Biomedical Applications and Toxicity of Nanomaterials

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Biomedical Applications and Toxicity of Nanomaterials
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Preface
Contents
Editors and Contributors
1. Macroporous Cryogel-Based Systems for Water Treatment Applications and Safety: Nanocomposite-Based Cryogels and Bacteria-Based Bioreactors
	Abbreviations
	1.1 Introduction
	1.2 Nanocomposite-Based Cryogels
		1.2.1 Nanocomposite Cryogel Preparation
			1.2.1.1 Direct method
			1.2.1.2 Immobilizing Nanoparticles on the Surface of Cryogels
			1.2.1.3 In Situ Preparation
		1.2.2 Application of Cryogel Nanocomposites for Water Treatment
			1.2.2.1 Adsorption
			1.2.2.2 Catalysis
		1.2.3 Assessment of the Safety of Nanocomposite Devices
			1.2.3.1 Assessment of Nanoparticle Leaching from Nanocomposites
			1.2.3.2 Assessment of Nanocomposite Toxicity
	1.3 Bacteria-Based Bioreactors
		1.3.1 Methods for Bacteria Immobilization
		1.3.2 Environmental Applications of Cryogels with Immobilized Bacteria
		1.3.3 Sensors for Monitoring Water Quality
	1.4 Concluding Remarks
	References
2. One-Dimensional Semiconducting Nanomaterials: Toxicity and Clinical Applications
	2.1 Introduction
	2.2 Fabrication of 1D Semiconductors
		2.2.1 Top-Down Fabrication
		2.2.2 Vapor-Liquid-Solid (VLS) Phase Growth
		2.2.3 Solution-Liquid-Solid (SLS) Method
		2.2.4 Vapor-Solid-Solid (VSS) Method
		2.2.5 Vapor-Solid (VS) Method
		2.2.6 Electrospinning
		2.2.7 Electrochemical Deposition
		2.2.8 Hydrothermal Synthesis
		2.2.9 Chemical Vapor Deposition (CVD)
		2.2.10 Intrinsic Growth
		2.2.11 Manipulating the Growth Using Capping Agents
		2.2.12 Self-Assembly
		2.2.13 Template-Assisted
		2.2.14 Electrochemical Anodization
	2.3 Biocompatibility
	2.4 Biomedical Applications
		2.4.1 Sensors for Medical Diagnosis
		2.4.2 Bone Applications
		2.4.3 Phototherapy
		2.4.4 Drug Delivery
		2.4.5 Other Applications
	2.5 Conclusion and Outlook
	References
3. Prospects of Safe Use of Nanomaterials in Biomedical Applications
	3.1 Introduction
	3.2 Biosensors
	3.3 Nanomaterials
		3.3.1 Surface Functionalization of Nanoparticles
	3.4 Cancer Biomarkers
		3.4.1 Lanthanum Hydroxide Nanoparticles (La(OH)3) Based Electrochemical Biosensor for Detection of Cyfra-21-1 Cancer Biomarker
		3.4.2 Detection of Cyfra-21-1 Cancer Biomarker Using Cubic Cerium Oxide-Reduced Graphene Oxide (CeO2-RGO) Nanocomposite-Based ...
		3.4.3 RGO Modified Mediator Paper-Based Electrochemical Biosensor for IL-8 Cancer Biomarker Detection
	3.5 Vitamin-D3 Biomarker
		3.5.1 Insoluble and Hydrophilic Electro Spun Cellulose Acetate Fiber-Based Electrochemical Biosensor for 25-OHD3 Biomarker Det...
	3.6 Carbon Dots (CDs) for Bioimaging Applications in Cancerous Cells
	3.7 Conclusion
	References
4. Hyaluronic Acid-Based Nanotechnologies for Delivery and Treatment
	4.1 Introduction: CD44 and Hyaluronic Acid Interaction
		4.1.1 CD44
		4.1.2 CD44 Role in Physiological Condition vs Cancer
		4.1.3 CD44 expression in normal, inflamed, and cancer tissues
		4.1.4 Hyaluronic Acid and Its physiological Role
			4.1.4.1 Role of Hyaluronic Acid in inflammation
			4.1.4.2 Role of Hyaluronic Acid in Cancer
		4.1.5 Internalization of Soluble Hyaluronic Acid
		4.1.6 Hyaluronic Acid and Current Treatments
			4.1.6.1 Role of Hyaluronic Acid as Therapeutic
			4.1.6.2 Ophthalmic and Injectable Hyaluronic Acid Treatments
			4.1.6.3 Hyaluronic Acid Conjugates
	4.2 Hyaluronic Acid-Based Nanotechnologies to Target CD44
		4.2.1 Current Strategies to Manufacture Hyaluronic Acid-Based Nanotechnologies
		4.2.2 Hyaluronic Acid-Based Nanoparticles and Design of Experiments
		4.2.3 Formulation of Nanoparticles for Delivery of Nucleic Acid to Cancer Cells
			4.2.3.1 Chitosan Hyaluronic Acid Nanoparticles and Impact of Formulation and Preparation Processes on Their Characteristics
			4.2.3.2 Design Criteria for the Formulation of Nanoparticles to Deliver Nucleic Acids to Target CD44+ Cells
		4.2.4 Considerations on the Single-Step Fabrication of Hyaluronic Acid Nanoparticles
	4.3 Manufacturing of Chitosan/Hyaluronic Acid Nanoparticles for the Delivery of Nucleic Acids
		4.3.1 Current Challenges to Deliver siRNA
		4.3.2 Models to Validate Delivery Via CD44: Internalization Mechanisms of Hyaluronic Acid Modified Chitosan Nanoparticles
	4.4 Conclusion
	References
5. Theranostics Nanomaterials for Safe Cancer Treatment
	5.1 Introduction: Cancer and Nanomedicine
	5.2 Bio-Inspired Organic Nanoparticles Used in Cancer
		5.2.1 Liposomes
		5.2.2 Lipid-Based Theranostic Nanoparticles (LNPs)
		5.2.3 Solid-Form Lipid Nanoparticles (SLNs)
		5.2.4 Lipid-Nano Structure (NLCs)
		5.2.5 Lipid-Based Nanocapsules (LNCs)
		5.2.6 Lipid Micelles
		5.2.7 Protein-Based Theranostic Nanoparticles
		5.2.8 Viral Nanoparticles (VNPs)
		5.2.9 Oligonucleotide Theranostic Nanoparticles
		5.2.10 Peptide Theranostic Nanoparticles
	5.3 Inorganic Theranostic Nanoparticles
		5.3.1 Gold Theranostic Nanoparticles (AuNPs)
		5.3.2 Silver Nanoparticles as Theranostic Agents (AgNPs)
		5.3.3 Iron Oxide Nanoparticles
	5.4 Conclusion
	References
6. Cardiovascular Safety Assessment of New Chemical Entities: Current Perspective and Emerging Technologies
	6.1 Introduction and Importance of Cardiovascular Safety Studies
	6.2 ICH S7A: Safety Pharmacology Studies for Human Pharmaceuticals
		6.2.1 Safety Pharmacology Core Battery
		6.2.2 Follow-up Safety Pharmacology Studies
		6.2.3 Supplemental Safety Pharmacology Studies
	6.3 ICH S7B Guidelines: The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolon...
		6.3.1 hERG Channels and QT Syndrome
	6.4 Conventional Techniques for CVS Safety Assessments
		6.4.1 In Vivo Telemetry Technique
		6.4.2 In Vitro hERG Assay and Isolated Systems
	6.5 Emerging Technologies Techniques for CVS Safety Assessments
		6.5.1 In Vivo Techniques
		6.5.2 In Vitro Techniques
	6.6 Newer Concepts in CVS Safety Assessment
		6.6.1 Front-Loading
		6.6.2 Integrated Core Battery Safety Studies
		6.6.3 Introduction of Alternate Models
		6.6.4 Exploration of Targets
	6.7 Journey to an Evolved CVS Safety Assessment Approach
		6.7.1 Application of Cardiac Stem Cells in CVS Safety Studies
		6.7.2 Cardiac Slice Preparation (In Vitro)
		6.7.3 Advanced and Superior Blood Pressure Recording with High Definition Oscillometry
		6.7.4 Cardiac Contractility a Core CVS Study Parameter
		6.7.5 Organ on Chips
	6.8 ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhyth...
	6.9 The Downside of the Current Approach on CVS Safety Assessment
	6.10 Development of a New Prototype for the Assessment of NCE Cardiovascular Liability
	6.11 Comprehensive In Vitro Proarrhythmia Assay (CiPA)
	6.12 In Silico Methods of CVS Safety Assessment: The Smart and Mathematical Future
	6.13 Conclusion
	References
7. Toxicology of Pharmaceutical Products During Drug Development
	7.1 Introduction
	7.2 Basic Principles of Toxicity Studies
	7.3 Role of Preclinical Toxicity Animal Models in Drug Development
	7.4 In-vivo Models
	7.5 Different Animal Models in Toxicological Studies
	7.6 In-vitro Models
	7.7 Types of (Systemic) Toxicity Studies: Acute, Subchronic, and Chronic Toxicology
	7.8 Fourteen to Twenty-Eight Day Repeated-Dose Toxicity Studies
	7.9 Ninety-Day Repeated-Dose Toxicity Studies
	7.10 180-Day Repeated-Dose Toxicity Studies
	7.11 Female Reproduction and Developmental Toxicity Studies
		7.11.1 Segment I-Female Fertility Study
		7.11.2 Segment II-Teratogenicity Study
		7.11.3 Segment III: Perinatal Study
	7.12 Special Toxicities Studies
		7.12.1 Local Toxicity
		7.12.2 Dermal Toxicity Study
		7.12.3 Photo-Allergy or Dermal Phototoxicity
		7.12.4 Vaginal Toxicity Test
		7.12.5 Rectal Tolerance Test
		7.12.6 Ocular Toxicity Studies
		7.12.7 Inhalation Toxicity Studies
		7.12.8 Allergenicity/Hypersensitivity
		7.12.9 Genotoxicity Studies
		7.12.10 Carcinogenicity Studies
	References
8. Safety and Risk Assessment of Food Items
	8.1 Introduction
		8.1.1 Chemical Risk Assessment
			8.1.1.1 Exposure to Toxic Substances Ingested Through Food
			8.1.1.2 Identifying and Characterizing Hazards
		8.1.2 Microbiological Risk Assessment
			8.1.2.1 Risk Characterization
		8.1.3 Application of Risk Assessment in the Context of Target Exposures
		8.1.4 Case Studies on Targeted Exposure Assessments
		8.1.5 Risk Communication and Risk Perception
	8.2 Conclusion
	References
9. Nontoxic Natural Products as Regulators of Tumor Suppressor Gene Function
	9.1 Introduction
	9.2 Cancer Critical Genes
		9.2.1 Tumor Suppressor Genes
		9.2.2 Cell Cycle Check Points
		9.2.3 Cell Cycle Control System
		9.2.4 Role of CKIs in the Regulation of Cell Cycle Control
		9.2.5 Role of RB in Cell Cycle Control
		9.2.6 Role of P53 Protein in Cell Cycle Regulation
		9.2.7 Role of APC as a Tumor Suppressor Gene
		9.2.8 BRCA1 and BRCA2
		9.2.9 PTEN
		9.2.10 WT1
		9.2.11 VHL
		9.2.12 NF1
	9.3 Natural Products and its Role in Regulating Tumor Suppressor Genes Function
		9.3.1 Honokiol
		9.3.2 Triptolide
		9.3.3 Lichochalcone A
		9.3.4 Acanthopanax gracilistilus
		9.3.5 Ginsenosides
		9.3.6 Curcumin
		9.3.7 Genistein
		9.3.8 Sesquiterpenoids
		9.3.9 Piperine
		9.3.10 Quercetin
		9.3.11 Artemisinin
		9.3.12 Plumbagin
		9.3.13 Thymoquinone
	9.4 Conclusion
	References
10. Advancements in the Safety of Plant Medicine: Back to Nature
	10.1 Introduction
	10.2 Relevance of Medicinal Plants/Plant-Derived Products and Challenges
	10.3 Quality Control and Modernization of Herbal Product Development
	10.4 Chemotaxonomic Approach for Sustainable Use of Natural Resources
	10.5 Case Studies on Chemotaxonomic Approach
	10.6 Acorus calamus L.
	10.7 Gloriosa superba L.
	10.8 Tribulus terrestris L.
	10.9 Coleus forskohlii Briq
	10.10 Costus speciosus (Koen. Ex Retz) Sm
	10.11 Ageratum conyzoides L.
	10.12 Centella asiatica L. (Urban)
	10.13 Integration of Herbal Products in the Mainstream: Policy Regulations
	10.14 Emerging Concept of Plant-Based Nano-Formulations: A New Face of Traditional Ayurvedic Bhasmas
	10.15 Conclusion
	References
11. Chemicals and Their Interaction in the Aquaculture System
	11.1 Introduction
	11.2 Chemical Practices in Aquaculture Systems
	11.3 Aquaculture Species of Commercial Importance: Worldwide Review
	11.4 Chemical Ingredients Purposed for Water Quality Management in Aquaculture
		11.4.1 Liming
		11.4.2 EDTA treatment
		11.4.3 Potassium Permanganate treatment
	11.5 Fertilizers
	11.6 Disinfectants
		11.6.1 Chlorination
		11.6.2 Formalin Treatment
		11.6.3 BKC Treatment
		11.6.4 Iodine Treatment
		11.6.5 Hydrogen Peroxide
		11.6.6 Malachite Green
	11.7 Anesthetics
	11.8 Chemical Structure of Benzocaine
	11.9 Antimicrobials
		11.9.1 Chloramphenicol
		11.9.2 Acriflavine
		11.9.3 Copper Compound
		11.9.4 Dipterex
	11.10 Feed Additives
	11.11 Pesticides
		11.11.1 Herbicides
		11.11.2 Insecticides
	11.12 Immunostimulants
	11.13 Breeding Inducing Agents
	11.14 Conclusion
	References
12. Zebrafish as a Biomedical Model to Define Developmental Origins of Chemical Toxicity
	12.1 Introduction
	12.2 Mechanisms of the DOHaD Paradigm
	12.3 Overview of DOHaD Studies in Environmental Health
	12.4 Strengths of the Zebrafish to Address the DOHaD of Environmental Chemicals
	12.5 DOHaD Toxicity Studies Using Zebrafish
	12.6 Study Design Considerations
	12.7 Future Directions and Challenges
	References
13. Green Synthesis of Nontoxic Nanoparticles
	13.1 Introduction
	13.2 Synthesis of Nanoparticles Using a Green Approach
	13.3 Nanoparticle Synthesis Mediated by Bacteria
	13.4 Nanoparticle Synthesis Mediated by Fungus and Yeast
	13.5 Nanoparticle Synthesis Mediated by Algae
	13.6 Nanoparticle Synthesis Mediated by Viruses
	13.7 Nanoparticle Synthesis Mediated by Plants
	13.8 Factors Affecting the Biosynthesis of Nanoparticles
	13.9 Characterization of the Synthesized Nanoparticle
	13.10 Safety Aspects of Green Synthesized Nanoparticles
	13.11 Application of Nanoparticles Developed by Green Synthesis
	13.12 Conclusion and Future Perspectives
	References
14. Synthesis, Characterization and Applications of Titanium Dioxide Nanoparticles
	14.1 Introduction
	14.2 Methods for Synthesis of TiO2 Nanoparticles
		14.2.1 Physical Methods
			14.2.1.1 Spray Pyrolysis Synthesis and Electrophoretic Concentration of TiO2 NPs
			14.2.1.2 Microwave-Assisted Method for Synthesis
			14.2.1.3 Laser Ablation
			14.2.1.4 Electrochemical Method
		14.2.2 Chemical Methods
			14.2.2.1 Sol-Gel Route of Synthesis
			14.2.2.2 Coprecipitation Method
			14.2.2.3 Solvothermal Method
			14.2.2.4 Hydrothermal Method
			14.2.2.5 Laser Vaporization and Condensation
		14.2.3 Biological Methods
	14.3 Characterization
	14.4 Applications
	14.5 Industrial Application
		14.5.1 Lithium Batteries
		14.5.2 Gas Sensors
		14.5.3 Paper Industry
		14.5.4 Food Industry
	14.6 Environmental
		14.6.1 Photocatalyst
		14.6.2 Photocatalytic Elimination of Water Pollutants
		14.6.3 Removal of Pollution/Deodorization Applications
	14.7 Biomedical Application
		14.7.1 Photodynamic Therapy (PDT)
		14.7.2 Targeted Drug Delivery
		14.7.3 Antibacterial Activity
		14.7.4 Bone and Dental Implants
	14.8 Conclusion
	References
15. Characterization of Nontoxic Nanomaterials for Biological Applications
	Abbreviations
	15.1 Introduction
	15.2 Physical and Morphological Characterization
		15.2.1 Scanning Electron Microscopy (SEM)
		15.2.2 Transmission Electron Microscope (TEM)
		15.2.3 Brunauer-Emmett-Teller (BET) Surface Area Analysis
		15.2.4 Atomic Force Microscopy (AFM)
	15.3 Chemical and Biological Characterization
		15.3.1 X-Ray Diffraction (XRD)
		15.3.2 Inductively Coupled Plasma Mass Spectrometry (ICP-MS)
		15.3.3 X-Ray Photoelectron Spectroscopy (XPS)
		15.3.4 Dynamic Light Scattering (DLS)
		15.3.5 X-Ray Absorption Spectroscopy (XAS)
	15.4 Spectral Characterization
		15.4.1 UV-VIS Spectroscopy
		15.4.2 Fourier Transform Infrared Spectroscopy (FTIR)
		15.4.3 Nuclear Magnetic Resonance Spectroscopy (NMR)
		15.4.4 Electron Spin Resonance Spectroscopy (ESR)
		15.4.5 Mossbauer Spectroscopy
	15.5 Thermal Characterization
		15.5.1 Thermogravimetric Analysis (TGA)
		15.5.2 Differential Scanning Calorimetry (DSC)
		15.5.3 Differential Thermal Analysis (DTA)
	15.6 Optical Characterization Techniques
		15.6.1 Photoluminescence Spectroscopy
		15.6.2 UV-Visible Spectroscopy
		15.6.3 Infrared (IR) Spectroscopy
		15.6.4 Raman Spectroscopy
	15.7 Magnetic, Rheological, and Electrical Characterization
		15.7.1 Magnetic Characterization
		15.7.2 Rheological Characterization
		15.7.3 Electrical Characterization
	15.8 Conclusion
	References
16. Toxicity Assessment of Nanoparticle
	16.1 Introduction
	16.2 Potential Mechanism of Nanoparticle-Induced Toxicity
	16.3 Toxicity Assessments
		16.3.1 In Vitro Toxicity Assessment
			16.3.1.1 MTT Assay
			16.3.1.2 Modified Tetrazolium Salts
			16.3.1.3 Neutral Red Uptake Assay
			16.3.1.4 Lactate Dehydrogenase Assay
			16.3.1.5 Sulforhodamine B Assay
			16.3.1.6 Resazurin Reduction Assay
			16.3.1.7 Assay of Intracellular ATP
			16.3.1.8 Calcein-AM/PI Dual Staining
		16.3.2 In Vivo Toxicity Assessments
			16.3.2.1 Embryonic Zebrafish Assay
			16.3.2.2 Reproductive Toxicity Assessment Using Drosophila melanogaster
			16.3.2.3 Toxicity Assessment Using Daphina magna
			16.3.2.4 Chick Chorioallantoic Membrane (CAM) Assay
			16.3.2.5 Acute and Chronic Toxicity Studies
			16.3.2.6 Micronucleus Assay
			16.3.2.7 Chromosomal Aberrations Assay
			16.3.2.8 DNA Damage Assay
			16.3.2.9 Immunotoxicity Assays
			16.3.2.10 Buehler Test (BT)
			16.3.2.11 The Guinea Pig Maximization Test (GPMT)
			16.3.2.12 Local Lymph Node Assay (LLNA)
	16.4 Challenges and Future Perspective in Toxicity Assessment of Nanoparticles
	References
17. Safety of Nanoparticles: Emphasis on Antimicrobial Properties
	17.1 Introduction
	17.2 Nanoparticles: An Overview
		17.2.1 Nanoparticles as Drug Carriers
			17.2.1.1 Chitosan
			17.2.1.2 Alginate
			17.2.1.3 Liposomes
			17.2.1.4 Solid Lipid Nanoparticles
			17.2.1.5 Polymeric Nanoparticles
			17.2.1.6 Dendrimers
			17.2.1.7 Quantum Dots
			17.2.1.8 Metallic Nanoparticles
			17.2.1.9 Carbon-Based Nanoparticles
		17.2.2 Advantages of Drug Administration Employing Nanoscience
		17.2.3 Disadvantages of Drug Administration Employing Nanoscience
	17.3 Applications of Nanoparticles
		17.3.1 Nanoparticles as Antibacterial Agents
		17.3.2 Nanoparticles as Antifungal Agents
		17.3.3 Nanoparticles as Antiviral Agents
		17.3.4 Nanoparticles as Anti-leishmanial Agents
	17.4 Conclusion and Future Perspectives
	References
18. Quantum Dots for Imaging and Its Safety
	18.1 Introduction
	18.2 Features of QDs
		18.2.1 Tunable Light Emission
		18.2.2 Broad Absorption Spectra and Narrow Emission Spectra
		18.2.3 High Quantum Yield and High Absorption Extinction Coefficient
		18.2.4 Excellent Photostability
	18.3 Synthesis of Quantum Dots
	18.4 Classification/Types of Quantum Dots
	18.5 Imaging Applications of Quantum Dots
		18.5.1 In Vitro Imaging
			18.5.1.1 Cellular and Biomolecular Imaging
			18.5.1.2 Tissue Staining
			18.5.1.3 Binding Assays
		18.5.2 In Vivo Imaging
			18.5.2.1 Tumor Imaging
			18.5.2.2 Deep Tissue Imaging
	18.6 Safety Concerns of QDs
	18.7 Conclusion
	References
19. Genotoxicity Evaluation of Nanosized Materials
	19.1 Introduction
	19.2 Genotoxicity Evaluation of Nanomaterials
	19.3 Mutagenicity Assay
		19.3.1 In Vitro Mutagenicity
			19.3.1.1 The Ames Test
		19.3.2 In Vitro Mammalian Cell Gene Mutation Test
			19.3.2.1 Hypoxanthine-Guanine Phosphoribosyl Transferase Test
			19.3.2.2 Xanthine-Guanine Phosphoribosyl Transferase Test
			19.3.2.3 The In Vitro Mouse Lymphoma Assay (Mutation at Tk Gene)
		19.3.3 In Vivo Mammalian Mutagenicity Assay
			19.3.3.1 LacI and LacZ Transgenic Mouse Model (Somatic Cells)
			19.3.3.2 Transgenic Rodent Assays (Germ Cell)
			19.3.3.3 Pig-a Assay in Rodents and Humans
	19.4 Chromosomal Damage Assays
		19.4.1 Single Cell Gel Electrophoresis (SCGE) Assay/Comet Assay
		19.4.2 General Requirements
		19.4.3 In Vitro Comet Assay
			19.4.3.1 Alkaline Single Cell Gel Electrophoresis/Alkaline Comet Assay
			19.4.3.2 Preparation of Sample
			19.4.3.3 Preparation of Slides for Electrophoresis and Visualization of Comets
		19.4.4 In Vivo Comet Assay
			19.4.4.1 Selection of Animals and Experimental Design
			19.4.4.2 Dose Selection, Administration, and Sampling
			19.4.4.3 Preparation of Sample and Work Procedure
			19.4.4.4 Analysis and Interpretation
	19.5 Micronucleus Assay
		19.5.1 In Vitro Mammalian Cell Micronucleus (MN) Assay
			19.5.1.1 General Principle
			19.5.1.2 Experimental Design
			19.5.1.3 Experimental Procedure
			19.5.1.4 Analysis and Interpretation of In Vitro Micronucleus Assay
		19.5.2 In Vivo MN Assay
			19.5.2.1 Experimental Design and General Requirements
			19.5.2.2 Analysis and Interpretation of In Vivo Micronucleus Assay
	19.6 Chromosomal Aberration Assay
		19.6.1 In Vitro Chromosomal Aberration Test
			19.6.1.1 Selection and Preparation of Sample
			19.6.1.2 Chromosome Harvest and Analysis
		19.6.2 In Vivo Chromosomal Aberration Test
			19.6.2.1 Experimental Design and Sample Preparation
			19.6.2.2 Chromosome Harvest Analysis and Interpretation
	19.7 DNA Damage
		19.7.1 Double-Strand Breaks (DSB) Assay
	19.8 High-ThroughPut Methods and Recent In Vitro Models
		19.8.1 Modified Versions of the Comet Assay
			19.8.1.1 Medium Throughput Methylation-Sensitive Comet Assay
			19.8.1.2 Endo III and FPG-Modified Comet Assay
			19.8.1.3 Comet-FISH
			19.8.1.4 High-Throughput Screening Using Comet Chip
			19.8.1.5 ToxTracker Assay
		19.8.2 Modified Techniques for MN Detection
			19.8.2.1 Flow Cytometry Method
			19.8.2.2 In Vitro Micronucleus Assay and FISH Analysis
	19.9 Advantages and Limitations of Genotoxicity Assays
	19.10 General Mechanisms of Genotoxicity
		19.10.1 Primary Genotoxicity
		19.10.2 Secondary Genotoxicity
	19.11 Conclusion
	References
20. Scaffold Materials and Toxicity
	20.1 Introduction
	20.2 Various Scaffold Materials and Their Possible Toxicity
		20.2.1 Synthetic Scaffolds Materials
		20.2.2 Natural Products Scaffold Materials
	20.3 Advances in Scaffold Engineering: Nanoscaffolds and Related Toxicity
	20.4 Toxicity Evaluation Tests of Scaffolds
	20.5 Conclusion
	References
21. Biological Safety and Cellular Interactions of Nanoparticles
	21.1 Introduction
	21.2 The Dynamics of Nanoparticle-Cell Interaction
		21.2.1 Cellular Internalization of Nanoparticles
		21.2.2 Interaction of Nanoparticles with Tumor Tissue
	21.3 Cellular Pathways for Nanoparticle Uptake
		21.3.1 Phagocytosis
		21.3.2 Macropinocytosis
		21.3.3 Clathrin-Mediated Endocytosis
		21.3.4 Caveolae-Mediated Endocytosis
		21.3.5 Clathrin- and Caveolin-Independent Endocytosis
	21.4 Physicochemical Properties of Nanoparticles Influencing the Interaction Mechanisms
		21.4.1 Size
		21.4.2 Shape
		21.4.3 Charge and Surface Hydrophobicity
	21.5 The Cell Mechanics Influencing Nanoparticle-Cell Interaction
		21.5.1 Cellular Adhesion
		21.5.2 Cytoskeleton Interactions
	21.6 Cell-Nanoparticle Interactions and Hemostasis
		21.6.1 The Formation of Protein Corona
		21.6.2 Nanoparticles and the Interaction with Blood Cells
	21.7 Intracellular Trafficking of NPs
		21.7.1 Endosomal Escape
		21.7.2 Organelle and Subcellular Targeting
		21.7.3 Exocytosis
	21.8 Cell-Nanoparticle Interactions and Cytotoxicity
	21.9 Exploring the Cellular Interaction of Nanoparticles
	21.10 Conclusion
	References
22. Role of Artificial Intelligence in the Toxicity Prediction of Drugs
	22.1 Introduction
		22.1.1 Toxicity Due to Chemicals and Drugs
		22.1.2 Artificial Intelligence
		22.1.3 Machine Learning Models
		22.1.4 Algorithms
		22.1.5 Performance Evaluation Measures
		22.1.6 Machine Learning Model Development
	22.2 Tools Used in Artificial Intelligence
		22.2.1 Neural Networks
		22.2.2 Deep Learning Frameworks and Libraries
			22.2.2.1 Cafe
			22.2.2.2 Theano
			22.2.2.3 TensorFlow
			22.2.2.4 Torch
			22.2.2.5 PyTorch
			22.2.2.6 Scikit-Learn
		22.2.3 Quantitative Structure-Activity Relationship (QSAR)
			22.2.3.1 Descriptors Based on a Different Dimension
			22.2.3.2 Model-Based QSAR Approach
			22.2.3.3 3D QSAR
				22.2.3.3.1 Comparative Molecular Field Analysis (CoMFA)
				22.2.3.3.2 Comparative Molecular Similarity Indices Analysis (CoMSIA)
			22.2.3.4 Machine Learning in QSAR
			22.2.3.5 Application of QSAR
		22.2.4 Docking
			22.2.4.1 Steps in Molecular Docking
			22.2.4.2 Different Types of Molecular Docking
			22.2.4.3 Machine Learning in Docking
			22.2.4.4 Application of Molecular Docking
	22.3 OECD Guidelines for Testing Chemicals
	22.4 Importance of Artificial Intelligence in Toxicity Predictions
		22.4.1 Toxicity Due to Drugs
		22.4.2 Toxicity Due to Drug-Drug Interactions
		22.4.3 Toxicity Due to Drug-Transporter Interaction
	22.5 Prediction of Toxicity in Different Organs by AI
		22.5.1 Liver
		22.5.2 Heart
		22.5.3 Eye and Skin
		22.5.4 Gastrointestinal
		22.5.5 Kidney
	22.6 Conclusion
	References
23. Chemicals and Rodent Models for the Safety Study of Alzheimer´s Disease
	23.1 The Mouse as an Animal Model System
	23.2 Mouse as an Animal Model System for Alzheimer´s Disease (AD) Research
		23.2.1 The Amyloid Hypothesis
		23.2.2 The Tau Hypothesis
		23.2.3 Cholinergic Hypothesis
	23.3 Commonly Used Mouse Model Systems to Study AD
		23.3.1 Transgenic Mouse Models of AD
		23.3.2 Chemical-Induced Models for Studying AD
			23.3.2.1 Streptozotocin and AD Development
			23.3.2.2 Scopolamine and AD Development
			23.3.2.3 Colchicine and AD Model
			23.3.2.4 Okadaic Acid and AD Development
			23.3.2.5 Sodium Azide-Induced AD Model
			23.3.2.6 Heavy Metal-Induced AD-Like Model
			23.3.2.7 Alcohol-Induced AD-Like Model
			23.3.2.8 Ibotenic Acid-Induced AD Model System
			23.3.2.9 LPS-Induced AD Model System
	References
24. Mitochondria-Targeted Liposomal Delivery in Parkinson´s Disease
	Abbreviations
	24.1 Introduction
	24.2 Mitochondrial Dysfunction and Parkinson´s Disease
	24.3 Liposomal Drug Delivery Across the BBB
	24.4 Mitochondria-Targeted Liposomal Formulations
	24.5 Advantages and Challenges of Liposomal Delivery
		24.5.1 Advantages of Liposomes
		24.5.2 Challenges of Liposomes
	24.6 Regulatory Challenges for Liposomes
	24.7 Conclusion
	References
25. Routes of Nano-drug Administration and Nano-based Drug Delivery System and Toxicity
	25.1 Introduction: Importance of Nanoparticle-Based Drug Delivery
	25.2 Routes of Nano-drug Delivery
		25.2.1 Oral Route of Drug Delivery
			25.2.1.1 Stomach Targeting Drug Delivery
			25.2.1.2 Small Intestine Targeting Drug Delivery
			25.2.1.3 Colon-Targeted Drug Delivery
		25.2.2 Nanocarriers in Oral Route
			25.2.2.1 Dendrimers
			25.2.2.2 Liposomes
			25.2.2.3 Others
		25.2.3 The Transdermal Route of Drug Delivery
			25.2.3.1 Anatomy of the Skin
			25.2.3.2 Drug Transportation Across the Skin
		25.2.4 Nanocarriers in Transdermal Route
		25.2.5 Methods of Transdermal Drug Delivery
			25.2.5.1 The Passive Method of Transdermal Delivery
				25.2.5.1.1 Chemical Enhancers
				25.2.5.1.2 Prodrugs
				25.2.5.1.3 Carriers and Vehicles
					Hydrogels
					Liposomes
					Vaccines
					Others
			25.2.5.2 The Active Method of Transdermal Delivery
				25.2.5.2.1 Electroporation
				25.2.5.2.2 Iontophoresis
				25.2.5.2.3 Sonophoresis
				25.2.5.2.4 Microneedles
				25.2.5.2.5 Others
		25.2.6 Ocular Route of Drug Delivery
			25.2.6.1 Anatomy of the Eye
		25.2.7 Nanocarriers in Ocular Route
			25.2.7.1 Niosomes
			25.2.7.2 Solid Lipid Nanoparticles
			25.2.7.3 Inorganic Nanoparticles
			25.2.7.4 Others
		25.2.8 Nasal Route of Drug Delivery
			25.2.8.1 Nose to Brain Targeting
			25.2.8.2 Mechanism of Transport to Brain
		25.2.9 Nanocarriers in Nasal Route
		25.2.10 Pulmonary Route of Drug Delivery
			25.2.10.1 Anatomy of Lungs
			25.2.10.2 Mechanism of Drug Deposition in Lungs
		25.2.11 Nanocarriers in Pulmonary Route
			25.2.11.1 Solid Lipid Nanoparticles
			25.2.11.2 Polymeric Nanoparticles
			25.2.11.3 Others
		25.2.12 Parenteral Route of Drug Delivery
		25.2.13 Nanocarriers in Parenteral Route
		25.2.14 Nanocarriers in Subcutaneous Route
		25.2.15 Nanocarriers in Intramuscular Route
		25.2.16 Nanocarriers in Intravenous Route
	25.3 Future Perspectives
	References
26. Green Synthesized Silver Nanoparticles Phytotoxicity and Applications in Agriculture: An Overview
	26.1 Introduction
	26.2 Capping Agents in Nanotechnology
	26.3 Silver Nanoparticles
	26.4 Importance of Biosynthesis of AgNPs
	26.5 Role of Plants in Green Synthesis of Nanoparticles
	26.6 Phytotoxicity Effect
	26.7 Applications of Silver Nanoparticles in Agriculture
	26.8 Plant Disease Management and Protection
	26.9 Nanofertilizers
	26.10 Pest Management
	26.11 Conclusion
	References
27. Status of Safety Concerns of Microplastic Detection Strategies
	27.1 Introduction
	27.2 Microplastics
		27.2.1 Types
			27.2.1.1 Sources
				27.2.1.1.1 Dust
				27.2.1.1.2 Plastic Pellets
				27.2.1.1.3 Synthetic Textiles
				27.2.1.1.4 Tires and Road Markings
		27.2.2 Physiochemical Properties
			27.2.2.1 Particle Size
				27.2.2.1.1 Surface Chemistry
				27.2.2.1.2 Particle Shape
				27.2.2.1.3 Surface Area
				27.2.2.1.4 Polymer Crystallinity
				27.2.2.1.5 Polymer Additives
				27.2.2.1.6 Polymer Types
	27.3 Separation Methods for Microplastics
		27.3.1 Density-Based Approaches
		27.3.2 Hydrophobicity-Based Approaches
		27.3.3 Size-Based Approaches
		27.3.4 Approaches for Nanoparticle Separation
	27.4 Methods for Microplastics Detection
		27.4.1 Spectroscopy-Based Detection Methods
			27.4.1.1 Raman Spectroscopy
			27.4.1.2 Infrared (IR) Spectroscopy
			27.4.1.3 Fourier Transform Infrared Spectroscopy (FTIR)
		27.4.2 Microscopy-Based Detection Methods
			27.4.2.1 Scanning Electron Microscopy (SEM)
		27.4.3 Mass Spectrometry (MS)-Based Detection Methods
			27.4.3.1 Pyrolysis-Gas Chromatography-Mass Chromatography (Py-GC-MS)
			27.4.3.2 Thermal Desorption Coupled with Gas Chromatography: Mass Spectrometry (TDS-GC-MS/TED-GC-MS)
		27.4.4 Chromatography-Based Detection Methods
			27.4.4.1 Size-Exclusion Chromatography (SEC)
		27.4.5 Composition-Based Analysis
			27.4.5.1 Density Separation with Subsequent C:H:N Analysis
		27.4.6 Novel Detection-Based Methods
			27.4.6.1 Atomic Force Microscopy (AFM) Coupled to IR or Raman Spectroscopy
			27.4.6.2 Dyes
	27.5 Factors Affecting MP Detection
		27.5.1 Sampling
		27.5.2 Size and morphology
	27.6 Conclusion
	References
28. Impact of Insecticides on Man and Environment
	28.1 Introduction
	28.2 History of Insecticide
	28.3 Classification of Insecticide
		28.3.1 Classification Based on Chemical Composition
			28.3.1.1 Inorganic Pesticide
			28.3.1.2 Synthetic Insecticides
				28.3.1.2.1 Organochlorides
				28.3.1.2.2 Organophosphates
				28.3.1.2.3 Carbamates
				28.3.1.2.4 Pyrethrins
				28.3.1.2.5 Neonicotinoids
				28.3.1.2.6 Biopesticides
		28.3.2 Mode of Entry
			28.3.2.1 Systemic Pesticides
			28.3.2.2 Contact Pesticides
			28.3.2.3 Fumigants
		28.3.3 Mode of Action
	28.4 Environmental Impact of Insecticides
	28.5 Impact of Insecticides on Human Health
	28.6 Alternative to Synthetic Insecticides
	28.7 Conclusion
	References