Nanoparticles (NPs) are becoming more commonly used in numerous consumer and medical applications, thereby increasing human exposure. To name a few uses, NPs are utilized as protective and antibacterial coatings, drug delivery vehicles, electronics, medical imaging, treatment of a wide range of diseases, cosmetics, and tissue engineering [1-8]. NPs are also found as a manufacturing byproduct and found from combustion processes, which poses a health hazard [9, 10]. The Food and Drug Administration (FDA) defines NPs as particles with a size of 1 - 100 nm, and the toxicity guidelines state they are documented as adaptive and flexible. Due to the rapid development of nanotechnology, the number of NPs exceeds our capability for testing their toxicity, thereby necessitating an understanding of the general mechanisms of their toxicity. The size range of NPs allows them to have unique interactions with proteins and cells, thus making them ideal for their development as therapeutics and imaging contrast agents in medical applications. The potential of using these NPs depends on fully characterizing their toxicity and adverse interactions with biological systems. The purpose of this dissertation study was to understand the role of key physicochemical properties (e.g. biocorona and chemical defects) of NPs on cellular stress and the subsequent toxicity. The first aim of this study examined the formation of a biocorona (BC) on silver nanoparticles (AgNPs), and their contribution to endoplasmic reticulum (ER) stress. Once a NP enters the blood stream or other biological fluids, proteins will form a corona around the NPs resulting in a new biological entity which then affects their interactions with various cells and tissues. Two BCs that were investigated are modeled after common circulating proteins that have been shown to interact with AgNPs; bovine serum albumin (BSA) and high-density lipoprotein (HDL). In addition, I used fetal bovine serum (FBS) to serve as a model for a complex corona comprised of multiple proteins and lipids attached to NPs. The results of hyperspectral imaging and dynamic light scattering showed that proteins bind to AgNPs. In addition, circular dichroism spectroscopy showed that the structure of the proteins is perturbed when associated with NPs. Importantly, AgNPs induce ER stress responses in endothelial cells through activation of the IRE pathway. Further, the presence of a BC on AgNPs modified the ER stress response which varied according to the composition of the BC. Lastly, I observed differences in the subcellular localization of NPs due to size differences that likely contributed to the ER stress response. The second aim of this dissertation was to examine the contribution of chemical defects in ZnO NPs to cellular stress and toxicity. Due to the manufacturing process, contaminants may be incorporated into the crystal structure of NPs resulting in changes in their physicochemical properties. The results of this study indicate that chemical defects modify the degree of ER stress and oxidative stress in endothelial cells. In contrast to AgNPs, ZnO NPs induced ER stress through the PERK pathway, and the response is enhanced by oxidation of ZnO NPs compared to pristine ZnO NPs with no chemical defects. Furthermore, the cellular redox potential was reduced in endothelial cells exposed to ZnO NPs with defects compared to cells treated with pristine ZnO NPs. I conclude that the interactions of NPs with proteins as well as chemical defects of the NPs contribute significantly to cellular stress and toxicity. Taken together, the results indicate additional physicochemical properties such as chemical defects and BC formation contribute to cell stress and toxicity and should be considered when screening for the safety of NPs for consumer and medical applications.

Engineered Nanoparticles: Structure, Properties and Mechanisms of Toxicity is an indispensable introduction to engineered nanomaterials (ENM) and their potential adverse effects on human health and the environment. Although research in the area of pharmacology and toxicology of ENM is rapidly advancing, a possible correlation between their physicochemical properties and biomedical properties or toxicity is not yet fully understood. This understanding is essential to develop strategies for the safe applications and handling of ENM. The book comprehensively defines the current understanding of ENM toxicity, first describing these materials and their physicochemical properties, and then discussing the toxicological theory and methodology before finally demonstrating the potential impact of ENM on the environment and human health. It represents an essential reference for students and investigators in toxicology, pharmacology, chemistry, material sciences, medicine, and those in related disciplines who require an introduction to ENM and their potential toxicological effects. - Provides state-of-the-art physicochemical descriptions and methodologies for the characterization of engineered nanomaterials (ENM) - Describes the potential toxicological effects of ENM and the nanotoxicological mechanisms of action - Presents how to apply theory to practice in a public health and risk assessment setting

This book provides relevant findings on nanoparticles’ toxicity, their uptake, translocation and mechanisms of interaction with plants at cellular and sub-cellular level. The small size and large specific surface area of nanoparticles endow them with high chemical reactivity and intrinsic toxicity. Such unique physicochemical properties draw global attention of scientists to study potential risks and adverse effects of nanoparticles in the environment. Their toxicity has pronounced effects and consequences for plants and ultimately the whole ecosystem. Plants growing in nanomaterials-polluted sites may exhibit altered metabolism, growth reduction, and lower biomass production. Nanoparticles can adhere to plant roots and exert physicochemical toxicity and subsequently cell death in plants. On the other hand, plants have developed various defense mechanisms against this induced toxicity. This books discusses recent findings as well as several unresolved issues and challenges regarding the interaction and biological effects of nanoparticles. Only detailed studies of these processes and mechanisms will allow researchers to understand the complex plant-nanomaterial interactions.

In today’s nanotechnology and pharmaceutical research, alternative toxicology testing methods are crucial for ethically and commercially sound practice. This book provides practical guidelines on how to develop and validate quantitative nanostructure-toxicity relationship (QNTR) models, which are ideal for rapidly exploring the effects of a large number of variables in complex scenarios. Through contributions by academic, industrial, and governmental experts, Modelling the Toxicity of Nanoparticles delivers clear instruction on these methods and their integration and use in risk assessment. Specific topics include the physico-chemical characteristics of engineered nanoparticles, nanoparticle interactions, in vivo nanoparticle processing, and more. A much-needed practical guide, Modelling the Toxicity of Nanoparticles is a key text for researchers as well as government and industry regulators.

In this book the recent progress accumulated in studies of the interaction of engineered nanoparticles with cells and cellular constituents is presented. The focus is on manufacturing and characterization of nanosized materials, their interactions with biological molecules such as proteins, the mechanisms of transport across biological membranes as well as their effects on biological functions. Fundamental molecular and cellular aspects are in the foreground of the book. A further particularity is the interdisciplinary approach, including fields such as preparatory and analytical chemistry, biophysics and the physics of colloids, advanced microscopy and spectroscopy for in-situ detection of nanoparticles, cellular toxicology and nanomedicine. Nanoscale particles are known to exhibit novel and unprecedented properties that make them different from their corresponding bulk materials. As our ability to control these properties is further advanced, a huge potential to create materials with novel properties and applications emerges. Although the technological and economic benefits of nanomaterials are indisputable, concerns have also been raised that nanoscale structuring of materials might also induce negative health effects. Unfortunately, such negative health effects cannot be deduced from the known toxicity of the corresponding macroscopic material. As a result, there is a major gap in the knowledge necessary for assessing their risk to human health.

Since the first publication of this book in 2007, the field of nanoscience and nanomedicine continues to grow substantially. This second edition, Nanotoxicology: Progress toward Nanomedicine, enlists internationally recognized experts to document the continuing development and rationale for the safe design of engineered nanomaterials (ENM). This includes new improved characterization endpoints, screening, and detection methods for in vitro and in vivo toxicity testing. These tools also contribute greatly to nanosafety research applied to nanomedicines. Topics include The impacts of nanotechnology on biomedicine, including functionalization for tissue-specific targeting, the biointeractions of multifunctional nanoparticle-based therapy, and the ability to control specific physicochemical properties of nanoparticles The requirements for proper detection, measurement, and assessment both for workplace exposure and in consumer products—with a focus on potential health and safety implications Predictive modeling, using quantitative nanostructure activity relationships to predict the pharmacokinetics and biodistribution of nanomaterials in the body Specific methodologies, imaging, and techniques to assess nanomaterials from the manufacturing process to nanomedicine applications Tools for assessing nanoparticle toxicity and the limitations of detection methods for assessing toxicity in both in vivo and in vitro systems and at the single cell and tissue levels Toxicity of nanomaterials to specific organ systems, cell–based targeting to tumors, and other biomedical applications The difficulty of conducting risk assessments and the need for addressing knowledge gaps, especially with long-term studies A roadmap for future research The development of nanotechnology-based products must be complemented with appropriate validated methods to assess, monitor, manage, and reduce the potential risks of ENM to human health and the environment. This volume provides a cogent survey of advances in this area by a well-respected and diverse group of international scientists.

Details the source, release, exposure, adsorption, aggregation, bioavailability, transport, transformation, and modeling of engineered nanoparticles found in many common products and applications Covers synthesis, environmental application, detection, and characterization of engineered nanoparticles Details the toxicity and risk assessment of engineered nanoparticles Includes topics on the transport, transformation, and modeling of engineered nanoparticles Presents the latest developments and knowledge of engineered nanoparticles Written by world leading experts from prestigious universities and companies