quantum dot 705, in mice. Environ Health Perspect 115:13391343. Yang, W. , J. I. Peters , and R. O. Williams . 2008. Inhaled nanoparticles: A current review. Int J Pharm 356:239247. Yim, Y. S. , J. S. Choi , S. B. Jang 2009. Pharmacokinetic properties and tissue storage of FITC conjugated nanomaterials in mice. Curr Appl Phys 9:E304E307. Yoon, K. Y. , B. J. Hoon , J. H. Park , and J. Hwang . 2007. Susceptibility constants of Escherichia coli and Bacillus subtilis to silver and copper nanomaterials. Sci Total Environ 373:572575. Zuckerman, J. E. , C. H. J. Choi , H. Han , and M. E. Davis . 2012. Polycation-siRNA nanomaterials can disassemble at the kidney glomerular basement membrane. Proc Natl Acad Sci SA 109:31373142.

Genomic Approach of Nanotoxicity Evaluation Afshari, C. A. , H. K. Hamadeh , and P. R. Bushel . 2011. The evolution of bioinformatics in toxicology: Advancing toxicogenomics. Toxicol Sci 120(Suppl 1):S225S237. Amorim, M. J. , S. C. Novais , V. K. Van Der , T. Vandenbrouck , A. M. Soares , and W. De Coen . 2011. Development of a microarray for Enchytraeus albidus (Oligochaeta): Preliminary tool with diverse applications. Environ Toxicol Chem 30(6):13951402. doi: 10.1002/etc.512 Barlow, P. G. , A. Clouter-Baker , K. Donaldson , J. MacCallum , and V. Stone . 2005. Carbon black nanoparticles induce type II epithelial cells to release chemotaxins for alveolar macrophages. Part Fibre Toxicol 2:11. Butte, A. 2002. The use and analysis of microarray data. Nat Rev Drug Discov 1:951960. Chae, Y. J. , C. H. Pham , J. Lee , E. Bae , J. Yi , and M. B. Gu . 2009. Evaluation of the toxic impact of silver nanoparticles on Japanese medaka (Oryzias latipes). Aquat Toxicol 94:320327. Chee, M. , R. Yang , E. Hubbell , A. Berno , X. C. Huang , D. Stern , J. Winkler , D. J. Lockhart , M. S. Morris , and S. P. Fodor . 1996. Accessing genetic information with high-density DNA arrays. Science 274:610614. Chen, N. , Y. He , Y. Su , X. Li , Q. Huang , H. Wang , X. Zhang , R. Tai , and C. Fan . 2012. The cytotoxicity of cadmium-based quantum dots. Biomaterials 33:12381244. doi: 10.1016/j.biomaterials.2011.10.070 Chen, Z. , H. A. Meng , G. M. Xing 2006. Acute toxicological effects of copper nanoparticles in vivo. Toxicol Lett 163:109120. Coccini, T. , E. Roda , M. Fabbri , M. G. Sacco , L. Gribaldo , and L. Manzo . 2012. Gene expression profiling in rat kidney after intratracheal exposure to cadmium-doped nanoparticles. J Nanopart Res 14:110. Donaldson, K. , V. Stone , A. Clouter , L. Renwick , W. MacNee . 2001. Ultrafine particles. Occup Environment Med 58:211216.460 Fortner, J. D. , D. Y. Lyon , C. M. Sayes 2005. C-60 in water: Nanocrystal formation and microbial response. Environ Sci Technol 39:43074316. Gao, G. , Y. Ze , B. Li 2012. Ovarian dysfunction and gene-expressed characteristics of female mice caused by long-term exposure to titanium dioxide nanoparticles. J Hazard Mater 243:1927. Gomes, S. I. L. , A. M. V. M. Soares , J. J. Scott-Fordsmand , and M. J. B. Amorim . 2013. Mechanisms of response to silver nanoparticles on Enchytraeus albidus (Oligochaeta): survival, reproduction and gene expression profile. J Hazard Mater 254255, 336344. Gonzalez, L. , D. Lison , and M. Kirsch-Volders . 2008. Genotoxicity of engineered nanomaterials: A critical review. Nanotoxicology 2(4):252273.

Gregus, Z. 2008. Mechanisms of toxicity. In: Cararett & Doull's Toxicology: The Basic Science of Poisons. 7th edition, ed. C. D. Klaassen . McGraw Hill: New York, pp. 45106. Griffitt, R. J. , K. Hyndman , N. D. Denslow , and D. S. Barber . 2009. Comparison of molecular and histological changes in zebrafish gills exposed to metallic nanoparticles. Toxicol Sci 107:404415. Gui, S. , X. Sang , L. Zheng , Y. Ze , X. Zhao , L. Sheng , Q. Sun , Z. Cheng , J. Cheng , R. Hu , L. Wang , F. Hong , and M. Tang . 2013. Intragastric exposure to titanium dioxide nanoparticles induced nephrotoxicity in mice, assessed by physiological and gene expression modifications. Part Fibre Toxicol 10:4. Husain, M. , A. T. Saber , C. Guo , N. R. Jacobsen , K. A. Jensen , C. L. Yauk , A. Williams , U. Vogel , H. Wallin , and S. Halappanavar . 2013. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation. Toxicol Appl Pharmacol 269:250262. Jaluria P. , K. Konstantopoulos , M. Betenbaugh , and J. Shiloach . 2007. A perspective on microarrays: Current applications, pitfalls, and potential uses. Microb Cell Fact 6:4. Kisin, E. R. , A. R. Murray , M. J. Keane 2007. Single-walled carbon nanotubes: Geno- and cytotoxic effects in lung fibroblast V79 cells. J Toxicol Environ Health A 70(24):20712079. Knaapen, A. M. , P. J. A. Borm , C. Albrecht , and R. P. F. Schins . 2004. Inhaled particles and lung cancer. Part A: mechanisms. Int J Cancer 109(6): 799809. Kouassi, G. K. and J. Irudayaraj . 2006. Magnetic and gold-coated magnetic nanoparticles as a DNA sensor. Anal Chem 78:32343241. doi: 10.1021/ac051621 Landa, P. , S. Prerostova , S. Petrova , V. Knirsch , R. Vankova , and T. Vanek . 2015. The transcriptomic response of arabidopsis thaliana to zinc oxide: A comparison of the impact of nanoparticle, bulk, and ionic zinc. Environ Sci Technol 15;49(24):1453714545. doi: 10.1021/acs.est.5b03330 Lee, H. Y. , Y. J. Choi , E. J. Jung 2015. Genomics-based screening of differentially expressed genes in the brains of mice exposed to silver nanoparticles via inhalation. Molecular & Cellular Toxicology 11:307314. Li, B. , Y. Ze , Q. Sun 2013. Molecular mechanisms of nanosized titanium dioxide-induced pulmonary injury in mice. PloS One 8:111. Li, X. , W. Gu , S. Mohan , and D. J. Baylink . 2002. DNA microarrays: their use and misuse. Microcirculation 9:1322. MacNee, W. and K. Donaldson . 2003. Mechanism of lung injury caused by PM10 and ultrafine particles with special reference to COPD. Eur Respir J 21(40 Suppl):47S51S.461 Marquis, B. J. , S. A. Love , K. L. Barun , and C. L. Haynes . 2009. Analytic methods to assess nanoparticle toxicity. Analyst 134(3):425439. Monrs, J. P. , C. Bernardo , C. Molina-Quiroz Roberto 2014. Microarray analysis of the Escherichia coli response to CdTe-GSH Quantum Dots: understanding the bacterial toxicity of semiconductor nanoparticles. BMC Genomics 15(1):1099. doi: 10.1186/1471-2164-15-1099 Nel, A. , T. Xia , H. Meng , X. Wang , L. Sijie , Z. Ji , and H. Zhang . 2013. Nanomaterial toxicity testing in the 21st century: Use of a predictive toxicological approach and high-throughput screening acc. Chem Res 46(3):607621. NSTC . 2008. National nanotechnology initiative strategy for nanotechnology-related environmental, health and safety research. NSTC, Washington, DC, http://www.nano.gov. Rogach, A. L. , T. Franzl , T. A. Klar , J. Feldmann , N. Gaponik , V. Lesnyak , A. Shavel , A. Eychmller , Y. P. Rakovich , and J. F. Donegan . 2007. Aqueous synthesis of thiol-capped CdTe nanocrystals: State-of-the-art. J Phys Chem C 111:1462814637. doi: 10.1021/jp072463y SCCP . 2007. Opinion on safety of nanomaterials in cosmetic products. December 18. Schena, M. , D. Shalon , R. W. Davis , and P. O. Brown . 1995. Quantitative monitoring of gene expression patternswith a complementary DNA microarray. Science 270:467470. Schins, R. P. F. and A. M. Knaapen . 2007. Genotoxicity of poorly soluble particles. Inhal Toxicol 19(1 Supp. 1):189198. Silva, F. O. , M. S. Carvalho , R. Mendona , W. A. Macedo , K. Balzuweit , P. Reiss , and M. A. Schiavon . 2012. Effect of surface ligands on the optical properties of aqueous soluble CdTe quantum dots. Nanoscale Res Lett 7:110. doi: 10.1186/1556-276X-7-536 Talapin, D. V. , I. Mekis , S. Gtzinger , A. Kornowski , O. Benson , and H. Weller . 2006. CdSe/CdS/ZnS and CdSe/ZnSe/ZnS core-shell-shell nanocrystals. J Phys Chem B 108:1882618831. doi: 10.1021/jp046481g Unfried, K. , C. Albrecht , L. O. Klotz , A. Von Mikecz , S. Grether-Beck , and R. P. F. Schins . 2007. Cellular responses tonanoparticles: Target structures and mechanisms. Nanotoxicology 1:5272. Vallyathan, V. and X. Shi . 1997. The role of oxygen free radicals in occupational and environmental lung diseases. Environ Health Perspect 105(Suppl 1):165177.

van Aerle, R. , A. Lange , A. Moorhouse , K. Paszkiewicz , K. Ball , B. D. Johnston , E. deBastos , T. Booth , C. R. Tyler , and E. M. Santos . 2013. Molecular mechanisms of toxicity of silver nanoparticles in zebrafish embryos. Environ Sc Technol 47:80058014. Wang, A. and D. E. Crowley . 2005. Global gene expression responses to cadmium toxicity in Escherichia coli . J Bacteriol 187:32593266. doi: 10.1128/JB.187.9.3259-3266.2005 Warheit, D. B. , T. R. Webb , C. M. Sayes , V. L. Colvin , and K. L. Reed . 2007. Pulmonary instillation studies with Nanoscale TiO2 rods and dots in Rats: Toxicity is not dependent upon particle size and surface area. Toxicol Sci 91:227236. Xia, T. , M. Kovochich , J. Brant , M. Hotze , J. Sempf , T. Oberley , C. Sioutas , J. I. Yeh , M. R. Wiesner , and A. E. Nel . 2006. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6:17941807.462 Xiang, Z. , Y. Yang , X. Ma , and W. Ding . 2003. Microarray expression profiling: analysis and applications. Curr Opin Drug Discov Devel 6:384395. Zhang, X. , T. Liu , T. V. Sreekumar 2003. Poly(vinyl alcohol)/SWNT composite film. Nanolett 3(9):12851288. Zhang, H. , D. Wang , and H. Mhwald . 2006a. Ligand-selective aqueous synthesis of onedimensional CdTe nanostructures. Angew Chem Int Ed 45:748751. doi: 10.1002/anie.200502751 Zhang, Y. , M. K. So , A. M. Loening , H. Yao , S. S. Gambhir , and J. Rao . 2006b. HaloTag protein-mediated site-specific conjugation of bioluminescent proteins to quantum dots. Angew Chem Int Ed 45:49364940. doi: 10.1002/anie.200601197 Zhao, Y. and H. S. Nalwa . 2006. Nanotoxicology. Stewenson Ranch (CA): American Scientific Publishers.

Nano-Genotoxicity Evaluation: A Review Abdel-Khalek, A. 2016. Comparative evaluation of genotoxic effects induced by CuO bulk and nano-particles in Nile Tilapia, Oreochromis niloticus . Water Air Soil Pollut 227:35. doi: 10.1007/s11270-015-2737-3 ACM (Advisory Committee on Mutagenesis) . 1988. Guidelines on the use of mutagenicity tests in the toxicological evaluation of chemicals. A report of the DNH & W/DOE environmental contaminants advisory committee on mutagenesis. National health and welfare and environment, Canada. Environ Mol Mutagen 11:261304. Ahamed, M. , M. S. Alsalhi , and M. K. Siddiqui . 2010. Silver nanoparticle applications and human health. Clinica Chimica Acta 14:18411848. Akhtar, M. J. , S. Kumar , H. A. Alhadlaq , S. A. Alrokayan , K. Abu-Salah , and M. Ahamed . 2016. Dose-dependent genotoxicity of copper oxide nanoparticles stimulated by reactive oxygen species in human lung epithelial cell. Toxicol Ind Health 32(5):809821. Akyl, D. , Y. Eren , M. Konuk , A. Tepekozcan , and E. Salam . 2016. Determination of mutagenicity and genotoxicity of indium tin oxide nanoparticle using the Ames test and micronucleus assay. Toxicol Ind Health 32(9):17201728.499 Alarifi, S. , D. Ali , A. Verma , S. Alakhtani , and B. A. Ali . 2013. Cytotoxicity and genotoxicity of copper oxide nanoparticles in human skin keratinocytes cells. Int J Toxicol 32(4):296307. Asare, N. , C. Instanes , W. J. Sandberg 2012. Cytotoxic and genotoxic effects of silver nanoparticles in testicular cells. Toxicology 291:6572. Attia, A. 2014. Evaluation of the testicular alterations induced by silver nanoparticles in male mice: Biochemical, histological and ultrastructural studies. Res J Pharma Biol Chem Sci 5(4):15581589. Awasthi, K. , R. Verma , A. Awasthi , K. Awasthi , I. Soni , and P. John . 2015. In vivo genotoxic assessment of silver nanoparticles in liver cells of Swiss albino mice using comet assay. Adv Mater Letter 6:187193. Bakare, A. , A. Mosuro , and O. Osibanjo . 2005. An in vivo evaluation of induction of abnormal sperm morphology in mice by land fill leachates. Mutat Res 582:2834. Bakare, A. A. , A. J. Udoakang , A. T. Anifiwoshe 2016. Genotoxicity of titanium dioxide nanoparticles using the mouse bone marrow micronucleus and sperm morphology assays. J Pollut Effects Control 4:156. Balasubramanyam, A. , N. Sailaja , M. Mahboob , M. F. Rahman , S. M. Hussain , and P. Grover . 2009. In vivo genotoxicity assessment of aluminum oxide nanomaterials in rat peripheral blood cells using the comet assay and micronucleus test. Mutagenesis 24(3):245251.

Balasubramanyam, A. , N. Sailaja , M. Mahboob , M. F. Rahman , S. M. Hussain , and P. Grover . 2010. In vitro mutagenicity assessment of aluminium oxide nanomaterials using the Salmonella/microsome assay. Toxicol In Vitro 24:18711878. Benaron, D. , J. Gray , B. Gledhill , S. Lake , A. Wyrobek , and I. Young 1982. Quantification of mammalian sperm morphology by slit-scan flow cytometry. Cytometry 2(5):344350. Bour, A. , F. Mouchet , L. Verneuil 2015. Toxicity of CeO2 nanoparticles at different trophic levelsEffects on diatoms, chironomids and amphibians. Chemosphere 120:230236. Brusick, D. 1980. Principles of Genetic Toxicology. New York: Plenum Press, 279pp. Butler, K. S. , D. J. Peeler , B. J. Casey , B. J. Dair , and R. K. Elespuru . 2015. Silver nanoparticles: Correlating nanoparticle size and cellular uptake with genotoxicity. Mutagenesis 30(4):577591. doi: 10.1093/mutage/gev020.pdf Carmona, E. R. , C. Inostroza-Blancheteau , V. Obando , L. Rubio , and R. Marcos . 2015. Genotoxicity of copper oxide nanoparticles in Drosophila melanogaster . Mutat Research 791:111. Chemes, H. and V. Rawe . 2003. Sperm pathology: A step beyond descriptive morphology, origin, characterization and fertility potential of abnormal sperm phenotypes in infertile men. Human Reproduction Update 9:405428. Chen, Z. , Y. Wang , T. Ba 2014. Genotoxic evaluation of titanium dioxide nanoparticles in vivo and in vitro . Toxicol Letters 226:314319. Cho, H. S. , J. H. Sung , K. S. Song 2013. Genotoxicity of silver nanoparticles in lung cells of Sprague Dawley rats after 12 weeks of inhalation exposure. Toxics 1:3645. doi: 10.3390/toxics1010036 CIOMS (International guiding principles for biomedical research involving animals) . 1985. http://www.cioms.ch/publications/guidelines/1985_texts_of_guidelines.htm (accessed August 23, 2014). Collins, A. , G. Koppen , V. Valdiglesias 2014. The comet assay as a tool for human biomonitoring studies: The ComNet Project. Mutat Res 759:2739.500 Demir, E. , D. Burgucu , F. Turna , S. Aksakal , and B. Kaya . 2013. Determination of titanium dioxide, ZrO2, and Al2O3 nanoparticles on genotoxic responses in human peripheral blood lymphocytes and cultured embyronic kidney cells. J Toxicol Environ Health A 76(16):9901002. Demir, E. , N. Kaya , and B. Kaya . 2014. Genotoxic effects of zinc oxide and titanium dioxide nanoparticles on root meristem cells of Allium cepa by comet assay. Turk J Biol 38:3139. Dhawan, A. , M. Bajpayee , and D. Parmar 2009. Comet assay: A reliable tool for the assessment of DNA damage in different models. Cell Biol Toxicol 25(1):532. Dhawan, A. , J. S. Taurozzi , A. K. Pandey 2006. Stable colloidal dispersions of C-60 fullerenes in water evidence for genotoxicity. Environ Sci Tech 40:73947401. Dobrzynska, M. M. , A. Gajowik , J. Radzikowska , A. Lankoff , M. Du sinska , and M. Kruszewski . 2014. Genotoxicity of silver and titanium dioxide nanoparticles in bone marrow cells of rats in vivo . Toxicol 315:8691. El Mahdy, M. M. , T. A. S. Eldin , H. S. Aly , F. F. Mohammed , and M. I. Shaalan . 2014. Evaluation of hepatotoxic and genotoxic potential of silver nanoparticles in albino rats. Exp Toxicol Pathol 67:2129. Flower, N. A. L. , B. Brabu , M. Revath 2012. Characterisation of synthesized silver nanoparticles and the assessment of its genotoxicity potentials using the alkaline comet assay. Mutat Res 742:6165. Gomaa, O. I. , M. H. Abdel Kader , T. S. Eldin , and O. A. Heikal . 2013. Evaluation of in vitro mutagenicity and genotoxicity of magnetite nanoparticles. Drug Discov Therap 7(3):116123. Gomes, T. , O. Araujo , R. Pereira , A. C. Almeida , A. Cravo , and M. J. Bebianno . 2013. Genotoxicity of copper oxide and silver nanoparticles in the mussel Mytilus galloprovincialis . Marine Environ Res 84:5159. Gosh, M. , J. Manivannan , S. Sinha , A. Chakraborty , S. K. Mallick , M. Bandyopadhyay , and A. Mukherjee . 2012. In vitro and in vivo genotoxicity of silver nanoparticles. Mutat Res 749:6069. Gromadzka-Ostrowska, J. , K. Dziendzikowska , A. Lankoff 2012. Silver nanoparticles effects on epididymal sperm in rats. Toxicol Letters 214: 251258. GuO, X. , Y. Li , J. Yan 2016. Coating-dependent cytotoxicity and genotoxicity of silver nanoparticles evaluated using in vitro standard assays. Nanotoxicol 10(9):13731384. Huk, A. , E. Izak-Nau , B. Reidy , M. Boyles , A. Dusch , I. Lynch and M. Duinska 2014. Is the toxic potential of nanosilver dependent on its size? Particle Fibre Toxicol 11:65. Huk, A. , E. Izak-Nau , N. E. Yamani 2015. Impact of nanosilver on various DNA lesions and HPRT gene mutationsEffects of charge and surface coating. Particle Fibre Toxicol 12:25. doi: 10.1186/s12989-015-0100-x Institute for Laboratory Animal Research (ILAR) . 2011. Guide for the Care and Use of Laboratory Animals (8th Ed). Washington DC: The National Academies Press, 246pp.

Isani, G. , M. L. Falcioni , G. Barucca 2013. Comparative toxicity of CuO nanoparticles and CuSO4 in rainbow trout. Ecotoxicol Environ Safety 97:4046. Kang, S. H. , J. Y. Kwon , J. K. Lee , and Y. R. Seo . 2013. Recent advances in in vivo genotoxicity testing: Prediction of carcinogenic potential using comet and micronucleus assay in animal models. J Cancer Prev 18(4):277288.501 Kang, S. J. , B. M. Kim , Y. Lee , and H. W. Chung . 2008. Titanium dioxide nanoparticles trigger p53-mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen 49:399405. Kang, S. J. , Y. J. Lee , B. M. Kim , Y. J. Choi , and H. W. Chung . 2011. Cytotoxicity and genotoxicity of titanium dioxide nanoparticles in UVA-irradiated normal peripheral blood lymphocytes. Drug Chem Toxicol 34(3):277284. Kim, H. R. , Y. J. Park , D. Y. Shin , S. M. Oh , and K. H. Chung . 2013. Appropriate In Vitro Methods for Genotoxicity Testing of Silver Nanoparticles. Environ Health Toxicol 28: 18. Kim, J. S. , J. H. Sung , J. H. Ji 2011. In vivo genotoxicity of silver nanoparticles after 90 days silver nanoparticle inhalation exposure. Saf Health Work 2:3438. Kim, S. , J. Choi , K. Chung , K. Park , K. Yi , and D. Ryu . 2009a. Oxidative stress- dependent toxicity of silver nanoparticles in human hepatoma cells. Toxicol in vitro 23: 10761084. Kim, Y. , H. Choi , M. Song , D. Youk , L. Kim , and J. Ryu . 2009b. Genotoxicity of aluminium oxide (Al2O3) nanoparticle in mammalian cell lines. Mol Cellular Toxicol 5(2):172178. Kim, Y. , J. Kim , H. Cho 2008. Twenty-eight-day oral toxicity, Genotoxicity and gender-related tissue distribution of silver nanoparticles in SpragueDawley rats. Inhalation Toxicol 20:575583. Kumar, A. and A. Dhawan 2013. Genotoxic and carcinogenic potential of engineered nanoparticles. An update. Arch Toxicol 87:18831900. Kumar, A. , S. Khan , and A. Dhawan . 2014. Metal oxide nanoparticles elicit geno-toxic responses in mammalian cells: A critical review. In: Nanoscience and Technology for Mankind. ed. Ashok Misra and Professor Jayesh Bellare . Humana Press, pp 160194. Kumar, A. , A. K. Pandey , S. S. Singh R. Shanker , and A. Dhawan . 2011. Cellular uptake and mutagenic potential of metal oxide nanoparticles in bacterial cells. Chemosphere 83:11241132. Kumari, M. , A. Mukherjee , and N. Chandrasekaran . 2009. Genotoxicity of silver nanoparticles in Allium cepa . Sci Total Environ 407:52435246. Kumari, M. , S. P. Singh , S. Chinde , M. F. Rahman , M. Mahboob , and P. Grover . 2014. Toxicity study of cerium oxide nanoparticles in human neuroblastoma cells. Int J Toxicol 33(2):8697. Kumari, M. , S. S. Khan , S. Pakrashi , A. Mukherjee , and N. Chandrasekaran . 2011. Cytogenetic and genotoxic effects of zinc oxide nanoparticles on root cells of Allium cepa . Journal of Hazardous Materials 190:613621. Kwon, J. Y. , H. L. Kim , J. Y. Lee 2014. Undetectable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests. Int J Nanomed 9(Suppl 2):173181. Lee, S. H. , S. Chung , I. Kim , and I. Lee . 2013. The genotoxic effect of ZnO and CuO nanoparticles on early growth of buckwheat, Fagopyrum esculentum. Water Air Soil Pollut 224:111. Li, Y. , D. H. Chen , J. Yan 2012. Genotoxicity of silver nanoparticles evaluated using the Ames test and in vitro micronucleus assay. Mutat Res 745:410. Maenosono, S. , T. Suzuki , and S. Saita . 2007. Mutagenicity of water-soluble FePt nanoparticles in Ames test. J Toxicol Sci 32: 575579. Ng, C.T. , J. J. Li , B. Bay , and L. Li . 2010. Current studies into the genotoxic effects of nanomaterials. J Nucleic Acids 20:19.502 OECD 2009. Preliminary Review of OECD Test Guidelines for Their Applicability to Manufactured Nanomaterials. Pari: Organization for Economic Cooperation and Development. Ordzhonikidze, C. G. , L. K. Ramaiyya , E. M. Egorova , and A. V. Rbanovich . 2009. Genotoxic effects of Silver nanoparticles on mice in vivo . Acta Naturae 3:99101. Ostling, O. and J. K. Johanson . 1984. Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. BBRC 123:291298. Paino, I. M. M. , V. S. Marangonia , R. Silva de Oliveirab , L. M. G. Antunesb , and V. Zucolottoa . 2012. Cyto and genotoxicity of gold nanoparticles in human hepatocellular carcinoma and peripheral blood mononuclear cells. Toxicol Letters 215:119125. Pakrashi, S. , N. Jain , S. Dalai , J. Jayakumar , P. T. Chandrasekaran , A. M. Raichur , N. Chandrasekaran , and A. Mukherjee . 2014. In vivo Genotoxicity assessment of Titanium dioxide nanoparticles by Allium cepa root tip assay at high exposure concentrations. PLoS ONE 9(2):e87789. doi: 10.1371/journal.pone.0087789 Pan, X. , J. E. Redding , P. A. Wiley , L. Wena , J. S. McConnell , and B. Zhang . 2010. Mutagenicity evaluation of metal oxide nanoparticles by the bacterial reverse mutation assay. Chemosphere 79:113116.

Park, E. , E. Bae , J. Yi 2010. Repeated dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles. Environ Toxicol Pharmacol 30:162168. Patlolla, A. K. , A. Berry , L. May , and P. B. Tchounwou . 2012. Genotoxicity of silver nanoparticles in Viciafaba: A pilot study on the environmental monitoring of nanoparticles. International Journal of Environmental Research and Public Health 9:16491662. Patlolla, A. K. , D. Hackett , and P. B. Tchounwou . 2015. Genotoxicity study of silver nanoparticles in bone marrow cells of SpragueDawley rats. Food Cheml Toxicol 85:5260. Perreault, F. , S. P. Melegari , C. H. da Costa , R. Popovic , and W. G. Matias . 2012. Genotoxic effects of CuONPs in Neuro 2A cell cultures. Sci Total Environ 441:117124. Pesnya, D. S. 2013. Cytogenetic effects of chitosan-capped silver nanoparticles in the Allium cepa test. Caryologia 66(3):275281. Pierscionek, B. K. , Y. Li , A. A. Yasseen 2010. Nanoceria have no genotoxic effect on human lens epithelial cells. Nanotechnol 21(3):035102. Rajeshwari, A. , S. Kavitha , A. A. Alex , D. Kumar , A. Mukherjee , N. Chandrasekaran , and A. Mukherjee . 2015. Cytotoxicity of aluminum oxide nanoparticles on Allium cepa root tip-effects of oxidative stress generation and biouptake. Environ Sci Poll Res Int 22(14):1105711066. Santo, C.E. , D. Quaranta , and G. Grass . 2012. Antimicrobial metallic copper surfaces kill Staphylococcus haemolyticus via membrane damage. Microbiol Open 1:4652. Sharma, V. , D. Anderson , and A. Dhawan . 2012a. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human liver cells (HepG2). Apoptosis 17(8):852870. Sharma, V. , P. Singh , A. Pandey , and A. Dhawan . 2012b. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res 745:8491.503 Shaymurat, T. , J. Gu , C. Xu , Z. Yang , Q. Zhao , Y. Liu , and Y. Liu . 2012. Phytotoxic and genotoxic effects of ZnO nanoparticles on garlic (Allium sativum L.): A morphological study. Nanotoxicol 6(3):241248. Shinohara, N. , K. Matsumoto , S. Endoh , K. Maru , and J. Nakanishi . 2009. In vitro and in vivo genotoxicity tests on fullerene C60 nanoparticles. Toxicology Letters 191:289296. Shukla, R. , A. Kumar , N. V. S. Vallabani , A. K. Pandey , and A. Dhawan . 2014. Titanium dioxide nanoparticle-induced oxidative stress triggers DNA damage and hepatic injury in mice. Nanomed 9(9):14231434. Siddiqui, M. A. , H. A. Alhadlaq , J. Ahmad , A. A. Al-Khedhairy , J. Musarrat , and M. Ahamed . 2013. Copper oxide nanoparticles induced mitochondria mediated apoptosis in human hepatocarcinoma cells. PLOS 8(8):e69534. doi: 10.1371/journal.pone.0069534 Singh, N. P. , M. T. McCoy , R. R. Tice , and E. L. Schneider . 1988. A simple technique for quantitation of low-levels of DNA damage in individual cells. Exp Cell Res 175(1):184191. Singh, S. P. , M. Kumari , S. I. Kumari , M. F. Rahman , M. Mahboob , and P. Grover . 2013a. Toxicity assessment of manganese oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral exposure. J Appl Toxicol 33:11651179. Singh, S. P. , M. Kumari , S. I. Kumari , M. F. Rahman , M. Mahboob , and P. Grover . 2013b. Genotoxicity of nano- and micron-sized manganese oxide in rats after acute oral treatment. Mutat Res 754(12):3950. Song, M. , Y. Li , H. Kasai , and K. Kawai . 2012. Metal nanoparticle-induced micronuclei and oxidative damage in mice. J Clini Biochem Nutr 5(3):211216. Speit, G. and A. Hartmann . 2005. The Comet assay: A sensitive genotoxicity test for the detection of DNA damage. Methods Mol Biol 291:8595. Srivastava, A. 2009. Antiviral activity of copper complexes of isoniazid against RNA tumor viruses. Resonance 14:754760. Szalay, B. , E. Ttrai , G. Nyr , T. Vezr , and G. Dura . 2012. Potential toxic effects of iron oxide nanoparticles in in vivo and in vitro experiments. J Appl Toxicol 32(6):446453. Takeda, K. , K. Suzuki , A. Ishihara , M. Kubo-Irie , R. Fujimoto , and M. Tabata . 2009. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve system. J Health Sci 55:95102. Tice, R. R. , E. Agurell , D. Anderson 2000. Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35:206221. Topham, J. C. 1980. Chemically induced transmissible abnormalities in sperm head shape. Mutatat Res 69: 149155. Triboulet, S. , C. Aude-Garcia , L. Armand 2015. Comparative proteomic analysis of the molecular responses of mouse macrophages to titanium dioxide and copper oxide nanoparticles unravels some toxic mechanisms for copper oxide nanoparticles in macrophages. PLoS ONE 10(4):e0124496. doi: 10.1371/journal.pone.0124496 Trouiller, B. , R. Reliene , A. Westbrook , P. Solaimani , and R. H. Schiestl . 2009. Titanium Dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res

69(22):87848789. Uboldi, C. , G. Giudetti , F. Broggi , D. Gilliland , J. Ponti , and F. Rossi . 2012. Amorphous silica nanoparticles do not induce cytotoxicity, cell transformation or Genotoxicity in Balb/3T3 mouse fibroblasts. Mutat Res 745:1120.504 Vecchio, G. , A. Galeone , V. Brunetti 2012. Mutagenic effects of gold nanoparticles induce aberrant phenotypes in Drosophila melanogaster . Nanomed 8:17. Wang, Z. , N. Li , J. Zhao , J. C. White , P. Qu , and B. Xing . 2012. CuO nanoparticle interaction with human epithelial cells: Cellular uptake, location, export, and genotoxicity. Chemical Research in Toxicology 25(7):15121521. doi: 10.1021/tx3002093 Wiwanitkit, V. , A. Sereemaspun , and R. Rojanathanes . 2009. Effect of gold nanoparticles on spermatozoa: The first world report. Fertility and Sterility 91(1):78. Woodruff, R. S. , Y. Li , J. Yan 2012. Genotoxicity evaluation of titanium dioxide nanoparticles using the Ames test and Comet assay. J Appl Toxicol 32(11):934943. Wyrobek, A. J. and W. R. Bruce . 1975. Chemical induction of sperm abnormalities in mice. PNAS 72:44254429. Wyrobek, A. J. , L. A. Gordon , J. G. Burkhart 1983. An evaluation of the mouse sperm morphology test and other sperm tests in non-human mammals. A report of the United States Environmental Protection Agency Gene-Tox Programme. Mutat Res 115:172. Xu, A. , Y. Chai , and T. K. Hei . 2009. Genotoxic responses to titanium dioxide nanoparticles and fullerene in gpt delta transgenic MEF cells. Particl Fibre Toxicol 6(3):113. Yoshida, R. , D. Kitamura , and S. Maenosono . 2009. Mutagenicity of water-soluble ZnO nanoparticles in Ames test. J Toxicol Sci 34:119122. Yoshida, S. , K. Hiyoshi , T. Ichinose 2008. Effect of nanoparticles on the male reproductive system of mice. International J Androl 32:337342. Zakhidov, S. T. , T. L. Marshak , and E. A. Malolina . 2010. Gold nanoparticles disturb nuclear chromatin decondensation in Mouse Sperm in vitro. Biochem (Moscow) Suppl. Series A: Membr. Cell Biol 4(3):293297.

Nanoinformatics: An Alternative of In Vitro and In Vivo Nanotoxicity Evaluations Burello, E. and A. P. Worth . 2011. QSAR modeling of nanomaterials. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3(3):298306. Cattaneo, A. G. , R. Gornati , E. Sabbioni , M. Chiriva-Internati , E. Cobos , M. R. Jenkins , and G. Bernardini . 2010. Nanotechnology and human health: Risks and benefits. J Appl Toxicol 30(8):730744. Chau, Y. T. and C. W. Yap . 2012. Quantitative nanostructure-activity relationship modelling of nanoparticles. RSC Advances 2(22):84898496. Chen, Y. , J. Chen , J. Dong , and Y. Jin . 2004. Comparing study of the effect of nanosized silicon dioxide and microsized silicon dioxide on fibrogenesis in rats. Toxicol Ind Health 20(15):2127. Delay, M. and F. H. Frimmel . 2012. Nanoparticles in aquatic systems. Anal Bioanal Chem 402(2):583592. Epa, V. C. , F. R. Burden , C. Tassa , R. Weissleder , S. Shaw , and D. A. Winkler . 2012. Modeling biological activities of nanoparticles. Nano Lett 12(11):58085812. Fourches, D. , D. Pu , C. Tassa , R. Weissleder , S. Y. Shaw , R. J. Mumper , and A. Tropsha . 2010. Quantitative nanostructure-activity relationship modeling. ACS Nano 4(10):57035712. Fourches, D. , D. Pu , and A. Tropsha . 2011. Exploring quantitative nanostructure-activity relationships (QNAR) modeling as a tool for predicting biological effects of manufactured nanoparticles. Comb Chem High Throughput Screen 14(3):217225. Gajewicz, A. , B. Rasulev , T. C. Dinadayalane , P. Urbaszek , T. Puzyn , D. Leszczynska , and J. Leszczynski . 2012. Advancing risk assessment of engineered nanomaterials: Application of computational approaches. Adv Drug Deliv Rev 64(15):16631693. Gajewicz, A. , N. Schaeublin , B. Rasulev , S. Hussain , D. Leszczynska , T. Puzyn , and J. Leszczynski . 2015. Towards understanding mechanisms governing cytotoxicity of metal oxides nanoparticles: Hints from nano-QSAR studies. Nanotoxicology 9(3):313325. Gaudin, C. , D. Cunha , E. Ivanoff , P. Horcajada , G. Chev , A. Yasri , O. Loget , C. Serre , and G. Maurin . 2012. A quantitative structure activity relationship approach to probe the influence of the functionalization on the drug encapsulation of porous metal-organic frameworks. Microporous Mesoporous Mater 157:124130.

Ghorbanzadeh, M. , M. H. Fatemi , and M. Karimpour . 2012. Modeling the cellular uptake of magnetofluorescent nanoparticles in pancreatic cancer cells: A quantitative structure activity relationship study. Ind Eng Chem Res 51(32):1071210718. Golbraikh, A. and A. Tropsha . 2002. Beware of q2! J Mol Graph Model 20(4):269276.524 Gordon, T. , L. C. Chen , J. M. Fine , R. B. Schlesinger , W. Y. Su , T. A. Kimmel , and M. O. Amdur . 1992. Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits. Am Ind Hyg Assoc J 53(8):503509. Handy, R. D. and B. J. Shaw . 2007. Toxic effects of nanoparticles and nanomaterials: Implications for public health, risk assessment and the public perception of nanotechnology. Health Risk Soc 9(2):125144. Kang, S. J. , B. M. Kim , Y. J. Lee , and H. W. Chung . 2008. Titanium dioxide nanoparticles trigger p53-mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen 49(5):399405. Kar, S. , A. Gajewicz , T. Puzyn , K. Roy , and J. Leszczynski . 2014. Periodic table-based descriptors to encode cytotoxicity profile of metal oxide nanoparticles: A mechanistic QSTR approach. Ecotoxicol Environ Saf 107:162169. Kar, S. , A. Gajewicz , K. Roy , J. Leszczynski , and T. Puzyn . 2016. Extrapolating between toxicity endpoints of metal oxide nanoparticles: Predicting toxicity to Escherichia coli and human keratinocyte cell line (HaCaT) with Nano-QTTR. Ecotoxicol Environ Saf 126:238244. Karlsson, H. L. , P. Cronholm , J. Gustafsson , and L. Moller . 2008. Copper oxide nanoparticles are highly toxic: A comparison between metal oxide nanoparticles and carbon nanotubes. Chem Res Toxicol 21(9):17261732. Lin, D. , X. Tian , F. Wu , and B. Xing . 2010. Fate and transport of engineered nanomaterials in the environment. J Environ Qual 39(6):18961908. Liu, R. , R. Rallo , S. George , Z. Ji , S. Nair , A. E. Nel , and Y. Cohen . 2011. Classification NanoSAR development for cytotoxicity of metal oxide nanoparticles. Small 7(8):11181126. Liu, R. , H. Y. Zhang , Z. X. Ji , R. Rallo , T. Xia , C. H. Chang , A. Nel , and Y. Cohen . 2013. Development of structure-activity relationship for metal oxide nanoparticles. Nanoscale 5(12):56445653. Luan, F. , V. V. Kleandrova , H. Gonzalez-Diaz , J. M. Ruso , A. Melo , A. Speck-Planche , and M. N. Cordeiro . 2014. Computer-aided nanotoxicology: Assessing cytotoxicity of nanoparticles under diverse experimental conditions by using a novel QSTR-perturbation approach. Nanoscale 6(18):1062310630. Lynch, I. , A. Afantitis , G. Leonis , G. Melagraki , and E. Valsami-Jones . 2017. Strategy for identification of nanomaterials critical properties linked to biological impacts: Interlinking of experimental and computational approaches. In Advances in QSAR Modeling: Applications in Pharmaceutical, Chemical, Food, Agricultural and Environmental Sciences, ed. Roy, K. Cham: Springer International Publishing, pp. 385424. Lyon, D. Y. , J. D. Fortner , C. M. Sayes , V. L. Colvin , and J. B. Hughe . 2005. Bacterial cell association and antimicrobial activity of a C60 water suspension. Environ Toxicol Chem 24(11):27572762. Martin, D. , U. Maran , S. Sild , and M. Karelson . 2007. QSPR modeling of solubility of polyaromatic hydrocarbons and fullerene in 1-octanol and n-heptane. J Phys Chem B 111(33):98539857. Melagraki, G. and A. Afantitis . 2014. Enalos InSilicoNano platform: An online decision support tool for the design and virtual screening of nanoparticles. RSC Adv 4:5071350725. Melagraki, G. and A. Afantitis . 2015. A risk assessment tool for the virtual screening of metal oxide nanoparticles through Enalos InSilicoNano platform. Curr Top Med Chem 15(18):18271836.525 Mikolajczyk, A. , A. Gajewicz , B. Rasulev , N. Schaeublin , E. Maurer-Gardner , S. Hussain , J. Leszczynski , and T. Puzyn . 2015. Zeta potential for metal oxide nanoparticles: A predictive model developed by a nano-quantitative structureproperty relationship approach. Chem Mater 27(7):24002407. Murdock, R. C. , L. Braydich-Stolle , A. M. Schrand , J. J. Schlager , and S. M. Hussain . 2008. Characterization of nanomaterial dispersion in solution prior to in vitro exposure using dynamic light scattering technique. Toxicol Sci 101(2):239253. Nel, A. , T. Xia , L. Madler , and N. Li . 2006. Toxic potential of materials at the nanolevel. Science 311(5761):622627. Oberdorster, G. , A. Maynard , K. Donaldson 2005. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part Fibre Toxicol 2:8. OECD . 2014. Guidance on Grouping of Chemicals, Second Edition, http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2014)4&d oclanguage=en.

Oh, E. , R. Liu , A. Nel , K. B. Gemill , M. Bilal , Y. Cohen , and I. L. Medintz . 2016. Metaanalysis of cellular toxicity for cadmium-containing quantum dots. Nat Nanotechnol 11(5):479486. Puzyn, T. , D. Leszczynska , and J. Leszczynski . 2009. Toward the development of nanoQSARs: Advances and challenges. Small 5(22):24942509. Puzyn, T. , B. Rasulev , A. Gajewicz , X. Hu , T. P. Dasari , A. Michalkova , H. M. Hwang , A. Toropov , D. Leszczynska , and J. Leszczynski . 2011. Using nano-QSAR to predict the cytotoxicity of metal oxide nanoparticles. Nat Nanotechnol 6(3):175178. Rehn, B. , F. Seiler , S. Rehn , J. Bruch , and M. Maier . 2003. Investigations on the inflammatory and genotoxic lung effects of two types of titanium dioxide: Untreated and surface treated. Toxicol Appl Pharmacol 189(2):8495. Sayes, C. and I. Ivanov . 2010. Comparative study of predictive computational models for nanoparticle-induced cytotoxicity. Risk Anal 30(11):17231734. Sayes, C. M. , J. D. Fortner , W. Guo 2004. The differential cytotoxicity of water-soluble fullerenes. Nano Lett 4(10):18811887. Schaafsma, G. , E. D. Kroese , E. L. Tielemans , J. J. Van de Sandt , and C. J. Van Leeuwen . 2009. REACH, non-testing approaches and the urgent need for a change in mind set. Regul Toxicol Pharmacol 53(1):7080. Schaeublin, N. M. , L. K. Braydich-Stolle , E. I. Maurer , K. Park , R. I. MacCuspie , A. R. Afrooz , R. A. Vaia , N. B. Saleh , and S. M. Hussain . 2012. Does shape matter? Bioeffects of gold nanomaterials in a human skin cell model. Langmuir 28(6):32483258. Shaw, S. Y. , E. C. Westly , M. J. Pittet , A. Subramanian , S. L. Schreiber , and R. Weissleder . 2008. Perturbational profiling of nanomaterial biologic activity. Proc Natl Acad Sci U S A 105(21):73877392. Shinohara, N. , K. Matsumoto , S. Endoh , J. Maru , and J. Nakanishi . 2009. In vitro and in vivo genotoxicity tests on fullerene C60 nanoparticles. Toxicol Lett 191(23):289296. Sushko, I. , S. Novotarskyi , R. Korner 2011. Online chemical modeling environment (OCHEM): Web platform for data storage, model development and publishing of chemical information. J Comput Aided Mol Des 25(6):533554. Tassa, C. , J. L. Duffner , T. A. Lewis , R. Weissleder , S. L. Schreiber , A. N. Koehler , and Shaw, S. Y. 2010. Binding affinity and kinetic analysis of targeted small molecule-modified nanoparticles. Bioconjug Chem 21(1):1419. doi: 10.1021/bc900438a.526 Toropov, A. A. , D. Leszczynska , and J. Leszczynski . 2007. Predicting water solubility and octanol water partition coefficient for carbon nanotubes based on the chiral vector. Comput Biol Chem 31(2):127128. Toropov, A. A. and A. P. Toropova . 2014. Optimal descriptor as a translator of eclectic data into endpoint prediction: Mutagenicity of fullerene as a mathematical function of conditions. Chemosphere 104:262264. Toropov, A. A. , A. P. Toropova , E. Benfenati , G. Gini , T. Puzyn , D. Leszczynska , and J. Leszczynski . 2012. Novel application of the CORAL software to model cytotoxicity of metal oxide nanoparticles to bacteria Escherichia coli. Chemosphere 89(9):10981102. Toropov, A. A. , A. P. Toropova , T. Puzyn , E. Benfenati , G. Gini , D. Leszczynska , and J. Leszczynski . 2013. QSAR as a random event: Modeling of nanoparticles uptake in PaCa2 cancer cells. Chemosphere 92(1):3137. Toropova, A. P. and A. A. Toropov . 2013. Optimal descriptor as a translator of eclectic information into the prediction of membrane damage by means of various TiO(2) nanoparticles. Chemosphere 93(10):26502655. Weissleder, R. , K. Kelly , E. Y. Sun , T. Shtatland , and L. Josephson . 2005. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat Biotechnol 23(11):14181423. Winkler, D. A. 2016. Recent advances, and unresolved issues, in the application of computational modelling to the prediction of the biological effects of nanomaterials. Toxicol Appl Pharmacol 299:96100. Zhang, H. , Z. Ji , T. Xia 2012. Use of metal oxide nanoparticle band gap to develop a predictive paradigm for oxidative stress and acute pulmonary inflammation. ACS Nano 6(5):43494368. Zhou, H. , Q. Mu , N. Gao 2008. A nano-combinatorial library strategy for the discovery of nanotubes with reduced protein-binding, cytotoxicity, and immune response. Nano Lett 8(3):859865.

In Silico Methods for Nanotoxicity Evaluation: Opportunities and Challenges Ahmed, L. 2013. Receptor- and ligand-based study of fullerene analogues: Comprehensive computational approach including quantum-chemical, QSAR and molecular docking simulations. Org Biomol Chem, 11(35):57985808. Andn, F. T. and B. Fadeel . 2014. Nanotoxicology: Towards Safety by Design. Cham, Switzerland: Springer International Publishing. . 2006. Regulation (EC) No 1907/2006 of the European Parliament and of the Council of December 18, 2006. Official Journal of the European Union, 396/1:1. Barnard, A. S. 2009. How can ab initio simulations address risks in nanotech? Nat Nano, 4(6):332335. Benyamini, H. 2006. Interaction of C60-Fullerene and carboxyfullerene with proteins: Docking and binding site alignment. Bioconjug Chem, 17(2):378386. Bigdeli, A. 2014. Towards defining new nano-descriptors: Extracting morphological features from transmission electron microscopy images. RSC Adv, 4(104):6013560143. Bigdeli, A. , M. R. Hormozi-Nezhad , and H. Parastar . 2015. Using nano-QSAR to determine the most responsible factor(s) in gold nanoparticle exocytosis. RSC Adv, 5(70):5703057037. Blaauboer, B. J. 2008. The contribution of in vitro toxicity data in hazard and risk assessment: Current limitations and future perspectives. Toxicol Lett, 180(2):8184.553 Bowes, J. , A. J. Brown , J. Hamon , W. Jarolimek , A. Sridhar , G. Waldron , and S. Whitebread . 2012. Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nat Rev Drug Discov, 11:909922. doi: 10.1038/nrd3845. Cedervall, T. 2007. Understanding the nanoparticleprotein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci, 104(7):20502055. Chau, Y. T. and C. W. Yap . 2012. Quantitative nanostructure-activity relationship modelling of nanoparticles. RSC Adv, 2(22):84898496. Cherkasov, A. 2014. QSAR modeling: Where have you been? Where are you going to. J Med Chem, 57(12):49775010. Cho, W.-S. 2012. Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles. Toxicol Sci, 126(2):469477. Chusuei, C. C. 2013. Cytotoxicity in the age of nano: The role of fourth period transition metal oxide nanoparticle physicochemical properties. Chem Biol Interact, 206(2):319326. Consonni, V. and Todeschini, R. 2010. Molecular descriptors. Recent Advances in QSAR Studies: Methods and Applications. In: eds. Puzyn, T. , J., Leszczynski , and T. M. Cronin . Dordrecht: Springer Netherlands, pp. 29102. Durdagi, S. 2008. Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations. Bioorg Med Chem, 16(23):99579974. Epa, V. C. 2012. Modeling Biological Activities of Nanoparticles. Nano Lett, 12(11):58085812. Fourches, D. 2010. Quantitative nanostructureactivity relationship modeling. ACS Nano, 4(10):57035712. Gajewicz, A. 2012. Advancing risk assessment of engineered nanomaterials: Application of computational approaches. Adv Drug Delivery Rev, 64(15):16631693. Gajewicz, A. 2017. Addressing a bottle neck for regulation of nanomaterials: Quantitative readacross (Nano-QRA) algorithm for cases when only limited data is available. Environ Sci: Nano, 4:346358. http://dx.doi.org/10.1039/C6EN00399K Gajewicz, A. 2015a. Novel approach for efficient predictions properties of large pool of nanomaterials based on limited set of species: Nano-read-across. Nanotechnology, 26(1):15701. Gajewicz, A. 2015b. Towards understanding mechanisms governing cytotoxicity of metal oxides nanoparticles: Hints from nano-QSAR studies. Nanotoxicology, 9(3):313325. George, S. 2011. Use of a high-throughput screening approach coupled with in vivo Zebrafish embryo screening to develop hazard ranking for engineered nanomaterials. ACS Nano, 5(3):18051817. Ghorbanzadeh, M. , M. H. Fatemi , and M. Karimpour . 2012. Modeling the cellular uptake of magnetofluorescent nanoparticles in pancreatic cancer cells: A quantitative structure activity relationship study. Ind Eng Chem Res, 51(32):1071210718. Gilkey, M. J. 2015. Physiologically based pharmacokinetic modeling of fluorescently labeled block copolymer nanoparticles for controlled drug delivery in leukemia therapy. CPT: Pharmacometrics & Systems Pharmacology, 4(3):167174.

Graham, K. R. 2014. Importance of the donor: Fullerene intermolecular arrangement for highefficiency organic photovoltaics. J Am Chem Soc, 136(27):96089618 554. Harper, B. 2015. Comparative hazard analysis and toxicological modeling of diverse nanomaterials using the embryonic zebrafish (EZ) metric of toxicity. J Nanoparticle Res: An Interdisciplinary Forum for Nanoscale Science and Technology, 17(6):250. Hartung, T. and S. Hoffmann . 2009. Food for thought on in silico methods in toxicology. ALTEX, 26:155156. Hjorth, R. 2017. The role of alternative testing strategies in environmental risk assessment of engineered nanomaterials. Environ Sci: Nano, 4:292301. Kar, S. 2014. Periodic table-based descriptors to encode cytotoxicity profile of metal oxide nanoparticles: A mechanistic QSTR approach. Ecotoxicol Environ Saf, 107:162169. Kar, S. 2016. Quantitative structure-property relationship model leading to virtual screening of fullerene derivatives: Exploring structural attributes critical for photoconversion efficiency of polymer solar cell acceptors. Nano Energy, 26:677691. Katritzky, A. R. 1996. Prediction of polymer glass transition temperatures using a general quantitative structureproperty relationship treatment. J Chem Inf Comput Sci, 36(4):879884. Kaweeteerawat, C. 2015. Toxicity of metal oxide nanoparticles in Escherichia coli correlates with conduction band and hydration energies. Environ Sci Technol, 49(2):11051112. Kim, J. A. , A. Salvati , C. berg , and K. A. Dawson . 2014. Suppression of nanoparticle cytotoxicity approaching in vivo serum concentrations: Limitations of in vitro testing for nanosafety. Nanoscale, 6(23):1418014184. doi: 10.1039/C4NR04970E. Kleandrova, V. V. 2014. Computational tool for risk assessment of nanomaterials: Novel QSTRperturbation model for simultaneous prediction of ecotoxicity and cytotoxicity of uncoated and coated nanoparticles under multiple experimental conditions. Adv Environ Sci Technol, 48(24):1468614694. Knowledgebase, N.-B. I. (Nanomaterial-Biological Interactions Knowledgebase) : http://nbi.oregonstate.edu/. Lai, D. Y. 2015. Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials. Food Chem Toxicol, 85:120126. Li, M. 2017. Physiologically based pharmacokinetic (PBPK) modeling of pharmaceutical nanoparticles. AAPS J, 19(1):2642. Liu, R. 2011. Classification NanoSAR development for cytotoxicity of metal oxide nanoparticles. Small, 7(8):11181126. Liu, R. 2014. Association rule mining of cellular responses induced by metal and metal oxide nanoparticles. Analyst, 139(5):943953. Liu, R. 2013. Nano-SAR development for bioactivity of nanoparticles with considerations of decision boundaries. Small, 9(910):18421852. Liu, R. 2015a. Prediction of nanoparticles-cell association based on corona proteins and physicochemical properties. Nanoscale, 7(21):96649675. Liu, R. 2015b. Evaluation of toxicity ranking for metal oxide nanoparticles via an in vitro dosimetry model. ACS Nano, 9(9):93039313. Marchese Robinson, R. L. 2016. How should the completeness and quality of curated nanomaterial data be evaluated? Nanoscale, 8(19):99199943 555. Mikolajczyk, A. 2015. Zeta potential for metal oxide nanoparticles: a predictive model developed by a nano-quantitative structureproperty relationship approach. Chem Mater, 27(7):24002407. Miller, F. J. , P. M. Schlosser , and D. B. Janszen . 2000. Haber's rule: A special case in a family of curves relating concentration and duration of exposure to a fixed level of response for a given endpoint. Toxicology, 149(1):2134. Modi, S. 2012. The value of in silico chemistry in the safety assessment of chemicals in the consumer goods and pharmaceutical industries. Drug Discov Today, 17(34):135142. Nanomanufacturing, I. for, InternanoResources for Nanomanufacturing : http://www.internano.org/ National Toxicology Program Database, National Toxicology Program Database : http://tools.niehs.nih.gov/ntp_tox/ Odziomek, K. 2017. Scanning electron microscopy image representativeness: Morphological data on nanoparticles. J Microsc, 265(1):3450. Oksel, C. , C. Y. Ma , and X. Z. Wang . 2015. Structure-activity relationship models for hazard assessment and risk management of engineered nanomaterials. Procedia Engineering, 102:15001510. Panneerselvam, S. and Choi, S. , 2014. Nanoinformatics: Emerging databases and available tools. Int J Mol Sci, 15(5):71587182. Papa, E. , J. P. Doucet , and A. Doucet-Panaye . 2015. Linear and non-linear modelling of the cytotoxicity of TiO2 and ZnO nanoparticles by empirical descriptors. SAR QSAR Environ Res,

26(79):647665. Patel, T. 2012. Toxicity profiling of engineered nanomaterials via multivariate dose-response surface modeling. The Ann Appl Stat, 6(4):17071729. Patel, T. 2013. Hierarchical rank aggregation with applications to nanotoxicology. Am J Agric, Biol Environ Stat, 18(2):159177. Pathakoti, K. 2014. Using experimental data of Escherichia coli to develop a QSAR model for predicting the photo-induced cytotoxicity of metal oxide nanoparticles. J Photochem Photobiol B BiolB: Biol, 130:234240. Puzyn, T. 2011. Using nano-QSAR to predict the cytotoxicity of metal oxide nanoparticles. Nat Nanotechnol, 6(3):175178. Puzyn, T. , D. Leszczynska , and J. Leszczynski . 2009. Toward the development of NanoQSARs: Advances and challenges. Small, 5(22):24942509. Raies, A. B. and V. B. Bajic . 2016. In silico toxicology: Computational methods for the prediction of chemical toxicity. Wiley Interdisciplinary Reviews: Computational Molecular Science, 6(2):147172. Rallo, R. 2011. Self-organizing map analysis of toxicity-related cell signaling pathways for metal and metal oxide nanoparticles. Environ Sci Technol, 45(4):16951702. Raunio, H. 2011. In silico toxicologynon-testing methods. Frontiers in Pharmacology, 2:33. Registry, N., Nanomaterial Registry : https://www.nanomaterialregistry.org/ Richarz, A.-N. 2015. Development of computational models for the prediction of the toxicity of nanomaterials. Perspectives in Science, 3(14):2729. Saleh, N. A. 2015. The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors. Spectrochim Acta Part A Mol Biomol Spectrosc, 136(Part):15231529. Sharma, V. K. 2009. Aggregation and toxicity of titanium dioxide nanoparticles in aquatic environmentA review. J Environ Sci Health, Part A, 44(14):14851495 556. Shaw, S. Y. 2008. Perturbational profiling of nanomaterial biologic activity. Proc Natl Acad Sci, 105 (21):73877392. Singh, K. P. and S. Gupta . 2014. Nano-QSAR modeling for predicting biological activity of diverse nanomaterials. RSC Advances, 4(26):1321513230. Sizochenko, N. 2014. From basic physics to mechanisms of toxicity: The liquid drop approach applied to develop predictive classification models for toxicity of metal oxide nanoparticles. Nanoscale, 6(22):1398613993. Sizochenko, N. 2015a. Causal inference methods to assist in mechanistic interpretation of classification nano-SAR models. RSC Advances, 5(95):7773977745. Sizochenko, N. 2015b. How the liquid Drop approach could be efficiently applied for quantitative structure-property relationship modeling of nanofluids. J Phys Chem C, 119(45):2554225547. Sizochenko, N. 2016. Optimal Selection of Descriptors for Structure-Activity Modeling of Nanoparticles Based on Causality Analysis. University of Gdansk, Gdansk. Sizochenko, N. 2016. Causation or only correlation? Application of causal inference graphs for evaluating causality in nano-QSAR models. Nanoscale, 8(13):72037208. Sizochenko, N. and Leszczynski, J. 2016. Review of current and emerging approaches for quantitative nanostructure-activity relationship modelingthe case of inorganic nanoparticles. Journal of Nanotoxicology and Nanomedicine, 1(1):116. Stone, V. 2016. Approaches to develop alternative testing strategies to inform human health risk assessment of nanomaterials. Risk Anal, 36(8):15381550. Tamm, K. 2016. Parametrization of nanoparticles: Development of full-particle nanodescriptors. Nanoscale, 8(36):1624316250. Tantra, R. 2015. Nano(Q)SAR: Challenges, pitfalls and perspectives. Nanotoxicology, 9(5):636642. Thomas, D. G. 2013. ISA-TAB-Nano: A specification for sharing nanomaterial research data in spreadsheet-based format. BMC Biotechnol, 13(1):115. Toropov, A. A. 2010. SMILES-based optimal descriptors: QSAR analysis of fullerene-based HIV-1 PR inhibitors by means of balance of correlations. J Comput Chem, 31(2):381392. Toropov, A. A. 2012. Novel application of the CORAL software to model cytotoxicity of metal oxide nanoparticles to bacteria Escherichia coli. Chemosphere, 89(9):10981102. Toropov, A. A. 2013. QSAR as a random event: Modeling of nanoparticles uptake in PaCa2 cancer cells. Chemosphere, 92(1):3137. Toropova, A. P. 2015a. Optimal descriptor as a translator of eclectic data into prediction of cytotoxicity for metal oxide nanoparticles under different conditions. Ecotoxicol Environ Saf, 112:3945. Toropova, A. P. 2015b. Optimal nano-descriptors as translators of eclectic data into prediction of the cell membrane damage by means of nano metal-oxides. Environmental Science and Pollution Research, 22(1):745757.

Turabekova, M. 2014. Immunotoxicity of nanoparticles: a computational study suggests that CNTs and C60 fullerenes might be recognized as pathogens by Toll-like receptors. Nanoscale, 6(7):34883495. U.S. Environmental Protection Agency : 2003. EPA's Report on the Environment. Valerio Jr., L. G. 2009. In silico toxicology for the pharmaceutical sciences. Toxicol Appl Pharmacol, 241(3):356370. Walkey, C. D. 2014. Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. ACS Nano, 8(3):24392455 557. Wang, X. Z. 2014. Principal component and causal analysis of structural and acute in vitro toxicity data for nanoparticles. Nanotoxicology, 8(5):465476. Winkler, D. A. 2014. Modelling and predicting the biological effects of nanomaterials. SAR QSAR Environ Res, 25(2):161172. Wu, W. 2015. Quantitative Structure-Property Relationship (QSPR) modeling of drug-loaded polymeric micelles via genetic function approximation. PLoS ONE, 10(3):e0119575. Yilmaz, H. 2015. Amino substituted nitrogen heterocycle ureas as kinase insert domain containing receptor (KDR) inhibitors: Performance of structure-activity relationship approaches. J Food Drug Anal, 23(2):168175. Zhang, H. 2012. Use of metal oxide nanoparticle band gap to develop a predictive paradigm for oxidative stress and acute pulmonary inflammation. ACS Nano, 6(5):43494368.

Sensors Used to Evaluate Nanotoxicity Absil, E. , G. Tessier , D. Fournier , M. Gross , and M. Atlan . 2008. Full field imaging and spectroscopy of individual gold nanoparticles. Eur Phys J Appl Phys 43(2):155158. EDP Sciences. doi: 10.1051/epjap:2008136 Adler, D. C. , S.-W. Huang , R. Huber , and J. G. Fujimoto . 2008. Photothermal detection of gold nanoparticles using phase-sensitive optical coherence tomography. Opt Express 16(7):4376. Optical Society of America. doi: 10.1364/OE.16.004376 Akimov, V. , E. Alfinito , J. Bausells 2008. Nanobiosensors based on individual olfactory receptors. Analog Integr Circuits Signal Process 57(3):197203. Kluwer Academic Publishers. doi: 10.1007/s10470-007-9114-0 An, F. , Qu, Y. , Liu, X. , Zhong, R. , and Luo, Y. 2015. Organ-on-a-chip: New platform for biological analysis. Anal. Chem. Insights 10:3945. Andreescu, S. , J. Njagi , C. Ispas , and M. T. Ravalli . 2009. JEM spotlight: Applications of advanced nanomaterials for environmental monitoring. J Environ Monit: JEM 11(1):2740. doi: 10.1039/b811063h Andreescu, S. , O. A. Sadik , and D. W. McGee . 2004. Effect of natural and synthetic estrogens cytotoxic, on A549 lung cancer cells: Correlation of chemical structures with effects. Anal Chem 76:23212330. Aoki, K. , N. Komatsu , E. Hirata , Y. Kamioka , and M. Matsuda . 2012. Stable expression of FRET biosensors: A new light in cancer research. Cancer Sci 103(4):614619. doi: 10.1111/j.1349-7006.2011.02196.x Asharani, P. V. , Y. L. Wu , Z. Gong , and S. Valiyaveettil . 2008. Toxicity of silver nanoparticles in zebrafish models. Nanotechnology 19(25):255102. doi: 10.1088/0957-4484/19/25/255102 Badihi-Mossberg, M. , V. Buchner , and J. Rishpon . 2007. Electrochemical biosensors for pollutants in the environment. Electroanalysis 19(1920):20152028. WILEY-VCH Verlag. doi: 10.1002/elan.200703946 Barry, R. C. , Y. Lin , J. Wang , G. Liu , and C. A. Timchalk . 2009. Nanotechnology-based electrochemical sensors for biomonitoring chemical exposures. J Expo Sci Environ Epidemiol 19(1):118. Nature Publishing Group. doi: 10.1038/jes.2008.71 Bayley, H. and P. S. Cremer . 2001. Stochastic sensors inspired by biology. Nature 413(6852):226230. doi: 10.1038/35093038 Benn, T. M. and P. Westerhoff . 2008. Nanoparticle silver released into water from commercially available sock fabrics. Environ Sci Technol 42(18):70257026. American Chemical Society. doi: 10.1021/es801501j Bernaus, A. , X. Gaona , A. Ivask , A. Kahru , and M. Valiente . 2005. Analysis of sorption and bioavailability of different species of mercury on model soil components using XAS techniques and sensor bacteria. Anal Bioanal Chem 382(7):15411548. Springer-Verlag. doi: 10.1007/s00216-005-3338-6 Bhatia, S. N. and D. I. Ingber . 2014. Microfluidic organs-on-chips. Nat Biotechnol 32:760772.

Biran, I. , D. M. Rissin , E. Z. Ron , and D. R. Walt . 2003. Optical imaging fiber based live bacterial cell array biosensor. Anal Chem 315(1):106113. Blanc-Bguin, F. , S. Nabily , J. Gieraltowski , A. Turzo , S. Querellou , and P. Y. Salaun . 2009. Cytotoxicity and GMI bio-sensor detection of maghemite nanoparticles internalized into cells. J Magn Magn Mater 321(3):192197. doi: 10.1016/j.jmmm.2008.08.104 584 Chatterjee, A. , M. Santra , N. Won , S. Kim , J. K. Kim , S. B. Kim , and K. H. Ahn . 2009. Selective fluorogenic and chromogenic probe for detection of silver ions and silver nanoparticles in aqueous media. J Am Chem Soc 131(6):20402041. Chaudhuri, B. , F. Hormann , and W. B. Frommer . 2011. Dynamic imaging of glucose flux impedance using fret sensors in wild-type arabidopsis plants. J Exp Bot 62(7):24112417. doi: 10.1093/jxb/erq444 Chen, C. , G. Xing , J. Wang 2005. Multihydroxylated [Gd@C82(OH)22]n nanoparticles: Antineoplastic activity of high efficiency and low toxicity. Nano Letters 5(10):20502057. doi:10.1021/nl051624b. Chen, G. , F. Song , X. Xiong , and Xiaojun Peng . 2013. Fluorescent nanosensors based on fluorescence resonance energy transfer (FRET). Ind Eng Chem Res 52(33):1122811245. American Chemical Society. doi: 10.1021/ie303485n Chen, Z. , H. Meng , G. Xing 2006. Acute toxicological effects of copper nanoparticles in vivo . Toxicol Lett 163(2):109120. doi: 10.1016/j.toxlet.2005.10.003 Corbisier, P. , E. Thiry , and L. Diels . 1996. Bacterial biosensors for the toxicity assessment of solid wastes. Environmental Toxicology and Water Quality 11(3):171177. Wiley Subscription Services, Inc., A Wiley Company. doi: 10.1002/(SICI)1098-2256(1996)11:33.0.CO;2-6. Cornell, B. A. , V. L. B. Braach-Maksvytis , L. G. King , P. D. J. Osman , B. Raguse , L. Wieczorek , and R. J. Pace . 1997. A biosensor that uses ion-channel switches. Nature 387(6633):580583. doi: 10.1038/42432 Dequaire, M. , C. Degrand , and B. Limoges . 2000. An electrochemical metalloimmunoassay based on a colloidal gold label. Anal Chem 72(22):55215528. Dockery, D. W. , C. A. Pope , X. Xu , J. D. Spengler , J. H. Ware , B. G. Fay , F. F. Ferris , and F. E. Speizer . 1993. An association between air pollution and mortality in six U.S. cities. N Engl J Med 329:17531759. Donaldson, K. , L. Tran , L. A. Jimenes , R. Duffin , D. E. Newby , N. Mills , W. MacNee , and V. Stone . 2005. Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure. Particle and Fibre Toxicology 2:1012. Durr, N. J. , T. Larson , D. K. Smith , B. A. Korgel , K. Sokolov , and A. Ben-Yakar . 2007. Twophoton luminescence imaging of cancer cells using molecularly targeted gold nanorods. Nano Lett 7:941945. Gani, A. A. , M. R. Ashari , and B. Kuswandi . 2010. An optical fiber biosensor for heavy metal ions based on a modified single sol-gel film of urease and chlorophenol red in flow system. Sens Lett 8(2):320327. doi: 10.1166/sl.2010.1272 Heinlaan, M. , A. Ivask , I. Blinova , H.-C. Dubourguier , and A. Kahru . 2008. Toxicity of nanosized and bulk ZnO, CuO and TiO2 to bacteria vibrio fischeri and crustaceans daphnia magna and thamnocephalus platyurus. Chemosphere 71(7):13081316. doi: 10.1016/j.chemosphere.2007.11.047 Hicks, E. M. , O. Lyandres , W. P. Hall , S. Zou , M. R. Glucksberg , and R. P. Van Duyne . 2007. Plasmonic properties of anchored nanoparticles fabricated by reactive ion etching and nanosphere lithography. J Phys Chem 111:41164124. Howe, P. D. , S. Dobson , World Health Organization, and International Programme on Chemical Safety . 2002. Silver and Silver Compounds: Environmental Aspects. Geneva: World Health Organization. Huang, D. , E. A. Swanson , C. P. Lin , J. S. Schuman , W. G. Stinson , W. Chang , M. R. Hee , T. Flotte , K. Gregory , and C. A. Puliafito . 1991. Optical coherence tomography. Sci (New York, N.Y.) 254(5035):11781181.585 Huang, G. S. , M.-T. Wang , M.-Y. Hong 2006. A versatile QCM matrix system for online and high-throughput bio-sensing. Analyst 131(3):382. The Royal Society of Chemistry. doi: 10.1039/b515722f Huang, Y.-W. , C.-H. Wu , and R. S. Aronstam . 2010. Toxicity of transition metal oxide nanoparticles: Recent insights from in vitro studies. Materials 3(10):48424859. doi: 10.3390/ma3104842 Huh, D. , D. C. Leslie , B. D. Matthews , J. P. Fraser , S. Jurek , G. A. Hamilton , K. S. Thorneloe , M. A. McAlexander , and D. E. Ingber . 2012. A human disease model of drug toxicityinduced pulmonary edema in a lung-on-a-chip microdevice. Sci Translational Med 4(159):18. doi: 10.1126/scitranslmed.3004249.

Ivask, A. , K. Hakkila , and M. Virta . 2001. Detection of organomercurials with sensor bacteria. Anal Chem 73(21):51685171. doi: 10.1021/AC010550V Ivask, A. , T. Rlova , A. Kahru 2009. A suite of recombinant luminescent bacterial strains for the quantification of bioavailable heavy metals and toxicity testing. BMC Biotechnol 9(1):41. BioMed Central. doi: 10.1186/1472-6750-9-41 Ivask, A. , M. Virta , and A. Kahru . 2002. Construction and use of specific luminescent recombinant bacterial sensors for the assessment of bioavailable fraction of cadmium, zinc, mercury and chromium in the soil. Soil Biol Biochem 34(10):14391447. doi: 10.1016/S00380717(02)00088-3 Jansson, J. K. 2003. Marker and reporter genes: Illuminating tools for environmental microbiologists. Curr Opin Microbiol 6(3):310316. Kada, G. , F. Kienberger , and P. Hinterdorfer . 2008. Atomic force microscopy in bionanotechnology. Nano Today 3(1):1219. Kahru, A. , H. C. Dubourguier , I. Blinova , A. Ivask , and K. Kasemets . 2008. Biotests and biosensors for ecotoxicology of metal oxide nanoparticles: A minireview. Sensors 8(8):51535170. doi: 10.3390/s8085153 Kahru, A. , A. Ivask , K. Kasemets , L. Pllumaa , I. Kurvet , M. Franois , and H.-C. Dubourguier . 2005. Biotests and biosensors in ecotoxicological risk assessment of field soils polluted with zinc, lead, and cadmium. Environ Toxicol Chem 24(11):29732982. Kane, A. B. and R. H. Hurt . 2008. Nanotoxicology: The asbestos analogy revisited. Nat Nanotechnol 3(1):378379. Karasinski, J. , S. Andreescu , O. A. Sadik , B. Lavine , and M. N. Vora . 2005. Multiarray sensors with pattern recognition for the detection, classification, and differentiation of bacteria at subspecies and strain levels. Anal Chem 77(2):79417949. Karasinski, J. , L. White , Y. Zhang , E. Wang , S. Andreescu , O. A. Sadik , B. K. Lavine , and M. Vora . 2007. Detection and identification of bacteria using antibiotic susceptibility and a multi-array electrochemical sensor with pattern recognition. Biosens Bioelectron 22(3):26432649. Karen, T. , B. Alistair , T. Steven , L. John , D. Helen , and H. Martin . 2008. Detection and characterization of engineered nanoparticles in food and the environment. Food Additives & Contaminants Part A 25(7):795821. Kassies, R. , K. O. van der Werf , A. Lenferink , C. N. Hunter , J. D. Olsen , V. Subramaniam , and C. Otto . 2005. Combined AFM and confocal fluorescence microscope for applications in bio-nanotechnology. J Microsc 217(1):109116. doi: 10.1111/j.0022-2720.2005.01428.x 586 Kato, H. , M. Suzuki , K. Fujita , M. Horie , S. Endoh , Y. Yoshida , H. Iwahashi , K. Takahashi , A. Nakamura , and S. Kinugasa . 2009. Reliable size determination of nanoparticles using dynamic light scattering method for in vitro toxicology assessment. Toxicol In Vitro 23(5):927934. doi: 10.1016/j.tiv.2009.04.006 Kirschner, A. N. , B. F. Erlanger , and S. R. Wilson . 2015. A Biosensor for Fullerenes and Carbon Nanotubes. Kolanjiyil, A. V. and C. Kleinstreuer . 2013. Mass transfer from lung airways to systemic regionsPart I: Whole-lung aerosol dynamics. J. Biomech Eng 132(12):121003(1-11) Kreibig, U. and M. Vollmer . 1995. Optical Properties of Metal Clusters. Berlin, Heidelberg: Springer. Kreyling, W. G. , J. D. Blanchard , J. J. Godleski 1999. Anatomic localization of 24- and 96-H particle retention in canine airways. J Appl Physiol 87:269284. Kroll, A. , M. H. Pillukat , D. Hahn , and J. Schnekenburger . 2009. Current in vitro methods in nanoparticle risk assessment: Limitations and challenges. Eur J Pharm Biopharm 72(2):370377. doi: 10.1016/j.ejpb.2008.08.009 Ku, B. K. and A. D. Maynard . 2005. Comparing aerosol surface-area measurements of monodisperse ultrafine silver agglomerates by mobility analysis, transmission electron microscopy and diffusion charging. J Aerosol Sci 36(9):11081124. doi: 10.1016/j.jaerosci.2004.12.003 Kuang, Y. , I. Biran , and D. R. Walt . 2004. Living bacterial cell array for genotoxin monitoring. Anal Chem 76(1):29022909. Kuswandi, B. 2003. Simple optical fibre biosensor based on immobilised enzyme for monitoring of trace heavy metal ions. Anal Bioanal Chem 376(7):11041110. doi: 10.1007/s00216-0032001-3 Kuswandi, B. 2016. Nanotechnology in food packaging. In: Nanoscience in Food and Agriculture 1 (1st Ed.), eds. Ranjan, S. , Nandita, D. and Lichtfouse, E. Springer International Publishing, Switzerland, p. 151. Kuswandi, B. , R. Andres , and R. Narayanaswamy . 2001. Optical fibre biosensors based on immobilised enzymes. Analyst 126(8):14691491. doi: 10.1039/b008311i

Kuswandi, B. and M. Mascini . 2005. Enzyme inhibition based biosensors for environmental monitoring. Current Enzyme Inhibition 1(1):1117. Kuswandi, B. , Nuriman , J. Huskens , and W. Verboom . 2007. Optical sensing systems for microfluidic devices: A review. Anal Chim Acta 601(2):141155. doi: 10.1016/j.aca.2007.08.046 Kuswandi, B. and F. Sevilla III . 2008. Electrochemical DNA biosensor for detection of aqueous toxicants. Sensors and Transducers 95:97107. Kuswandi, B. , M. N. Taib , and R. Narayanaswamy . 1999. New solid state instrument for optical toxic metal ions sensing. Sens Actuators A, Phys 76(13):183190. doi: 10.1016/S09244247(99)00009-6 Kuswandi, B. , S. Tombelli , G. Marazza , and M. Mascini . 2005. Recent advances in optical DNA biosensors technology. Chimia 59(5):236242. Khler, S. , S. Belkin , and R. D. Schmid . n.d. Reporter gene bioassays in environmental analysis. Fresenius J Anal Chem 366(67):769779. Lambrianou, A. , S. Demin , and E. A. H. Hall . 2008. Protein engineering and electrochemical biosensors. Adv Biochem Engin/Biotechnol 109: 6596. doi: 10.1007/10_2007_080 Lee, K. S. and M. A. El-Sayed . 2006. Gold and silver nanoparticles in sensing and imaging: Sensitivity of plasmon response to size, shape, and metal composition. J Phys Chem B 110:1922019225.587 Lee, S. , J. S. Choi , and S. H. Kang . 2007. Combination of DIC with prism-type total internal fluorescence microscope for direct observation of PAMAM dendrimer nanoparticle as a gene delivery in living human cells. J Nanosci Nanotechnol 7:36893694. Lewis, J. C. , A. Feltus , C. M. Ensor , S. Ramanathan , and S. Daunert . 1998. Applications of reporter genes. Anal Chem 70(17):579A585A. Lindfors, K. , T. Kalkbrenner , P. Stoller , and V. Sandoghdar . 2004. Detection and spectroscopy of gold nanoparticles using supercontinuum white light confocal microscopy. Phys Rev Lett 93(3):37401. American Physical Society. doi: 10.1103/PhysRevLett.93.037401 Liu, Y. , Y.-W. Yang , Y. Chen 2005. Thio[2-(Benzoylamino)ethylamino]--CD fragment modified gold nanoparticles as recycling extractors for [60]fullerene. Chem Commun 253(33):4208. The Royal Society of Chemistry. doi: 10.1039/b507650a Looger, L. L. , M. A. Dwyer , J. J. Smith , and H. W. Hellinga . 2003. Computational design of receptor and sensor proteins with novel functions. Nature 423(6936):185190. Nature Publishing Group. doi: 10.1038/nature01556 Lu, S. and Y. Wang . 2010. Fluorescence resonance energy transfer biosensors for cancer detection and evaluation of drug efficacy. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 16(15):38223824. NIH Public Access. doi: 10.1158/1078-0432.CCR-10-1333 Luo, X. , A. Morrin , A. J. Killard , and M. R. Smyth . 2006. Application of nanoparticles in electrochemical sensors and biosensors. Electroanalysis 18(4):319326. WILEY-VCH Verlag. doi: 10.1002/elan.200503415 Malcik, N. , O. Oktar , M. E. Ozser , P. Caglar , L. Bushby , A. Vaughan , B. Kuswandi , and R. Narayanaswamy . 1998. Immobilised reagents for optical heavy metal ions sensing. Sens Actuators B, Chem 53(3):211221. doi: 10.1016/S0925-4005(99)00004-0 Marquis, B. J. , S. A. Love , K. L. Braun , and C. L. Haynes . 2009a. Analytical methods to assess nanoparticle toxicity. Analyst 134(3):425439. Marquis, B. J. , S. A. Love , K. L. Braun , and C. L. Haynes . 2009b. No title. Analyst 134:425439. Marquis, B. J. , A. D. McFarland , K. L. Braun , and C. L. Haynes . 2008. Dynamic measurement of altered chemical messenger secretion after cellular uptake of nanoparticles using carbon-fiber microelectrode amperometry. Anal Chem 80(9):34313437. doi: 10.1021/AC800006Y Meng, J. , D.-L. Wang , P. C. Wang , L. Jia , C. Chen , and X.-J. Liang . 2010. Biomedical activities of endohedral metallofullerene optimized for nanopharmaceutics. J Nanosci Nanotechnol 10(12):86108616. NIH Public Access. Miyawaki, A. and S. Karasawa . 2007. Memorizing spatiotemporal patterns. Nat Chem Biol 3(10):598601. Nature Publishing Group. doi: 10.1038/nchembio1007-598 Moller, W. , W. Barth , M. Kohlhaufl , K. Haussinger , W. Stahlhofen , and J. Hey-der . 2001. Human alveolar long-term clearance of ferromagnetic iron oxide microparticles in healthy and diseased subjects. Exp Lung Res 27(1):547568. Mueller, N. C. and B. Nowack . 2008. Exposure modeling of engineered nanoparticles in the environment. Environ Sci Technol 42(12):44474453. American Chemical Society. doi: 10.1021/es7029637 Murphy, C. J. , A. M. Gole , S. E. Hunyadi , J. W. Stone , P. N. Sisco , A. Alkilany , B. E. Kinard , and P. Hankins . 2008. Chemical sensing and imaging with metallic nanorods. Chem Commun (Cambridge, England) 5(February):544557. doi: 10.1039/b711069c 588

Murthy, C. N. , K. E. Geckeler , T. Andersson 2001. The water-soluble -cyclodextrin[60]fullerene complex. Chem Commun 98(13):11941195. The Royal Society of Chemistry. doi: 10.1039/b102142g Musameh, M. , J. Wang , A. Merkoci , and Y. Lin . 2002. Low-potential stable NADH detection at carbon-nanotube-modified glassy carbon electrodes. Electrochem Commun 4:722726. doi: 10.1016/S1388-2481(02)00451-4 Nel, A. , T. Xia , L. Mdler , and N. Li . 2006. Toxic potential of materials at the nanolevel. Science 311(5761):622627. doi: 10.1126/science.1114397 Nel, A. , T. Xia , H. Meng , X. Wang , S. Lin , Z. Ji , and H. Zhang . 2013. Nanomaterial toxicity testing in the twenty-first century: Use of a predictive toxicological approach and highthroughput screening. Acc Chem Res 46(3):607621. doi: 10.1021/ar300022h Ngamwongsatit, P. , P. P. Banada , W. Panbangred , and A. K. Bhunia . 2008. WST-1-based cell cytotoxicity assay as a substitute for MTT-based assay for rapid detection of toxigenic bacillus species using CHO cell line. J Microbiol Methods 73(3):211215. doi: 10.1016/j.mimet.2008.03.002 Oberdorster, G. , J. Ferin , and B. E. Lehnert . 1994. Correlation between Parti- Cle size, in vivo particle persistence, and lung injury. Environ Health Perspect 102(Suppl 5):173179. Oberdorster, G. , A. Maynard , K. Donaldson 2005a. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Particle and Fibre Toxicology 2(1):813. Oberdorster, G. , E. Oberdorster , and J. Oberdorster . 2005b. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823839. Okumoto, S. , A. Jones , and W. B. Frommer . 2012. Quantitative imaging with fluorescent biosensors. Annu Rev Plant Biol 63(1):663706. doi: 10.1146/annurev-arplant-042110-103745 Omole, M. A. , I. O. K'Owino , and O. A. Sadik . 2007. Palladium nanoparticles for catalytic reduction of Cr(VI) using formic acid. Applied Catalysis B: Environmental 76(1):158167. doi: 10.1016/j.apcatb.2007.05.018 Oomen, A. G. , E. A. J. Bleeker , P. M. J. Bos 2015. Grouping and read-across approaches for risk assessment of nanomaterials. Int J Environ Res Public Health 12(10):1341513434. Palchetti, I. and M. Mascini . 2008. Electroanalytical biosensors and their potential for food pathogen and toxin detection. Anal Bioanal Chem 391(2):455471. Springer-Verlag. doi: 10.1007/s00216-008-1876-4 Pandey, P. , M. Datta , and B. D. Malhotra . 2008. Prospects of nanomaterials in biosensors. Anal Lett 41(2):159209. Papazisis, K. T. , G. D. Geromichalos , K. A. Dimitriadis , and A. H. Kortsaris . 1997. Optimization of the sulforhodamine B colorimetric assay. J Immunol Methods 208(2):151158. Peng, C. , Z. Li , Y. Zhu 2009. Simultaneous and sensitive determination of multiplex chemical residues based on multicolor quantum dot probes. Biosens Bioelectron 24:36573662. Pic, E. , L. Bezdetnaya , F. Guillemin , and F. Marchal . 2009. Quantification techniques and biodistribution of semiconductor quantum dots. Anticancer Agents Med Chem 9(1):295303.589 Pingarrn, J. M. , P. Yez-Sedeo , and A. Gonzlez-Corts . 2008. Gold nanoparticle-based electrochemical biosensors. Electrochim Acta 53(19):58485866. doi: 10.1016/j.electacta.2008.03.005 Prieto-Simn, B. , M. Cortina , M. Camps , and C. Calas-Blanchard . 2008. Electrochemical biosensors as a tool for antioxidant capacity assessment. Sens Actuators B, Chem 129(1):459466. doi: 10.1016/j.snb.2007.08.004 Pumera, M. , S. Snchez , I. Ichinose , and J. Tang . 2007. Electrochemical nanobiosensors. Sens Actuators B, Chem 123(2):11951205. doi: 10.1016/j.snb.2006.11.016 Ranjan, S. , D. Nandita , and E. Lichtfouse . 2016. Nanoscience in Food and Agriculture 1 (1st Ed.). Switzerland: Springer International Publishing. doi: 10.1007/978-3-319-39303-2 Roa, W. , X. Yang , L. Guo , B. Huang , S. Khatibisepehr , S. Gabos , J. Chen , and J. Xing . 2011. Real-time cell-impedance sensing assay as an alternative to clonogenic assay in evaluating cancer radiotherapy. Anal Bioanal Chem 400(7):20032011. doi: 10.1007/s00216011-4934-2 Rogers, K. R. 2006. Recent advances in biosensor techniques for environmental monitoring. Anal Chim Acta 568(2):222231. Ruge, C. A. , U. F. Schaefer , J. Herrmann 2012. The interplay of lung surfactant proteins and lipids assimilates the macrophage clearance of nanoparticles. Edited by Tarl Wayne Prow . PLoS ONE 7(7):e40775. Public Library of Science. doi: 10.1371/journal.pone.0040775 Sadik, O. A. , A. L. Zhou , S. Kikandi , N. Du , Q. Wang , and K. Varner . 2009. Sensors as tools for quantitation, nanotoxicity and nanomonitoring assessment of engineered nanomaterials. J Environ Monit: JEM 11(10):17821800. doi: 10.1039/b912860c Sahin, O. 2008. Probe microscopy: Scanning below the cell surface. Nat Nanotechnol 3(8):461462. doi: 10.1038/nnano.2008.222

Sarnat, J. A. , P. Demokritou , and P. Koutrakis . 2003. Measurement of fine, coarse and ultrafine particles. Ann Ist Super Sanita 39(3):351355. Sayes, C. M. , A. M. Gobin , K. D. Ausman , J. Mendez , J. L. West , and V. L. Colvin . 2005. Nano-C60 cytotoxicity is due to lipid peroxidation. Biomaterials 26(36):75877595. doi: 10.1016/j.biomaterials.2005.05.027 Shelley, M. , A. Wagner , S. Hussain , and C. Bleckmann . 2008. Modeling the in vivo case with in vitro nanotoxicity data. Int J Toxicol 27(5):359367. doi: 10.1080/10915810802503487 Shrivastava, S. , T. Bera , A. Roy 2007. Characterization of enhanced antibacterial effects of novel silver nanoparticles. Nanotechnology 18(22):225103. IOP Publishing. doi: 10.1088/09574484/18/22/225103 Sin, A. , K. C. Chin , M. F. Jamil , Y. Kostov , G. Rao , and M. L. Shuler . 2008. The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog 20(1):338345. doi: 10.1021/bp034077d Solly, K. , X. Wang , X. Xu , B. Strulovici , and W. Zheng . 2004. Application of real-time cell electronic sensing (RT-CES) technology to cell-based assays. Assay Drug Dev Technol 2(4):363372. doi: 10.1089/adt.2004.2.363 Suzuki, K. , Y. Naruse , H. Funaki , K. Itaya , and S. Uchikoga . n.d. Nanoparticle manipulator by a novel designed MEMS based reactor for physical antibiotics. In: IEEE InternationalElectron Devices Meeting, 2005. IEDM Technical Digest. IEEE International, Washington, DC, pp. 485487. doi: 10.1109/IEDM.2005.1609386 590 Tauriainen, S. , M. Karp , W. Chang , and M. Virta . 1998. Luminescent bacterial sensor for cadmium and lead. Biosens Bioelectron 13(9):931938. Tibazarwa, C. , P. Corbisier , M. Mench , A. Bossus , P. Solda , M. Mergeay , L. Wyns , and D. van der Lelie . 2001. A microbial biosensor to predict bioavailable nickel in soil and its transfer to plants. Environ Pollut (Barking, Essex: 1987) 113(1):1926. Tyner, K. M. , A. M. Wokovich , W. H. Doub , L. F. Buhse , L.-P. Sung , S. S. Watson , and N. Sadrieh . 2009. Comparing methods for detecting and characterizing metal oxide nanoparticles in unmodified commercial sunscreens. Nanomedicine 4(2):145159. Future Medicine Ltd London, UK. doi: 10.2217/17435889.4.2.145 Urban, G. A. 2009. Micro- and nanobiosensors-state of the art and trends. Meas Sci Technol 20(1):12001. Velasco-Garcia, M. N. 2009. Optical biosensors for probing at the cellular level: A review of recent progress and future prospects. Semin Cell Dev Biol 20(1):2733. doi: 10.1016/j.semcdb.2009.01.013 Wagner, A. J. , C. A. Bleckmann , R. C. Murdock , A. M. Schrand , J. J. Schlager , and S. M. Hussain . 2007. Cellular interaction of different forms of aluminum nanoparticles in rat alveolar macrophages. J Phys Chem B 111(25):73537359. doi: 10.1021/jp068938n Walt, D. R. 2006. Fiber optic array biosensors. BioTechniques 41(5):529535. doi: 10.2144/000112303 Wang, C. and C. Yu . 2013. Detection of chemical pollutants in water using gold nanoparticles as sensors: A review. Rev Anal Chem 32(1):114. doi: 10.1515/revac-2012-0023 Wang, H. F. , J. Wang , X. Y. Deng , H. F. Sun , Z. J. Shi , Z. N. Gu , Y. F. Zhao , L. Liu , and Y. L. Zhao . 2004. Biodistribution of carbon single-wall carbon nanotubes in mice. J Nanosci Nanotechnol 4(1):10191024. Wang, J. 2005a. Nanomaterial-based electrochemical biosensors. Analyst 130(4):421426. Wang, J. 2005b. Nanomaterial-based amplified transduction of biomolecular interactions. Small 1(11):10361043. doi: 10.1002/smll.200500214 Wang, Q. and C. Yu . 2012. Chemical and biological sensing and imaging using plasmonic nanoparticles and nanostructures. In: Biomedical Nanosensors, J. M. Irudayaraj (Ed.). Boca Raton: Taylor and Francis, CRC Press, pp. 5996. Wang, Y. 1995. Voltage-induced color-selective absorption with surface plasmon. Phys Lett 67(19):27592761. Wikswo, J. P. , E. L. Curtis , Z. E. Eagleton 2013. Scaling and systems biology for integrating multiple organs-on-a-chip. Lab Chip 13(18):3496. The Royal Society of Chemistry. doi: 10.1039/c3lc50243k Wrobel, N. , W. Deininger , P. Hegemann , and V. M. Mirsky . 2003. Covalent immobilization of oligonucleotides on electrodes. Colloids Surf B, Biointerfaces 32(2):157162. doi: 10.1016/S0927-7765(03)00155-3 Xiao, Y. and C. M. Li . 2008. Nanocomposites: From fabrications to electrochemical bioapplications. Electroanalysis 20(6):648662. Wiley-Vch Verlag. doi: 10.1002/elan.200704125 Xu, H. , J. W. Aylott , R. Kopelman , T. J. Miller , and M. A. Philbert . 2001. A real-time ratiometric method for the determination of molecular oxygen inside living cells using sol-gelbased spherical optical nanosensors with applications to rat C6 glioma. Anal Chem 73(17):41244133.591

Yamanaka, M. , K. Hara , and J. Kudo . 2005. Bactericidal actions of a silver ion solution on escherichia coli, studied by energy-filtering transmission electron microscopy and proteomic analysis. Appl Environ Microbiol 71(11):75897593. American Society for Microbiology (ASM). doi: 10.1128/AEM.71.11.7589-7593.2005 Yin, P. , C. J. Burns , P. D. J. Osman , and B. A. Cornell . 2003. A tethered bilayer sensor containing alamethicin channels and its detection of amiloride based inhibitors. Biosens Bioelectron 18(4):389397. Yogeswaran, U. and S.-M. Chen . 2008. A review on the electrochemical sensors and biosensors composed of nanowires as sensing material. Sensors 8(1):290313. Molecular Diversity Preservation International. doi: 10.3390/s8010290 Yu, Z. T. F. , K.-I. Kamei , H. Takahashi 2009. Integrated microfluidic devices for combinatorial cell-based assays. Biomed Microdevices 11(3):547555. NIH Public Access. doi: 10.1007/s10544-008-9260-x Zhou, H. , Q. Mu , N. Gao 2008. A nano-combinatorial library strategy for the discovery of nanotubes with reduced protein-binding, cytotoxicity, and immune response. Nano Lett 8(3):859865. American Chemical Society. doi: 10.1021/nl0730155

Nanosensors: The Future of Efficient Sensing Technologies in Nanomedicine Abuzairi, T. , M. Okada , Y. Mochizuki , N. R. Poespawati , R. W. Purnamaningsih , and M. Nagatsu . 2015. Maskless functionalization of a carbon nanotube dot array biosensor using an ultrafine atmospheric pressure plasma jet. Carbon 89:208216. Bandodkar, A. J. and J. Wang . 2014. Non-invasive wearable electrochemical sensors: A review. Trends Biotechnol 32(7):363371. Barone, P. W. , R. S. Parker , and M. S. Strano . 2005. In Vivo fluorescence detection of glucose using a single-walled carbon nanotube optical sensor: Design, fluorophore properties, advantages, and disadvantages. Anal Chem 77(23):75567562. Benincasa, M. , S. Pacor , W. Wu , M. Prato , A. Bianco , and R. Gennaro . 2010. Antifungal activity of amphotericin B conjugated to carbon nanotubes. ACS Nano 5(1):199208.609 Cai, L. , L. Song , P. Luan 2013. Super-stretchable, transparent carbon nanotube-based capacitive strain sensors for human motion detection. Sci Rep 3:3048. Chang, Y.-T. , J.-H. Huang , M.-C. Tu , P. Chang , and T.-R. Yew . 2013. Flexible direct-growth biosensors. Biosens Bioelectron 41:898902. Cheng, L. , Y. Li , X. Zhai , B. Xu , Z. Cao , and W. Liu . 2014. Polycation-b-polyzwitterion copolymer grafted luminescent carbon dots as a multifunctional platform for serum-resistant gene delivery and bioimaging. ACS Appl Mater Interfaces 6(22):2048720497. Choi, Y. , S. Kim , M.-H., Choi , S.-R. Ryoo , J. Park , D.-H. Min , B.-S. Kim . 2014. Highly Biocompatible carbon nanodots for simultaneous bioimaging and targeted photodynamic therapy in vitro and in vivo. Adv Funct Mater 24(37):57815789. Fowley, C. , N. Nomikou , A. P. McHale , B. McCaughan , and J. F. Callan . 2013. Extending the tissue penetration capability of conventional photosensitisers: A carbon quantum dotProtoporphyrin IX conjugate for use in two-photon excited photodynamic therapy. Chem Commun 49(79):89348936. Gao, W. , S. Emaminejad , H. Y. Y. Nyein 2016. Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis. Nature 529(7587):509514. Giraldo, J. P. , M. P. Landry , S.-Y. Kwak 2015. A ratiometric sensor using single chirality nearinfrared fluorescent carbon nanotubes: Application to in vivo monitoring. Small 11(32):39733984. Gogoi, N. and D. Chowdhury . 2014. Novel carbon dot coated alginate beads with superior stability, swelling and pH responsive drug delivery. J Mater Chem B 2(26):40894099. He, L. , T. Wang , J. An 2014. Carbon Nanodots@ Zeolitic imidazolate framework-8 nanoparticles for simultaneous pH-responsive drug delivery and fluorescence Imaging. Cryst Eng Comm 16(16):32593263. Hola, K. , Y. Zhang , Y. Wang , E. P. Giannelis , R. Zboril , and A. L. Rogach . 2014. Carbon dotsEmerging light emitters for bioimaging, cancer therapy and optoelectronics. Nano Today 9(5):590603. Hsu, P.-C. and H.-T. Chang . 2012. Synthesis of high-quality carbon nanodots from hydrophilic compounds: Role of functional groups. Chem Commun 48(33):39843986. Hsu, P.-C. , Z.-Y. Shih , C.-H. Lee , and H.-T. Chang . 2012. Synthesis and analytical applications of photoluminescent carbon nanodots. Green Chem 14(4):917920.

Huang, P. , J. Lin , X. Wang 2012. Light-triggered theranostics based on photosensitizerconjugated carbon dots for simultaneous enhanced-fluorescence imaging and photodynamic therapy. Adv Mater 24(37):51045110. Jeerapan, I. , J. R. Sempionatto , A. Pavinatto , J.-M. You , and J. Wang . 2016. Stretchable biofuel cells as wearable textile-based self-powered sensors. J Mater Chem A 4(47):1834218353. Jia, W. , A. J. Bandodkar , G. Valds-Ramrez 2013. Electrochemical tattoo biosensors for realtime noninvasive lactate monitoring in human perspiration. Anal Chem 85(14):65536560. Karthik, S. , B. Saha , S. K. Ghosh , and N. D. Pradeep Singh . 2013. Photoresponsive quinoline tethered fluorescent carbon dots for regulated anticancer drug delivery. Chem Commun 49(89):1047110473. Khosravi, F. , P. Trainor , S. N. Rai , G. Kloecker , E. Wickstrom , and B. Panchapakesan . 2016. Label-free capture of breast cancer cells spiked in buffy coats using carbon nanotube antibody micro-arrays. Nanotechnology 27(13):13LT02.610 Li, C.-L. , C.-M. Ou , C.-C. Huang 2014. Carbon dots prepared from ginger exhibiting efficient inhibition of human hepatocellular carcinoma cells. J Mater Chem B 2(28):45644571. Liu, H. , Q. Wang , G. Shen 2014. A multifunctional ribonuclease A-conjugated carbon dot cluster nanosystem for synchronous cancer imaging and therapy. Nanoscale Res Lett 9(1):1. Pandey, S. , M. Thakur , A. Mewada , D. Anjarlekar , N. Mishra , and M. Sharon . 2013. Carbon dots functionalized gold nanorod mediated delivery of doxorubicin: Tri-functional nano-worms for drug delivery, photothermal therapy and bioimaging. J Mater Chem B 1(38):49724982. Pang, C. , C. Lee , and K.-Y. Suh . 2013. Recent advances in flexible sensors for wearable and implantable devices. J Appl Polym Sci 130(3):14291441. Peng, J. , W. Gao , B. K. Gupta 2012. Graphene quantum dots derived from carbon fibers. Nano Lett 12(2):844849. Qin, Y.-P. , D.-Y. Li , X.-W. He , W.-Y. Li , and Y.-K. Zhang . 2016. Preparation of highefficiency cytochrome c-imprinted polymer on the surface of magnetic carbon nanotubes by epitope approach via metal chelation and six-membered ring. ACS Appl Mater Interfaces 8(16):1015510163. Roy, P. , A. P. Periasamy , C. Chuang , Y. R. Liou , Y. F. Chen , J. Joly , C. T. Liang , and H. T. Chang . 2014. Plant leaf-derived graphene quantum dots and applications for white LEDs. New J Chem 38(10):49464951. Roy, P. , P.-C. Chen , A. P. Periasamy , Y.-N. Chen , and H.-T. Chang . 2015a. Photoluminescent carbon nanodots: Synthesis, physicochemical properties and analytical applications. Mater Today 18(8):447458. Roy, P. , A. P. Periasamy , C.-Y. Lin 2015b. Photoluminescent graphene quantum dots for in vivo imaging of apoptotic cells. Nanoscale 7:25042510. Saetia, K. , J. M. Schnorr , M. M. Mannarino 2014. Spray-layer-by-layer carbon nanotube/electrospun fiber electrodes for flexible chemiresistive sensor applications. Adv Funct Mater 24(4):492502. Shim, B. S. , W. Chen , C. Doty , C. Xu , and N. A. Kotov . 2008. Smart electronic yarns and wearable fabrics for human biomonitoring made by carbon nanotube coating with polyelectrolytes. Nano Lett 8(12):41514157. Sudibya, H. G. , J. Ma , X. Dong 2009. Interfacing glycosylated carbon-nanotube-network devices with living cells to detect dynamic secretion of biomolecles. Angew Chem Int Ed 48(15):27232726. Tang, J. , B. Kong , H. Wu 2013. Carbon nanodots featuring efficient FRET for real-time monitoring of drug delivery and two-photon imaging. Adv Mater 25(45):65696574. Vedamalai, M. , A. P. Periasamy , C.-W. Wang 2014. Carbon nanodots prepared from OPhenylenediamine for sensing of Cu2+ ions in cells. Nanoscale 6(21):1311913125. Wang, H. , J. Shen , Y. Li 2014a. Magnetic iron oxidefluorescent carbon dots integrated nanoparticles for dual-modal imaging, near-infrared light-responsive drug carrier and photothermal therapy. Biomater Sci 2(6):915923. Wang, J. , Z. Zhang , S. Zha 2014b. Carbon nanodots featuring efficient FRET for two-photon photodynamic cancer therapy with a low fs laser power density. Biomaterials 35(34):93729381. Wang, Q. , X. Huang , Y. Long 2013. Hollow luminescent carbon dots for drug delivery. Carbon 59:192199.611 Wang, Q. , C. Zhang , G. Shen , H. Liu , H. Fu , and D. Cui . 2014c. Fluorescent carbon dots as an efficient siRNA nanocarrier for its interference therapy in gastric cancer cells. J Nanobiotechnol. 12(1):1. Yamada, T. , Y. Hayamizu , Y. Yamamoto 2011. A stretchable carbon nanotube strain sensor for human-motion detection. Nat Nanotechnol 6(5):296301. Zhang, Y. , C. Wu , X. Zhou 2013. Graphene quantum dots/gold electrode and its application in living cell H2O2 detection. Nanoscale 5(5):18161819.

Zhao, J. , G. Chen , L. Zhu , and G. Li . 2011. Graphene quantum dots-based platform for the fabrication of electrochemical biosensors. Electrochem Commun 13(1):3133. Zheng, A.-X. , Z.-X. Cong , J.-R. Wang , J. Li , H.-H. Yang , and G.-N. Chen . 2013. Highlyefficient peroxidase-like catalytic activity of graphene dots for biosensing. Biosens Bioelectron 49:519524. Zhou, L. , Z. Li , Z. Liu , J. Ren , and X. Qu . 2013. Luminescent carbon dot-gated nanovehicles for pH-triggered intracellular controlled release and imaging. Langmuir 29(21):63966403.

Embryonic Stem Cell as a Cellular Model for Testing the Toxicity of Engineered Nanoparticles Ahamed, M. , M. S. Alsalhi , and M. Siddiqui , 2010. Silver nanoparticle applications and human health. Clinica Chimica Acta 411(23):18411848. Akhavan, O. , E. Ghaderi , and A. Akhavan , 2012. Size-dependent genotoxicity of graphene nanoplatelets in human stem cells. Biomaterials 33(32):80178025. Allport, J. R. and R. Weissleder . 2001. In vivo imaging of gene and cell therapies. Exp Hematol 29(11):12371246. Ansari, S. A. and Q. Husain . 2012. Potential applications of enzymes immobilized on/in nano materials: A review. Biotechnol Adv 30(3):512523. Arai, T. , T. Kofidis , J. W. Bulte 2006. Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t. Magnetic Reson Med 55(1):203209. Arbab, A. S. , V. Frenkel , S. D. Pandit 2006. Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis. Stem Cells 24(3):671678. Arbab, A. S. , G. T. Yocum , H. Kalish 2004. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood 104(4):12171223. Asharani, P. , M. P. Hande , and S. Valiyaveettil . 2009. Anti-proliferative activity of silver nanoparticles. BMC Cell Biol 10(1):1. Asharani, P. , Y. Lianwu , Z. Gong , and S. Valiyaveettil . 2011. Comparison of the toxicity of silver, gold and platinum nanoparticles in developing zebrafish embryos. Nanotoxicology 5(1):4354. Beer, C. , R. Foldbjerg , Y. Hayashi , D. S. Sutherland , and H. Autrup . 2012. Toxicity of silver nanoparticlesnanoparticle or silver ion? Toxicol Lett 208(3):286292. Bettinger, C. J. , Z. Zhang , S. Gerecht , J. T. Borenstein , and R. Langer . 2008. Enhancement of in vitro capillary tube formation by substrate nanotopography. Adv Mater 20(1):99103.630 Borm, P. , F. C. Klaessig , T. D. Landry 2006. Research strategies for safety evaluation of nanomaterials, Part V: Role of dissolution in biological fate and effects of nanoscale particles. Toxicol Sci 90(1):2332. Braydich-Stolle, L. K. , B. Lucas , and A. Schrand . 2010. Silver nanoparticles disrupt GDNF/Fyn kinase signaling in spermatogonial stem cells. Toxicol Sci 116(2):577589. Bruchez, M. , M. Moronne , P. Gin , S. Weiss , and A. P. Alivisatos . 1998. Semiconductor nanocrystals as fluorescent biological labels. Science 281(5385):20132016. Bulte, J. W. , T. Douglas , B. Witwer 2001. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19(12):11411147. Bulte, J. W. , D. L. Kraitchman , A. M. Mackay , and M. F. Pittenger . 2004. Chondrogenic differentiation of mesenchymal stem cells is inhibited after magnetic labeling with ferumoxides. Blood 104(10):34103413. Chakraborty, S. K. , J. A. Fitzpatrick , J. A. Phillippi 2007. Cholera toxin B conjugated quantum dots for live cell labeling. Nano Lett 7(9):26182626. Chen, H. , I. Titushkin , M. Stroscio , and M. Cho . 2007. Altered membrane dynamics of quantum dot-conjugated integrins during osteogenic differentiation of human bone marrow derived progenitor cells. Biophys J 92(4):13991408. Comfort, K. K. , E. I. Maurer , L. K. Braydich-Stolle , and S. M. Hussain . 2011. Interference of silver, gold, and iron oxide nanoparticles on epidermal growth factor signal transduction in epithelial cells. ACS Nano 5(12):1000010008. Corsi, K. , F. Chellat , L. H. Yahia , and J. C. Fernandes . 2003. Mesenchymal stem cells, MG63 and HEK293 transfection using chitosan-DNA nanoparticles. Biomaterials 24(7):12551264. Dang, J. M. and K. W. Leong . 2007. Myogenic induction of aligned mesenchymal stem cell sheets by culture on thermally responsive electrospun nanofibers. Adv Mater 19(19):27752779.

Deng, X. , Q. Luan , W. Chen , Y. Wang , M. Wu , H. Zhang , and Z. Jiao . 2009. Nanosized zinc oxide particles induce neural stem cell apoptosis. Nanotechnology 20(11):115101. Deng, Y. , Y. Wu , Y. Qian , X. Ouyang , D. Yang , and X. Qiu . 2010. Adsorption and desorption behaviors of lignosulfonate during the self-assembly of multilayers. Bio Resour 5(2):11781196. Derfus, A. M. , W. C. Chan , and S. N. Bhatia . 2004. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett 4(1):1118. Dorrer, C. and J. Rhe . 2011. Micro to nano: Surface size scale and superhydrophobicity. Beilstein J Nanotechnol 2(1):327332. Dubertret, B. , P. Skourides , D. J. Norris , V. Noireaux , A. H. Brivanlou , and A. Libchaber . 2002. In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 298(5599):17591762. Elechiguerra, J. L. , J. L. Burt , J. R. Morones 2005. Interaction of silver nanoparticles with HIV1. J Nanobiotechnol 3(1):1. Eom, H-J. and J. Choi . 2010. p38 MAPK activation, DNA damage, cell cycle arrest and apoptosis as mechanisms of toxicity of silver nanoparticles in Jurkat T cells. Environ Sci Technol 44(21):83378342. Ferreira, L. , J. M. Karp , L. Nobre , and R. Langer . 2008a. New opportunities: The use of nanotechnologies to manipulate and track stem cells. Cell Stem Cell 3(2):136146.631 Ferreira, L. , T. Squier , H. Park , H. Choe , D. S. Kohane , and R. Langer . 2008b. Human embryoid bodies containing nano-and microparticulate delivery vehicles. Adv Mater 20(12):22852291. Foldbjerg, R. , P. Olesen , M. Hougaard , D. A. Dang , H. J. Hoffmann , and H. Autrup . 2009. PVP-coated silver nanoparticles and silver ions induce reactive oxygen species, apoptosis and necrosis in THP-1 monocytes. Toxicol Lett 190(2):156162. Greulich, C. , S. Kittler , M. Epple , G. Muhr , and M. Kller . 2009. Studies on the biocompatibility and the interaction of silver nanoparticles with human mesenchymal stem cells (hMSCs). Langenbeck's Arch Surg 394(3):495502. Gubbels-van Hal, W. , B. Blaauboer , H. Barentsen , M. Hoitink , I. Meerts , and J. Van Der Hoeven . 2005. An alternative approach for the safety evaluation of new and existing chemicals, an exercise in integrated testing. Regul Toxicol Pharmacol 42(3):284295. Guzman, R. , N. Uchida , T. M. Bliss 2007. Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci 104(24):1021110216. Haffor, A. and F. Abou-Tarboush . 2004. Testicular cellular toxicity of cadmium: Transmission electron microscopy examination. J Environ Biol/Academy of Environ Biol, India 25(3):251258. Hashi, C. K. , Y. Zhu , G.-Y. Yang 2007. Antithrombogenic property of bone marrow mesenchymal stem cells in nanofibrous vascular grafts. Proc Natl Acad Sci 104(29):1191511920. Hoehn, M. , E. Kstermann , J. Blunk 2002. Monitoring of implanted stem cell migration in vivo: A highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci 99(25):1626716272. Hoffman, G. S. , G. S. Kerr , and R. Y. Leavitt . 1992. Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 116(6):488498. Hofmann, M. C. , L. Braydich-Stolle , L. Dettin , E. Johnson , and M.F. Dym . 2005b. Immortalization of mouse germ line stem cells. Stem Cells 23(2):200210. Hofmann, M-C. , L. Braydich-Stolle , and M. Dym . 2005a. Isolation of male germ-line stem cells; influence of GDNF. Dev Biol 279(1):114124. Hsiao, J. K. , M. F. Tai H. H. Chu 2007. Magnetic nanoparticle labeling of mesenchymal stem cells without transfection agent: Cellular behavior and capability of detection with clinical 1.5 T magnetic resonance at the single cell level. Magn Reson Med 58(4):717724. Ittrich, H. , C. Lange , and F. Tgel . 2007. In vivo magnetic resonance imaging of iron oxidelabeled, arterially-injected mesenchymal stem cells in kidneys of rats with acute ischemic kidney injury: Detection and monitoring at 3 T. J Magn Reson Imaging 25(6):11791191. Jendelov, P. , V. Herynek , and L. Urdzikova . 2004. Magnetic resonance tracking of transplanted bone marrow and embryonic stem cells labeled by iron oxide nanoparticles in rat brain and spinal cord. J Neurosci Res 76(2):232243. Joshi, A. , S. Punyani , S. S. Bale , H. Yang , T. Borca-Tasciuc , and R. S. Kane . 2008. Nanotube-assisted protein deactivation. Nat Nanotechnol 3(1):4145. Kang, S. J. , I-g. Ryoo , Y. J. Lee , and M.-K. Kwak . 2012. Role of the Nrf2-heme oxygenase-1 pathway in silver nanoparticle-mediated cytotoxicity. Toxicol Appl Pharmacol 258(1):8998.632 Kawata, K. , M. Osawa , and S. Okabe . 2009. In vitro toxicity of silver nanoparticles at noncytotoxic doses to HepG2 human hepatoma cells. Environ Sci Technol 43(15):60466051.

Kraitchman, D. L. , A. W. Heldman , E. Atalar 2003. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107(18):22902293. Kraitchman, D. L. , M. Tatsumi , W. D. Gilson 2005. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 112(10):14511461. Kumari, A. and S. K. Yadav . 2011. Cellular interactions of therapeutically delivered nanoparticles. Expert Opin Drug Deliv 8(2):141151. Kuriyama, S. N. , C. E. Talsness , K. Grote , and I. Chahoud . 2005. Developmental exposure to low-dose PBDE-99: Effects on male fertility and neurobehavior in rat offspring. Environ Health Perspect 113(2):149154. Kutsuzawa, K. , T. Akaike , and E. H. Chowdhury . 2008. The influence of the cell-adhesive proteins E-cadherin and fibronectin embedded in carbonate-apatite DNA carrier on transgene delivery and expression in a mouse embryonic stem cell line. Biomaterials 29(3):370376. Lei, Y. , H. Tang , L. Yao , R. Yu , M. Feng , and B. Zou . 2007. Applications of mesenchymal stem cells labeled with Tat peptide conjugated quantum dots to cell tracking in mouse body. Bioconjug Chem 19(2):421427. Lewin, M. , N. Carlesso , C.-H. Tung 2000. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol 18(4):410414. Lin, S. , X. Xie , M. R. Patel 2007. Quantum dot imaging for embryonic stem cells. BMC Biotechnol 7(1):1. Lovri, J. , H. S. Bazzi , Y. Cuie , G. R. Fortin , F. M. Winnik , and D. Maysinger . 2005. Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots. J Mol Med 83(5):377385. Magrez, A. , S. Kasas , V. Salicio 2006. Cellular toxicity of carbon-based nanomaterials. Nano Lett 6(6):11211125. Mailander, V. and K. Landfester . 2009. Interaction of nanoparticles with cells. Biomacromolecules 10(9):23792400. Michalet, X. , F. Pinaud , and L. Bentolila . 2005. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307(5709):538544. Oberdrster, G. , A. Maynard , K. Donaldson 2005a. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part Fibre Toxicol 2(1):1. Oberdrster, G. , E. Oberdrster , and J. Oberdrster . 2005b. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113(7):823839. Oberdrster, G. , V. Stone , and K. Donaldson . 2007. Toxicology of nanoparticles: A historical perspective. Nanotoxicology 1(1):225. Olteanu, D. , A. Filip , C. Socaci 2015. Cytotoxicity assessment of graphene-based nanomaterials on human dental follicle stem cells. Colloids and Surfaces B: Biointerfaces 136:791798. Park, M. V. , W. Annema , A. Salvati 2009. In vitro developmental toxicity test detects inhibition of stem cell differentiation by silica nanoparticles. Toxicol Appl Pharmacol 240(1):108116.633 Peng, H. , X. Zhang , Y. Wei 2012. Cytotoxicity of silver nanoparticles in human embryonic stem cell-derived fibroblasts and an L-929 cell line. J Nanomater 2012:10. Politi, L. S. , M. Bacigaluppi , E. Brambilla 2007. Magnetic resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis. Stem Cells 25(10):25832592. Rajanahalli, P. , C. J. Stucke , and Y. Hong 2015. The effects of silver nanoparticles on mouse embryonic stem cell self-renewal and proliferation. Toxicol Rep 2:758764. Reimer, P. and T. Balzer . 2003. Ferucarbotran (Resovist): A new clinically approved RESspecific contrast agent for contrast-enhanced MRI of the liver: Properties, clinical development, and applications. Eur Radiol 13(6):12661276. Rikans, L. E. and T. Yamano . 2000. Mechanisms of cadmium-mediated acute hepatotoxicity. J Biochem Mol Toxicol 14(2):110117. Ryman-Rasmussen, J. P. , J. E. Riviere , and N. A. Monteiro-Riviere . 2007. Variables influencing interactions of untargeted quantum dot nanoparticles with skin cells and identification of biochemical modulators. Nano Lett 7(5):13441348. Shah, B. S. , P. A. Clark , E. K. Moioli , M. A. Stroscio , and J. J. Mao . 2007. Labeling of mesenchymal stem cells by bioconjugated quantum dots. Nano Lett 7(10):30713079. Singh, R. and H. S. Nalwa . 2011. Medical applications of nanoparticles in biological imaging, cell labeling, antimicrobial agents, and anticancer nanodrugs. J Biomed Nanotechnol 7(4):489503. Song, Y. S. and J. H. Ku . 2007. Monitoring transplanted human mesenchymal stem cells in rat and rabbit bladders using molecular magnetic resonance imaging. Neurourol Urodyn 26(4):584593.

Song, Y. S. , J. H. Ku , E. S. Song 2007. Magnetic resonance evaluation of human mesenchymal stem cells in corpus cavernosa of rats and rabbits. Asian J Androl 9(3):361367. Terrovitis, J. V. , J. W. Bulte , and S. Sarvananthan . 2006. Magnetic resonance imaging of ferumoxide-labeled mesenchymal stem cells seeded on collagen scaffolds-relevance to tissue engineering. Tissue Eng 12(10):27652775. Tran, D. N. , L. C. Ota , J. D. Jacobson , W. C. Patton , and P. J. Chan . 2007. Influence of nanoparticles on morphological differentiation of mouse embryonic stem cells. Fertil Steril 87(4):965970. Veerapandian, M. and Yun, K. 2011. Functionalization of biomolecules on nanoparticles: Specialized for antibacterial applications. Appl Microbiol Biotechnol 90(5):16551667. Walczak, P. , D. Kedziorek , A. Gilad , S. Lin , and J. Bulte . 2005. Instant MR labeling of stem cells using magnetoelectroporation. Magn Reson Med 54(4):769774. Wang, F. , I. Lee , and N. Holmstrm . 2006. Magnetic resonance tracking of nanoparticle labelled neural stem cells in a rat's spinal cord. Nanotechnology 17(8):1911. Whitesides, G. M. 2003. The right size in nanobiotechnology. Nat Biotechnol 21(10):11611165. Wiechers, J. W. and N. Musee . 2010. Engineered inorganic nanoparticles and cosmetics: Facts, issues, knowledge gaps and challenges. J Biomed Nanotechnol 6(5):408431. Xing, Y. , W. Xiong , L. Zhu , E. Osawa , S. Hussin , and L. Dai . 2011. DNA damage in embryonic stem cells caused by nanodiamonds. ACS Nano 5(3):23762384.634 Zhang, H. 2008. Iron Oxide Nanoparticles-Poly-L-Lysine Complex. Molecular Imaging and Contrast Agent Database (MICAD), National Center for Biotechnology Information, NLM, NIH, Bethesda, MD. Zhu, J. , Zhou L. , and F. Xing Wu . 2006. Tracking neural stem cells in patients with brain trauma. N Engl J Med 355(22):23762378. Zhu, L. , D. W. Chang , L. Dai , and Y. Hong , 2007. DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano Lett 7(12):35923597.

Regulations for Safety Assessment of Nanomaterial Bakand, S. and A. Hayes . 2016. Toxicological considerations, toxicity assessment, and risk management of inhaled nanoparticles. Int J Molecular Sci 17:929. Bowman, D. M. and V. G. Calster . 2008. Reelecting on REACH: Global Implications of the European Union's Chemicals Legislation. Nanotechnology Law and Business. Brussels: E.C. http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm (accessed September 9, 2016). Braakhuis, H. M. B. , A. G. Oomen , and F. R. Cassee . 2016. Grouping nanomaterials to predict their potential to induce pulmonar inflammation. Toxicol Appl Pharmacol 299:37. Burtscher, H. and K. Schepp . 2012. The occurrence of ultrafine particles in the specific environment of children. Paediatr Respir Rev 3:8994. Cao, Y. , L. Juan , L. Fang 2016. Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: A review. Env Toxicol Pharmacol 46:206210. Debia, M. , C. Beaudry , and S. Weichenthal . 2013. Characterization and Control of Occupational Exposure to Nanoparticles and Ultrafine Particles, Report R-777. Montral: Institut de recherche Robert-Sauv en sant et en scurit du travail (IRSST). http://www.irsst.qc.ca/media/documents/pubirsst/r-777.pdf (accessed Mai 12, 2017). Donaldson, K. , V. Stone , and A. Clouter . 2001. Ultrafine particles. Occup Environ Med 58:211216. EC . 2008. Nanomaterials. http://ec.europa.eu/health/scientific_committees/opinions_layman/nanomaterials/en/index.htm# 6 (accessed November 15, 2016). EFSA . 2011. Guidance on the risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain. EFSA Scientific Committee, EFSA Journal. http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2011.2140/epdf (accessed November 15, 2016). EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids) . 2016. Scientific opinion on the safety assessment of the substance zinc oxide, nanoparticles, for use in food contact materials. EFSA Journal 14(3):44084416. EPA . 2011. Glossary. Integrated Risk Information System (IRIS) Glossary. https://iaspub.epa.gov/sor_internet/registry/termreg/searchandretrieve/glossariesandkeywordlist s/search.do;jsessionid=MgNKB4ayD4GoEvj0_meAsEPfNH_nv82AryoJZiOhqAvGxHUC90o!12

55301345?details=andvocabName=IRIS%20GlossaryandfilterTerm=riskandcheckedAcronym=f alseandcheckedTerm=falseandhasDefinitions=falseandfilterTerm=riskandfilterMatchCriteria=Co ntains (accessed November 15, 2016). EPA . 2014. Technical Fact Sheet Nanomaterials. https://www.epa.gov/sites/production/files/201403/documents/ffrrofactsheet_emergingcontamin ant_nanomaterials_jan2014_final.pdf (accessed November 15, 2016).646 EPA . 2016a. Human Risk Assessment. https://www.epa.gov/risk/human-health-riskassessment (accessed November 15, 2016). EPA . 2016b. Control of Nanoscale Materials under the Toxic Substances Control Act. https://www.epa.gov/reviewing-new-chemicals-under-toxic-substances-control-act-tsca/controlnanoscale-materials-under (accessed November 15, 2016). EU-OSHA . 2008. Literature Review: Workplace Exposure to Nanoparticles. https://osha.europa.eu/en/toolsandpublications/publications/literature_reviews/workplace_exposure_to_nanoparticles (accessed September 12, 2016). EUROPEAN COMISSION. REACH in Brief. Brussels: E.C . 2008. http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm (accessed August 12, 2016). Friedlander, S. K. and D. Y. H. Pui . 2003. NSF Workshop Report on Emerging Issues in Nanoparticle Aerosol Science and Technology (NAST). University of California, Los Angeles. Hadrup, N. , A. K. Sharma , M. Poulsen 2015. Toxicological risk assessment of elemental gold following oral exposure to sheets and nanoparticles: A review. Reg Toxicol Pharmacol 72:216221. ISO (International Standardization Organization) . ISO/TC 229 Nanotechnologies. http://www.iso.org/iso/iso_technical_committee?commid=381983 (accessed September 13, 2016). Kim, Y. R. , S. H. Park , J. K. Lee 2014. Organization of research team for nano-associated safety assessment in effort to study nanotoxicology of zinc oxide and silica nanoparticles. Int J Nanomedicine 9:2. Kumar, C. 2011. Glutathione revisited: A vital function in iron metabolism and ancillary role in thiol-redox control. EMBO J 30(10):20442056. Kumar, D. 2010. Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res 38(12):39753983. Li, Y. , P. Li , H. Yu 2016. Recent advances (20102015) in studies of cerium oxide nanoparticles health effects. Env Toxicol Pharmacol 44:2529. NIH . 2014. Nanotechnology Safety and Health Program. https://www.ors.od.nih.gov/sr/dohs/Documents/Nanotechnology%20Safety%20and%20Health %20Program.pdf (accessed November 15, 2016). NIH (National Institutes of Health) . 2014. Division of Occupational Health and Safety. Nanotechnology Safety and Health Program. https://www.ors.od.nih.gov/sr/dohs/Documents/Nanotechnology%20Safety%20and%20Health %20Program.pdf (accessed September 21, 2016). NIOSH (The National Institute for Occupational Health and Safety) . 2016. Building a safety program to protect the nanotechnology workforce: a guide for small to medium-sized enterprises. Hodson L , Hull M. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication no. 2016-102. https://www.cdc.gov/niosh/docs/2016-102/pdfs/2016-102.pdf (accessed November 20, 2016). NSTC (National Science and Technology Council) . 2011. Committee on Technology. National Nanotechnology Initiative. Environmental, Health, and Safety Research Strategy. http://www.nano.gov/sites/default/files/pub_resource/nni_2011_ehs_research_strategy.pdf (accessed September 13, 2016). OECD (Organisation for Economic Cooperation) . 2007. OECD Working Party on Nanotechnology (WPN): Vision Statement. http://www.oecd.org/sti/nano/oecd workingpartyonnanotechnologywpnvisionstatement.htm (accessed November 24, 2016).647 SCCS (Scientific Committee on Consumer Safety) . 2012. Guidance on Safety Assessment of Nanomaterials in Cosmetics. 62 p. http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_s_005.pdf (accessed November 24, 2016). SCENIHR (Scientific Committee on Emerging and Newly Identified Health Risks) . 2015. Final Opinion on the Guidance on the Determination of Potential Health Effects of Nanomaterials Used in Medical Devices. http://ec.europa.eu/health/scientific_committees/emerging/docs/SCENIHR_o_045.pdf (accessed November 24, 2016). Slezakova, K. , S. Morais , and M. C. Pereira . 2013. Atmospheric Nanoparticles and Their Impacts on Public Health, Current Topics in Public Health.

http://www.intechopen.com/books/current-topics-in-public-health/atmospheric-nanoparticlesand-their-impacts-on-public-health (accessed November 24, 2016). Thomassen, Y. , W. Koch , W. Dunkhorst 2006. Ultrafine particles at workplaces of a primary aluminium smelter. J Environ Monit 8(1):127133. U.S. Food and Drug Administration . 2014. Guidance for Industry Considering Whether an FDARegulated Product Involves the Application of Nanotechnology. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM401695.pdf (accessed November 24, 2016). U.S. Food and Drug Administration . 2014. Guidance for Industry Safety of Nanomaterials in Cosmetic Products. 16 p. http://www.fda.gov/downloads/Cosmetics/GuidanceRegulation/GuidanceDocuments/UCM3009 32.pdf (accessed November 24, 2016). WHO (World Health Organization) . 2016. WHO Library Cataloguing-in-Publication Data WHO human health risk assessment toolkit: chemical hazards. (IPCS harmonization project document; no. 8). http://www.who.int/ipcs/publications/methods/harmonization/toolkit.pdf?ua=1 (accessed November 24, 2016).

Challenges, Recommendations, and Strategies for Nanotoxicology Evaluation and Its Management ConsExpo . RIVM Committed to health and sustainability. http://www.rivm.nl/en/healthanddisease/productsafety/ConsExpo.jsp, Accesses April 2, 2016. Dhawan, A. , V. Sharma , and D. Parmar 2009. Nanomaterials: A challenge for toxicologists. Nanotoxicology 3: 19. Donaldson, K. , C. A. Poland , and R. P. Schins 2010. Possible genotoxic mechanisms of nanoparticles: Criteria for improved test strategies. Nanotoxicology 4: 414420. Drobne, D. 2007. Nanotoxicology for safe and sustainable nanotechnology. Arh Hig Rada Toksikol 58: 471478. EC . October 13, 2016. http://ec.europa.eu/growth/sectors/chemicals/reach/nanomaterials/index_en.htm ECHA . 2012. https://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf Jahnel, J. 2015. Addressing the challenges to the risk assessment of nanomaterials. In: Patricia I. D. (Ed.) Nanoengineering: Global Approaches to Health and Safety Issues, Elsevier, pp. 485521. doi: 10.1016/B978-0-444-62747-6.00015-4 Maynard, A. D. 2016. Assessing Nanoparticle Risks to Human Health: The Challenge of Nanomaterial Risk Assessment, Assessing Nanoparticle Risks to Human Health (2nd Ed.) (pp. 120). http://scitechconnect.elsevier.com/wp-content/uploads/2016/05/3-s2.0B9780323353236000013-main.pdf SCENIHR (Scientific Committee on Emerging and Newly Identified Health Risks) 2006. Opinion on the Appropriateness of Existing Methodologies to Assess the Potential Risks Associated with Engineered and Adventitious Products of Nanotechnology, 10 March 2006, http://ec.europa.eu/health/scientific_committees/emerging/opinions/scenihr_opinions_en.htm Tran, L. and J. M. N. Antn 2009. Nanotoxicology and engineered nanoparticle risk assessment. Industrial Hygiene. Seguridad y Medio Ambiente 114: 111. Villum, F. 2015. Risk management of nanomaterials presentation of specific project activity on the risk management measures for nanomaterials. https://www.oeko.de/oekodoc/2250/2015026-en.pdf