Health hazards of nanoparticles: understanding the toxicity mechanism of nanosized ZnO in cosmetic products

In recent years, nanoparticles are being used extensively in personal healthcare products such as cosmetics, sunscreens, soaps, and shampoos. Particularly, metal oxide nanoparticles are gaining competence as key industrial constituents, progressing toward a remarkable rise in their applications. Zinc oxide and titanium oxide nanoparticles are the most commonly employed metal oxide nanoparticles in sunscreens, ointments, foot care, and over the counter topical products. Dermal exposure to these metal oxides predominantly occurs through explicit use of cosmetic products and airway exposure to nanoparticle dusts is primarily mediated via occupational exposure. There is a compelling need to understand the toxicity effects of nanoparticles which can easily enter the cells and induce oxidative stress. Consequently, these products have become a direct source of pollution in the environment and thereby greatly impact our ecosystem. A complete understanding of the toxicity mechanism of nano-ZnO is intended to resolve whether and to what extent such nanoparticles may pose a threat to the environment and to human beings. In this review article, we have discussed the characteristics of metal oxide nanoparticles and its applications in the cosmetic industry. We have also highlighted about their toxicity effects and their impact on human health.     

The immunomodulatory effects of titanium dioxide and silver nanoparticles

Due to their characteristic physical, chemical and optical properties, titanium dioxide and silver nanoparticles are attractive tools for use in a wide range of applications. The use of nanoparticles for biological applications is, however, dependent upon their biocompatibility with living cells. Because of the importance of inflammation as a modulator of human health, the safe and efficacious in vivo use of titanium dioxide and silver nanoparticles is inherently linked to a favorable interaction with immune system cells. However, both titanium dioxide and silver nanoparticles have demonstrated potential to exert immunomodulatory and immunotoxic effects. Titanium dioxide and silver nanoparticles are readily internalized by immune system cells, may accumulate in peripheral lymphoid organs, and can influence multiple manifestations of immune cell activity. Although the factors influencing the biocompatibility of titanium dioxide and silver nanoparticles with immune system cells have not been fully elucidated, nanoparticle core composition, size, concentration and the duration of cell exposure seem to be important. Because titanium dioxide and silver nanoparticles are widely utilized in pharmaceutical, commercial and industrial products, it is vital that their effects on human health and immune system function be more thoroughly evaluated.     

Silver nanoparticles: a brief review of cytotoxicity and genotoxicity of chemically and biogenically synthesized nanoparticles

In recent years interest in silver nanoparticles and their applications has increased mainly because of the important antimicrobial activities of these nanomaterials, allowing their use in several industrial sectors. However, together with these applications, there is increasing concerning related to the biological impacts of the use of silver nanoparticles on a large scale, and the possible risks to the environment and health. In this scenario, some recent studies have been published based on the investigation of potential inflammatory effects and diverse cellular impacts of silver nanoparticles. Another important issue related to nanoparticle toxicity in biological media is the capacity for increased damage to the genetic material, since nanoparticles are able to cross cell membranes and reach the cellular nucleus. In this regard, there is increasing interest in the analysis of potential nanoparticle genotoxicity, including the effects of different nanoparticle sizes and methods of synthesis. However, little is known about the genotoxicity of different silver nanoparticles and their effects on the DNA of organisms; thus further studies in this field are required. This mini‐review aims to present and to discuss recent publications related to genotoxicity and the cytotoxicity of silver nanoparticles in order to better understand the possible applications of these nanomaterials in a safe manner. This present work concludes that biogenic silver nanoparticles are generally less cyto/genotoxic in vivo compared with chemically synthesized nanoparticles. Furthermore, human cells were found to have a greater resistance to the toxic effects of silver nanoparticles in comparison with other organisms. Copyright © 2012 John Wiley & Sons, Ltd.     

Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials

With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials.     

Nanotoxicology and in vitro studies: the need of the hour

Nanotechnology is considered as one of the key technologies of the 21st century and promises revolution in our world. Objects at nano scale, take on novel properties and functions that differ markedly from those seen in the corresponding bulk counterpart primarily because of their small size and large surface area. Studies have revealed that the same properties that make nanoparticles so unique could also be responsible for their potential toxicity. Nanotechnology is rapidly advancing, with more than 1000 nanoproducts already on the market. Considering the fact that intended as well as unintended exposure to nanomaterials is increasing and presently no clear regulatory guideline(s) on the testing/evaluation of nanoparticulate materials are available, the in vitro toxicological studies become extremely relevant and important. This review presents a summary of nanotoxicology and a concise account of the in vitro toxicity data on nanomaterials. For nanomaterials to move into the applications arena, it is important that nanotoxicology research uncovers and understands how these multiple factors influence their toxicity so that the ensuing undesirable effects can be avoided.     

SILAC-based quantitative proteomics identifies size-dependent molecular mechanisms involved in silver nanoparticles-induced toxicity

Abstract

Silver nanoparticles are currently one of the most widely used metallic nanoparticles. Due to their antibacterial properties, they are applied in textiles, house-holds items, and medical devices, among many other products. Understanding the potential toxicity associated with silver nanoparticles and the differential effect that nanoparticles of different size might induce is crucial, due to the increasing human and environmental exposure to this type of nanoparticles. In this work, we explored the different biomolecular mechanisms underlying the toxicity of silver nanoparticles in a size-dependent manner. Quantitative proteomic analysis of hepatic cells exposed to 10 and 60?nm silver nanoparticles demonstrated the alteration of a different set of proteins depending on the particle size. We demonstrated that while 10?nm silver nanoparticles induce nucleolar stress and ribosome biogenesis halt, both types of nanoparticles induce DNA damage and oxidative stress but through different pathways. In addition, both types of nanoparticles also affected cell proliferation, disrupted the cell cycle and ultimately, induced apoptosis. The alteration of different cellular mechanisms in a size-dependent manner, have relevant implications not only from a toxicity point of view, but also for the potential applications of silver nanoparticles.     

Occupational exposure limit for silver nanoparticles: considerations on the derivation of a general health-based value

With the increased production and widespread commercial use of silver nanoparticles (AgNPs), human and environmental exposures to silver nanoparticles are inevitably increasing. In particular, persons manufacturing and handling silver nanoparticles and silver nanoparticle containing products are at risk of exposure, potentially resulting in health hazards. While silver dusts, consisting of micro-sized particles and soluble compounds have established occupational exposure limits (OELs), silver nanoparticles exhibit different physicochemical properties from bulk materials. Therefore, we assessed silver nanoparticle exposure and related health hazards in order to determine whether an additional OEL may be needed. Dosimetric evaluations in our study identified the liver as the most sensitive target organ following inhalation exposure, and as such serves as the critical target organ for setting an occupational exposure standard for airborne silver nanoparticles. This study proposes an OEL of 0.19?μg/m³ for silver nanoparticles derived from benchmark concentrations (BMCs) from subchronic rat inhalation toxicity assessments and the human equivalent concentration (HEC) with kinetic considerations and additional uncertainty factors. It is anticipated that this level will protect workers from potential health hazards, including lung, liver, and skin damage.     

Cyto and genotoxicity of gold nanoparticles in human hepatocellular carcinoma and peripheral blood mononuclear cells

Engineered nanomaterials have been extensively applied as active materials for technological applications. Since the impact of these nanomaterials on health and environment remains undefined, research on their possible toxic effects has attracted considerable attention. It is known that in humans, for example, the primary site of gold nanoparticles (AuNps) accumulation is the liver. The latter has motivated research regarding the use of AuNps for cancer therapy, since specific organs can be target upon appropriate functionalization of specific nanoparticles. In this study, we investigate the geno and cytotoxicity of two types of AuNps against human hepatocellular carcinoma cells (HepG2) and peripheral blood mononuclear cells (PBMC) from healthy human volunteers. The cells were incubated in the presence of different concentrations of AuNps capped with either sodium citrate or polyamidoamine dendrimers (PAMAM). Our results suggest that both types of AuNps interact with HepG2 cells and PBMC and may exhibit in vitro geno and cytotoxicity even at very low concentrations. In addition, the PBMC were less sensitive to DNA damage toxicity effects than cancer HepG2 cells upon exposure to AuNps.     

Acute toxicity test of CuO nanoparticles using human mesenchymal stem cells

Despite the growing interest in nanoparticles (NPs), standardized procedures for the evaluation of their toxicity have not been defined. The risk of human exposure is rapidly increasing and reliable toxicity test systems are urgently needed. In vitro methods are ideal in toxicology research because they can rapidly provide reproducible results while preventing the use of animals. Recently, a new test for acute toxicity based on the use of human bone marrow mesenchymal stem cells (hBMMSCs) has been developed and successfully tested in our laboratory following the Interagency Coordinating Committee on the Validation of Alternative Methods guidelines. Along these lines, the aim of this study is to evaluate the acute cytotoxicity of copper oxide (CuO) NPs using the new toxicity test based on hBMMSCs. Our results show that CuO NPs are much more toxic compared to micrometer ones. Specifically, CuO NP exposure exhibits a significant cytotoxicity at all the concentrations used, with an IC₅₀ value of 2.5?±?0.53?µg/ml. On the other hand, CuO microsized particle exposure exhibits a very low cytotoxicity at the same concentrations, with an IC₅₀ value of 72.13?±?16.2?µg/ml.     

The effect of airborne Palladium nanoparticles on human lung cells,endothelium and blood – A combinatory approach using three in vitro models

A better understanding of the mechanisms behind adverse health effects caused by airborne fine particles and nanoparticles (NP) is essential to improve risk assessment and identification the most critical particle exposures. While the use of automobile catalytic converters is decreasing the exhausts of harmful gases, concentrations of fine airborne particles and nanoparticles (NPs) from catalytic metals such as Palladium (Pd) are reaching their upper safe level. Here we used a combinatory approach with three in vitro model systems to study the toxicity of Pd particles, to infer their potential effects on human health upon inhalation. The three model systems are 1) a lung system with human lung cells (ALI), 2) an endothelial cell system and 3) a human whole blood loop system. All three model systems were exposed to the exact same type of Pd NPs. The ALI lung cell exposure system showed a clear reduction in cell growth from 24 h onwards and the effect persisted over a longer period of time. In the endothelial cell model, Pd NPs induced apoptosis, but not to the same extent as the most aggressive types of NPs such as TiO₂. Similarly, Pd triggered clear coagulation and contact system activation but not as forcefully as the highly thrombogenic TiO₂ NPs. In summary, we show that our 3-step in vitro model of the human lung and surrounding vessels can be a useful tool for studying pathological events triggered by airborne fine particles and NPs.     

Silver nanoparticles: Their potential toxic effects after oral exposure and underlying mechanisms – A review

Because of their antimicrobial properties, the use of silver nanoparticles (AgNPs) is increasing fast in industry, food, and medicine. In the food industry, nanoparticles are used in packaging to enable better conservation products such as sensors to track their lifetime, and as food additives, such as anti-caking agents and clarifying agents for fruit juices. Nanoemulsions, used to encapsulate, protect and deliver additives are also actively developed. Nanomaterials in foods will be ingested and passed through the digestive tract. Those incorporated in food packaging may also be released unintentionally into food, ending up in the gastrointestinal tract. It is therefore important to make a risk assessment of nanomaterials to the consumer. Thus, exposure to AgNPs is increasing in quantity and it is imperative to know their adverse effects in man. However, controversies still remain with respect to their toxic effects and their mechanisms. Understanding the toxic effects and the interactions of AgNPs with biological systems is necessary to handle these nanoparticles and their use. They usually generate reactive oxygen species resulting in increased pro-inflammatory reactions and oxidative stress via intracellular signalling pathways. Here, we mainly focus on the routes of exposure of AgNPs, toxic effects and the mechanisms underlying the induced toxicity.     

The potential exposure and hazards of copper nanoparticles: A review

Copper is an essential element for metabolism in plants and animals. In its nanoform, copper has found various applications, thus increasing potential environmental exposure. Released nanoparticles in the environment undergo various transformation processes while bioaccumulation and toxicity of copper nanoparticles have been demonstrated in plants and animals. This toxicity is thought to be a combined effect of intracellular particles and the release of dissolved copper ions. Oxidative stress responses have been studied in copper nanoparticle induced effects as well as other pathways to cytotoxicity. The antimicrobial potential of copper nanoparticles makes them excellent components for application in biomedicine and more recently, they have been investigated for applications as drug delivery agents in cancer therapy. These properties of copper nanoparticles necessitate a thorough review and understanding of toxic mechanisms of action and the associated implications of exposure to human and environmental health.     

Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles

In general, gold nanoparticles are recognized as being as nontoxic. Still, there have been some reports on their toxicity, which has been shown to depend on the physical dimension, surface chemistry, and shape of the nanoparticles. In this study, we carry out an in vivo toxicity study using 13 nm-sized gold nanoparticles coated with PEG (MW 5000). In our findings the 13 nm sized PEG-coated gold nanoparticles were seen to induce acute inflammation and apoptosis in the liver. These nanoparticles were found to accumulate in the liver and spleen for up to 7 days after injection and to have long blood circulation times. In addition, transmission electron microscopy showed that numerous cytoplasmic vesicles and lysosomes of liver Kupffer cells and spleen macrophages contained the PEG-coated gold nanoparticles. These findings of toxicity and kinetics of PEG-coated gold nanoparticles may have important clinical implications regarding the safety issue as PEG-coated gold nanoparticles are widely used in biomedical applications.     

Safety assessment of personal care products/cosmetics and their ingredients

We attempt to review the safety assessment of personal care products (PCP) and ingredients that are representative and pose complex safety issues. PCP are generally applied to human skin and mainly produce local exposure, although skin penetration or use in the oral cavity, on the face, lips, eyes and mucosa may also produce human systemic exposure. In the EU, US and Japan, the safety of PCP is regulated under cosmetic and/or drug regulations. Oxidative hair dyes contain arylamines, the most chemically reactive ingredients of PCP. Although arylamines have an allergic potential, taking into account the high number of consumers exposed, the incidence and prevalence of hair dye allergy appears to be low and stable. A recent (2001) epidemiology study suggested an association of oxidative hair dye use and increased bladder cancer risk in consumers, although this was not confirmed by subsequent or previous epidemiologic investigations. The results of genetic toxicity, carcinogenicity and reproductive toxicity studies suggest that modern hair dyes and their ingredients pose no genotoxic, carcinogenic or reproductive risk. Recent reports suggest that arylamines contained in oxidative hair dyes are N-acetylated in human or mammalian skin resulting in systemic exposure to traces of detoxified, i.e. non-genotoxic, metabolites, whereas human hepatocytes were unable to transform hair dye arylamines to potentially carcinogenic metabolites. An expert panel of the International Agency on Research of Cancer (IARC) concluded that there is no evidence for a causal association of hair dye exposure with an elevated cancer risk in consumers. Ultraviolet filters have important benefits by protecting the consumer against adverse effects of UV radiation; these substances undergo a stringent safety evaluation under current international regulations prior to their marketing. Concerns were also raised about the safety of solid nanoparticles in PCP, mainly TiO₂ and ZnO in sunscreens. However, current evidence suggests that these particles are non-toxic, do not penetrate into or through normal or compromised human skin and, therefore, pose no risk to human health. The increasing use of natural plant ingredients in personal care products raised new safety issues that require novel approaches to their safety evaluation similar to those of plant-derived food ingredients. For example, the Threshold of Toxicological Concern (TTC) is a promising tool to assess the safety of substances present at trace levels as well as minor ingredients of plant-derived substances. The potential human systemic exposure to PCP ingredients is increasingly estimated on the basis of in vitro skin penetration data. However, new evidence suggests that the in vitro test may overestimate human systemic exposure to PCP ingredients due to the absence of metabolism in cadaver skin or misclassification of skin residues that, in vivo, remain in the stratum corneum or hair follicle openings, i.e. outside the living skin. Overall, today's safety assessment of PCP and their ingredients is not only based on science, but also on their respective regulatory status as well as other issues, such as the ethics of animal testing. Nevertheless, the record shows that today's PCP are safe and offer multiple benefits to quality of life and health of the consumer. In the interest of all stakeholders, consumers, regulatory bodies and producers, there is an urgent need for an international harmonization on the status and safety requirements of these products and their ingredients.     

Nanoparticles: a review of particle toxicology following inhalation exposure

It is expected that the rapid expansion of nanotechnology will bring many potential benefits. However, initial investigations have demonstrated that nanomaterials may adversely affect human health and the environment. By increasing the application of nanoparticles, protection of the human respiratory system from exposure to airborne nanoparticles and ultrafine particulates has become an emerging health concern. Available research has demonstrated an association between exposure to ambient airborne particulates and ultrafine particles and various adverse heath effects including increased morbidity and mortality. Nanomaterial structures are more likely to be toxic than the same materials of conventional sized samples and can be inhaled more deeply into the lungs. While the respiratory tract is considered as the primary target organ for inhaled nanoparticles, recent research has demonstrated that extrapulmonary organs are also affected. The very small size distribution and large surface area of nanoparticles available to undergo reactions may play a significant role in nanotoxicity, yet very little is known about their interactions with biological systems. This review explores the possible underlying toxicity mechanisms of nanoparticles following inhalational exposure. Nanoparticles differ from the same conventional material at a larger scale in physical, chemical and biological characteristics; therefore it is critical to recognize the potential risk of nanoparticle exposure using appropriate toxicity test methods. Current advances and limitations of toxicity assessment methods of nanoparticles are discussed highlighting the recent improvements of in vitro screening tools for the safety evaluation of the rapidly expanding area of nanotechnology.     

Current major cancer targets for nanoparticle systems

This review presents some common features of nanoparticles - activity, toxicity and biological activity. Humans are exposed to tiny particles via dust storms, volcanic ash, and other natural processes and the body systems are well adapted to protect from these potentially harmful intruders. Technological advancement has also changed the character of particulate pollution, increasing the proportion of nanometer-sized particles - "nanoparticles" and expanding the variety of chemical compositions. Studies have shown a strong correlation between particulate air pollution levels, respiratory and cardiovascular diseases, various cancers, and mortality. Adverse effects of nanoparticles on human health depend on individual factors such as genetics and existing disease, as well as exposure, and nanoparticle chemistry, size, shape, agglomeration state, and electromagnetic properties. The key to understand the toxicity of nanoparticles is their size, smaller than cells and cellular organelles, which allows them to penetrate these basic biological structures, disrupting their normal function. Examples of toxic effects include tissue inflammation, and altered cellular redox balance toward oxidation, causing abnormal function or cell death. Some of these materials have desirable characteristics for industrial applications, as nanostructured materials often exhibit beneficial properties, from UV absorbance in sunscreen to oil-less lubrication of motors. In the sense of the huge surrounding positive and negative influence of known and unknown NP-impacts it seems very important to understand and forecast the processes in the body, due to the interaction between these two sides - organism. How nanoparticles can be used as drug delivery systems and imaging devices to increase the efficacy per dose of therapeutic or imaging contrast agents; how nanoparticles will be further developed to improve their functionality in cancer treatment and imaging? How reacts the immune system of the organism after introducing nanoparticles with the aim to defeat tumors? Here the aim was to discuss the right and wrong applications of NP and to answer to some of these questions. In the mean time there will appear much more investigations because of the important application of the NP not only as drug delivery systems, but as diagnostics as well.     

Interaction between iron oxide nanoparticles (IONs) and primary human immune cells: An up-to-date review of the literature

Nanotechnology has been gaining more and more momentum lately and the potential use of nanomaterials such as nanoparticles (NPs) continues to grow in a variety of activity sectors. Among the NPs, iron oxide nanoparticles (IONs) have retained an increasing interest from the scientific community and industrials due to their superparamagnetic properties allowing their use in many fields, including medicine. However, some undesired effects of IONs and potential risk for human health are becoming increasingly reported in several studies. Although many in vivo studies reported that IONs induce immunotoxicity in different animal models, it is not clear how IONs can alter the biology of primary human immune cells. In this article, we will review the works that have been done regarding the interaction between IONs and primary immune cells. This review also outlines the importance of using primary immune cells in risk assessment of NPs as a reliable strategy for encouraging non-animal studies approaches, to determine risks that might affect the human immune system following different exposure scenarios. Taken all together, the reported observations help to get a more global picture on how IONs alter the human immune system especially the fact that inflammation, known to involve several immune cell types, is frequently reported as an undesired effect of IONs.     

Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles.

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products.     

Data gaps in toxicity testing of chemicals allowed in food in the United States

In the United States, chemical additives cannot be used in food without an affirmative determination that their use is safe by FDA or additive manufacturer. Feeding toxicology studies designed to estimate the amount of a chemical additive that can be eaten safely provide the most relevant information. We analyze how many chemical additives allowed in human food have feeding toxicology studies in three toxicological information sources including the U.S. Food and Drug Administration's (FDA) database. Less than 38% of FDA-regulated additives have a published feeding study. For chemicals directly added to food, 21.6% have feeding studies necessary to estimate a safe level of exposure and 6.7% have reproductive or developmental toxicity data in FDA's database. A program is needed to fill these significant knowledge gaps by using in vitro and in silico methods complemented with targeted in vivo studies to ensure public health is protected.     

Zinc oxide nanoparticles in modern sunscreens: An analysis of potential exposure and hazard

Abstract

Sunscreens containing metal oxide nanoparticles appear transparent on the skin and provide excellent protection against sunburn caused by UV radiation. While it is likely that nanoparticles remain on the surface of the skin of healthy adult humans, and thus are considered safe for use in sunscreens, there has been no comprehensive assessment of the impact on human health from exposure to the metal oxide nanoparticles destined for use in sunscreens, either in the workplace during the manufacturing process, in long-term use across a range of skin conditions, or upon release into the broader environment, either accidentally or consequent of normal sunscreen use. In this review, we focus on zinc oxide nanoparticles destined for use in modern sunscreens, and discuss the potential for human exposure and the health hazard at each stage of their manufacture and use. We highlight where there is a need for further research.