Exposure, Toxicology, and Impact on Human Health is a critical and authoritative resource that provides an orientation for toxicologists, pharmacologists, and clinicians, as well as regulators and policymakers, and others directly involved in nanosafety. This book, written by leading international experts in nanotoxicology and nanomedicine, gives a comprehensive view of the health impact of engineered nanomaterials ENM , focusing on their potential adverse effects in exposed workers, consumers and patients.
By reviewing and translating current research, this essential reference bridges the gap between experimental findings on toxicological effects of ENM and occupational and environmental exposure to ENM, and the clinico-pathological consequences of such exposure in the human population. Contains information on occupational exposure assessment and biomonitoring of exposure and adverse health effects of ENM Provides a critical discussion of commonly used in vitro and in vivo toxicity tests and of computational approaches to nanosafety Offers a systematic evaluation of the human organs and organ systems which may be affected by exposure to ENM Highlights current and future biomedical applications of nanoparticles in relation to nanosafety Provides global, clinical, occupational, and regulatory perspectives given the backgrounds of the well-renowned contributing authors and their expertise in health and safety issues related to ENM Related Titles:.
Interpretation and Relevance in Drug Safety Evaluation, 4 th edition, , Risks, Regulation and Management, , Would you like to tell us about a lower price? Multi-authored book written by leading US and European experts on nanotoxicology and nanomedicine Discusses the health implications and a clinical translation of experimental data in this area Takes a schematic, non-exhaustive approach to summarize the most important research data in this field Includes a glossary, with a brief explanation of the term and with a reference to where the term or phrase has been used will be included within the book.
Read more Read less. Kindle Cloud Reader Read instantly in your browser. Editorial Reviews Review "This book is clearly presented with chapters by well-renowned contribution authors. Contains information on occupational exposure assessment and biomonitoring of exposure and adverse health effects of ENM Provides a critical discussion of commonly used in vitro and in vivo toxicity tests and of computational approaches to nanosafety Offers a systematic evaluation of the human organs and organ systems which may be affected by exposure to ENM Highlights current and future biomedical applications of nanoparticles in relation to nanosafety Provides global, clinical, occupational, and regulatory perspectives given the backgrounds of the well-renowned contributing authors and their expertise in health and safety issues related to ENM Related Titles: See all Editorial Reviews.
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Learn more about Amazon Giveaway. Exposure, Toxicology, and Impact on Human Health. Set up a giveaway. There's a problem loading this menu right now. Learn more about Amazon Prime. Get fast, free shipping with Amazon Prime. Get to Know Us. The framework also embraces research that feeds each of the elements of the risk assessment with the necessary information. For the current review, this framework provides a systematic method to work through the many issues surrounding the potential health effects of ENMs.
The first element, hazard identification, addresses whether there is any evidence that an agent causes an adverse effect. Hazard identification represents the lowest hurdle in the process, since the evidence could come from any number of sources, including laboratory or field observations, and might only be suggestive.
The next element, dose-response assessment, is more rigorous and asks whether there is a relationship between the dose of the agent and the incidence or magnitude of adverse effect. This element is based on the fundamental tenet in toxicology and pharmacology of dose response; that is, as the dose increases so does the effect. This information is often not directly available for humans, so laboratory animal studies are typically used.
Exposure assessment is the next element. If evidence indicates an agent poses a hazard, and the hazard is dose-related, the next step is to determine the extent of occupational or daily life exposure. Information from all elements is then combined into a risk characterization, which estimates the likelihood of an adverse effect occurring in the exposed population or a segment of the population. Risk assessment is regarded as a scientific undertaking whereas risk management uses the science to regulate exposure to the agent in ways that take into account social benefits, economic costs, and legal precedents for action.
The following sections are arranged to follow the NRC paradigm. Examples are given of adverse effects of ENMs to show why there may be reason for concern. Reports on exposure levels, the likelihood of adverse effects resulting from exposure, and options for minimizing risk are also summarized. This is not, however, an all-inclusive review of the literature; interested readers are referred to the reference section for a number of comprehensive reviews of many of the topics pertaining to ENMs and their effects.
In the occupational context, hazard identification can be re-stated as "What effects do ENMs have on workers' health? Workers within nanotechnology-related industries have the potential to be exposed to uniquely engineered materials with novel sizes, shapes, and chemical properties, at levels far exceeding ambient concentrations Information about ENMs might be obtained from well-documented retrospective analyses of unintended exposures. The most extensive exposures to ENMs likely occur in the workplace, particularly research laboratories; start-up companies; pilot production facilities; and operations where ENMs are processed, used, disposed, or recycled [ 51 ].
Occupational hygienists can contribute to the knowledge and understanding of ENM safety and health effects by thorough documentation of exposures and effects. It also illustrates the most likely paths of translocation re-distribution or migration , enabling ENMs to reach organs distal to the site of uptake. The four gray shaded boxes indicate the primary routes of ENM exposure. The arrows down from these uptake sites show potential translocation pathways. The translocation pathways are described in more detail in Section II, D.
Clearance of ENMs, their translocation to distal sites, and persistence. For example, the lung might be the primary route of exposure or might be a distal site after uptake from another route and translocation to the lung. ENMs might enter the brain from the nasal cavity or from blood, across the blood-brain barrier. The inhalation route has been of greatest concern and the most studied, because it is the most common route of exposure to airborne particles in the workplace.
The skin has also been investigated. Most studies have shown little to no transdermal ENM absorption. Direct uptake of nanoscale materials from the nasal cavity into the brain via the olfactory and trigeminal nerves has been shown. Each of these routes is discussed in more detail below. Routes that avoid first-pass clearance and metabolism in the gastrointestinal tract and liver include uptake absorption from the nasal cavity either into systemic circulation or directly into the brain , orotransmucosal e.
These routes may present a greater risk of ENM-induced adverse effects because more ENM is likely to reach the target organ s of toxicity. Hazard identification has revealed that the physico-chemical properties of ENMs can greatly influence their uptake. ENMs show greater uptake and are more biologically active than larger-sized particles of the same chemistry, due to their greater surface area per mass [ 52 , 53 ].
Additional ENM characteristics that may influence their toxicity include size, shape, surface functionalization or coating, solubility, surface reactivity ability to generate reactive oxidant species , association with biological proteins opsonization , binding to receptors, and, importantly, their strong tendency to agglomerate. An agglomeration is a collection of particles that are loosely bound together by relatively weak forces, including van der Waals forces, electrostatic forces, simple physical entanglement, and surface tension, with a resulting external surface area similar to the sum of the surface area of the individual components [ 9 , 54 ].
Agglomeration is different from aggregation. Aggregated particles are a cohesive mass consisting of particulate subunits tightly bound by covalent or metallic bonds due to a surface reconstruction, often through melting or annealing on surface impact, and often having an external surface area significantly smaller than the sum of calculated surface areas of the individual components [ 9 , 54 ].
Airborne ENMs behave very much like gas particles. Studies of ENMs in occupational settings showed airborne particulates were most commonly to and to nm [ 51 , 56 ]. ENMs also agglomerate in liquids, resulting in micrometer sized particles [ 57 ]. One study showed that concentration and smaller ENM size positively correlated with speed of agglomeration [ 58 ]. Changes in ENM surface area can profoundly uptake and effects. The aspect ratio length: Inhaled asbestos containing high aspect-ratio fibers is more toxic than lower aspect-ratio fibers.
Foreign materials are often cleared by macrophage phagocytosis, but when too large to be phagocytosed they are not effectively cleared from the lung. This results in release of inflammatory mediators, discussed below. A review concluded there is a critical size for ENMs at which new properties typically appear. Additionally, the optimal particle radius to accelerate adhesion to a cell-surface lipid bilayer is 15 and 30 nm for cylindrical and spherical particles, respectively [ 61 , 62 ].
Therefore, 10 to 30 nm diameter ENMs that have a spherical or similar shape appear to have the potential for more profound biological effects than either smaller or larger ENMs. Second generation active ENMs are being developed, such as targeted control-release systems for drugs.
There is utility in the use of CNTs as drug delivery systems. Additionally, observations of workers exposed to ENMs can greatly add to this understanding, to increase confidence in the predicted effects of future ENMs. ENMs are rapidly coated in biological milieu, primarily by proteins [ 62 , 64 - 66 ]. Due to high energetic adhesive forces close to the surface, ENMs can agglomerate and adsorb to the next available surface and other small molecules [ 67 ]. Similarly, addition of PEG to poly di-lactic acid-co-malic acid coated magnetic ENMs enhanced their uptake by macrophages [ 69 ].
Cells that line the airways produce mucus. Lung surfactants incorporate ENMs [ 71 , 72 ]. Mucus, which is secreted by goblet cells in the respiratory tract, eye, nasal cavity, stomach, and intestine, entraps ENMs [ 65 ]. All of these surface coatings on ENMs would be expected to affect their uptake and effects. To understand ENM-induced effects and their mechanisms of action, cells in culture and other in vitro systems have been utilized.
However, these systems cannot model the complexities of the entire organism, including the limitation of uptake provided by such barriers as the skin and first-pass metabolism, opsonization, metabolism that may inactivate or activate a substrate, translocation to distal sites, activation of homeostatic defenses, or inflammatory processes that release cytokines and other factors that can act at distant sites from their release.
Therefore, this review primarily cites examples of whole-animal studies to address ENM uptake and translocation. There has been much interest in the health effects of airborne particles, specifically PM 10 thoracic fraction , PM 2. One- to 5-nm air-suspended ENMs that enter the lungs are not predicted to reach the alveoli; instead a high percentage is likely to deposit in the mucus-lined upper airways tracheo-bronchial region due to their strong diffusion properties.
Deposition is greater during exercise. Chronic obstructive pulmonary disease increases tracheo-broncheolar and decreases alveolar particle deposition [ 74 , 75 ]. Uptake from the nasal cavity into the olfactory nerve, followed by retrograde axonal transport to the olfactory bulb and beyond, was shown in studies of the polio virus 30 nm and colloidal silver-coated gold 50 nm [ 76 - 78 ].
The increase of Mn in brain regions other than the olfactory bulb may have resulted from translocation to the brain by route s other than via the olfactory nerve, such as through cerebrospinal fluid or across the blood-brain barrier [ 80 ]. The nasal cavity is the only site where the nervous system is exposed directly to the environment. This is an often overlooked potential route of uptake of small amounts of ENMs into the brain.
Skin is composed of 3 primary layers, the outermost epidermis which contains the stratum corneum, stratum granulosum and stratum spinosum , dermis, and hypodermis. The hair follicle is an invagination of the stratum corneum, lined by a horny layer acroinfundibulum.
Adverse Effects of Engineered Nanomaterials : Exposure, Toxicology, and Impact on Human Health
Dermal uptake routes are intercellular, intracellular, and follicular penetration. Uptake is primarily by diffusion. Materials that penetrate the stratum corneum into the stratum granulosum can induce the resident keratinocytes to release pro-inflammatory cytokines. Materials that penetrate to the stratum spinosum, which contains Langerhans cells dendritic cells of the immune system , can initiate an immunological response.
This is mediated by the Langerhans cells, which can become antigen-presenting cells and can interact with T-cells. Once materials reach the stratum granulosum or stratum spinosum there is little barrier to absorption into the circulatory and lymphatic systems. Whereas dry powder ENMs pose a greater risk for inhalation exposure than those in liquids, liquid dispersed ENMs present a greater risk for dermal exposure. Consumer materials most relevant to dermal exposure include quantum dots, titania, and zinc oxide in sunscreens, and silver as an anti-microbial agent in clothing and other products.
Prolonged dermal application of microfine titania sunscreen suggested penetration into the epidermis and dermis [ 81 ]. However, subsequent studies did not verify penetration of titania from sunscreens into the epidermis or dermis of human, porcine or psoriatic skin [ 82 - 87 ], or find evidence of skin penetration of zinc oxide from sunscreen or positively- or negatively-charged iron-containing ENMs [ 88 , 89 ].
Nanoparticles with a dye penetrated deeper into hair follicles of massaged porcine skin in vitro and persisted longer in human skin in vivo than the dye in solution [ 82 , 90 , 91 ]. Thirty-nm carboxylated quantum dots applied to the skin of mice were localized in the folds and defects in the stratum corneum and hair follicles. A small amount penetrated as deep as the dermis. Ultraviolet radiation increased penetration, raising concern that these results might generalize to nanoscale sunscreens [ 92 ].
Cadmium, determined by ICP-MS, from cadmium-containing quantum dots was seen in liver, spleen, and heart; however, it is uncertain if this was from dissolved cadmium or translocation of the quantum dots because methods were not used to show the presence of quantum dots. The above results suggest topically-applied ENMs that penetrate to the dermis might enter the lymphatic system, and the ENMs or dissolved components distribute systemically [ 93 ]. To address these concerns ENMs intended for dermal application, such as titania, are often surface coated, e.
One goal of the surface treatments is to minimize toxicity by trapping the free radicals of reactive oxygen species ROS [ 94 ]. An in vitro study showed that mechanical stretching of human skin increased penetration of and nm fluorescent dextran particles through the stratum corneum, with some distribution into the epidermis and dermis [ 95 ].
Similarly, mechanical flexing increased penetration of a 3. The contribution of skin flexing and immune system response was further addressed with three titania formulations applied to minipigs. There was some ENM penetration into epidermis and abdominal and neck dermis, but no elevation of titanium in lymph nodes or liver [ 97 ]. Topical exposure of mice to SWCNTs resulted in oxidative stress in the skin and skin thickening, demonstrating the potential for toxicity not revealed by in vitro studies of ENM skin penetration [ 98 ].
There are no reports of long-term studies with topical ENM exposure. In the absence of organic solvents, the above suggests that topically applied ENMs do not penetrate normal skin. As the fullerenes were not detected in systemic circulation, there was no evidence of systemic absorption. Little is known about the bioavailability of ENMs from the buccal cavity or the sub-lingual site, or possible adverse effects from oral ingestion.
Particle absorption from the intestine results from diffusion though the mucus layer, initial contact with enterocytes or M microfold or membranous specialized phagocytic enterocyte cells, cellular trafficking, and post-translocation events [ ]. Colloidal bismuth subcitrate particles 4. Particles appeared to penetrate only in regions of gastric epithelial disruption [ ]. Greater uptake of 50 to 60 nm polystyrene particles was seen through Peyer's patches and enterocytes in the villous region of the GI tract than in non-lymphoid tissue, although the latter has a much larger intestinal surface area [ , ].
Peyer's patches are one element of gut-associated lymphoid tissue, which consist of M cells and epithelial cells with a reduced number of goblet cells, resulting in lower mucin production [ , ]. The mechanism of GI uptake of 4, 10, 28 or 58 nm colloidal maltodextran gold ENMs from the drinking water of mice was shown to be penetration through gaps created by enterocytes that had died and were being extruded from the villus. Gold abundance in peripheral organs inversely correlated with particle size [ ].
The absorption site seems to be regions of compromised gastric epithelial integrity and low mucin content. Ocular exposure might occur from ENMs that are airborne, intentionally placed near the eye e. This route of exposure could result in ENM uptake through the cornea into the eye or drainage from the eye socket into the nasal cavity through the nasolacrimal duct.
Other than a study that found uptake of a polymer ENM into conjunctival and corneal cells, this route has been largely ignored in research studies of ENM exposure [ ]. Public concerns about ENMs and health may arise with reports of some effect s in a laboratory study or their presence in human tissue or another organism. Any report must be interpreted carefully before concluding ENMs are risky for one's health. To start with, risk is defined as a joint function of a chemical's ability to produce an adverse effect and the likelihood or level of exposure to that chemical.
In a sense, this is simply a restatement of the principle of dose-response; for all chemicals there must be a sufficient dose for a response to occur. Additionally, advances in analytical chemistry have led to highly sensitive techniques that can detect chemicals at remarkably low levels e. The detectable level may be far lower than any dose shown to produce an adverse effect.
Further, a single finding in the literature may garner public attention, and it may be statistically significant, but its scientific importance remains uncertain until it is replicated, preferably in another laboratory. The above discussion reflects many of the issues that have gained prominence in the fields of risk perception and risk communication see for example [ , ] , neither of which were dealt with by the NRC in their landmark publication. The knowledge of ultrafine-particle health effects has been applied to ENMs.
However, the toxicity from ultrafine materials and ENMs is not always the same [ ]. For example, toxicity was greater from cadmium-containing quantum dots than the free cadmium ion [ ]. Some metal and metal oxide ENMs are quite soluble e. Studies of ENM inhalation and intratracheal instillation as well as with lung-derived cells in culture have increased concern about potential adverse health effects of ENMs.
SWCNTs containing residual catalytic metals produced greater pulmonary toxicity, including epithelioid granulomas and some interstitial inflammation, than ultrafine carbon black or quartz. These effects extended into the alveolar septa [ ]. A review of eleven studies of carbon nanotube introduction to the lungs of mice, rats, and guinea pigs revealed most found granuloma, inflammation, and fibrosis [ ]. MWCNTs produced greater acute lung and systemic effects and were twice as likely to activate the immune system as SWCNTs, suggesting the former have greater toxic potential [ ].
Further adding to the concern of ENM-induced adverse health effects are reports that inhaled CNTs potentiate airway fibrosis in a murine model of asthma [ ], and that exposure of a cell line derived from normal human bronchial epithelial BEAS-2B cells to SWCNTs and graphite nanofibers produced genotoxicity and decreased cell viability [ ]. However, a point of contention is that the lung response to intratracheal and inhaled MWCNTs differed among studies. These differences create uncertainties regarding the utility of some routes of pulmonary ENM exposure used in laboratory studies to predict potential toxicity in humans [ ].
Studies exposing lung-derived cells in culture to ENMs have demonstrated similar effects. Carbon-based ENMs produced pro-inflammatory, oxidative-stress, and genotoxic effects [ , ]. Several groups have studied the effects of CNT introduction into the peritoneal cavity. Clearance of ENMs, their translocation to distal sites, and persistence , and the internal surfaces of the peritoneal and pleural cavities are lined with a mesothelial cell layer, responses in the peritoneal cavity appear to be relevant to the pleural cavity. Toxicity has also been seen from pulmonary introduction of metal and metal oxide ENMs.
Ten and 20 nm anatase titania induced in BEAS-2B cells oxidative DNA damage, lipid peroxidation, increased H 2 O 2 and nitric oxide production, decreased cell growth, and increased micronuclei formation indicating genetic toxicity [ 52 ]. Exposure of BEAS-2B cells to to nm ceria or nm titania resulted in an increase of ROS, increased expression of inflammation-related genes, induction of oxidative stress-related genes, induction of the apoptotic process, decreased glutathione, and cell death [ , ]. Various metal oxides differentially inhibited cell proliferation and viability, increased oxidative stress, and altered membrane permeability of human lung epithelial cells [ ].
They displayed extracellular release of H 2 O 2 and the superoxide radical and hyper-polarization of mitochondrial membrane potential [ ]. Intravenous ceria administration to rats altered brain oxidative stress indicators and anti-oxidant enzymes [ 23 , ]. These results demonstrate the ability of metal oxide ENMs to produce neurotoxicity.
Potential toxicity from dermal exposure was demonstrated with silver ENMs, that decreased human epidermal keratinocyte viability [ ]. These results demonstrate the ability of metal oxide ENMs to also produce dermatotoxicity. Common findings of many studies are induction of inflammatory processes and oxidative stress.
However, correspondence between responses of cells in culture and in vivo models is often low [ 24 , 43 ]. In light of the pressure to minimize whole animal e. Additionally, there has been considerable use of alternative model organisms e. Dose or concentration may not be the best metric to predict ENM effects [ 42 , 53 , ]. Neutrophil influx following instillation of dusts of various nanosized particles to rats suggested it may be more relevant to describe the dose in terms of surface area than mass [ ].
The pro-inflammatory effects of in vitro and in vivo nanoscale titania and carbon black best correlated when dose was normalized to surface area [ ]. Secretion of inflammatory proteins and induction of toxicity in macrophages correlated best with the surface area of silica ENM [ ]. Analysis of in vitro reactive oxygen species generation in response to different sized titania ENMs could be described by a single S-shaped concentration-response curve when the results were normalized to total surface area, further suggesting this may be a better dose metric than concentration [ 53 ].
7 editions of this work
Similarly, using surface area as the metric, good correlations were seen between in vivo PMN number after intratracheal ENM instillation and in vitro cell-free assays [ 42 ]. Nonetheless, most studies of ENMs have expressed exposure based on dose or concentration. The relatively small amount of literature has generally shown dose- or concentration-response relationships, as is usually the case for toxicity endpoints. Ceria ENM uptake into human lung fibroblasts was concentration-dependent for several sizes, consistent with diffusion-mediated uptake [ 58 ].
Positive, dose-dependent correlations were seen in blood, brain, liver, and spleen following iv ceria infusion in rats, measured by elemental analysis as cerium [ 23 ], as well as brain titanium after ip titania injection [ ], and lung cobalt after inhalation of cobalt-containing MWCNTs [ ]. Concentration-dependent inhibition of RAW Activated Kupffer cell count increased with iv ceria dose; the increase in hippocampal 4-hydroxy trans -nonenal and decrease in cerebellar protein carbonyls indicators of oxidative stress were dose-dependent up to a maximum that did not increase further at the highest dose [ 23 ].
Some studies demonstrating adverse effects of CNT introduction to the lung have been criticized for using doses or concentrations that far exceeded anticipated human exposure [ ]. Most studies assessing potential adverse effects of ENMs have utilized a single exposure. Both of these features make extrapolation of results to prolonged or episodic periodic human exposure difficult.
When adverse effects are seen following some reasonable e. As with the above studies that inform about uptake, the clearance and translocation of ENMs from the initial site of exposure to distal sites is best understood from whole-animal studies. The solutes of dissolved particles in the lung can transfer to blood and lymphatic circulation. Some ENMs in the airway wall that slowly dissolve or are insoluble will be cleared within a few days from the lung by cough or the mucociliary escalator. Slowly dissolving and insoluble ENMs that reach the alveoli may be taken up by macrophages.
Macrophage-mediated phagocytosis is the main mechanism for clearing foreign material from the deep lungs alveoli and from other organs. They engulf the particle in a vacuole phagosome containing enzymes and oxidizing moieties that catabolize it. Particles resistant to catabolism may remain inside the macrophage. After the death of the macrophage the material may be engulfed by another cell. Therefore, it may take a long time for insoluble material to be cleared from the body. The elimination half-live of insoluble inert particles from the lung can be years [ ].
This raises the question of the ultimate fate of "poorly digestible" ENMs that are engulfed by macrophages in the lung, liver Kupffer cells , brain microglia , and other organs. Alveolar macrophages that cannot digest high-aspect-ratio CNTs termed "frustrated phagocytosis" can produce a prolonged release of inflammatory mediators, cytokines, chemokines, and ROS [ ].
This can result in sustained inflammation and eventually fibrotic changes. Studies have demonstrated MWCNT-induced pulmonary inflammation and fibrosis, similar to that produced by chrysotile asbestos and to a greater extent than that produced by ultrafine carbon black or SWCNTs [ ]. Greater toxicity from a high-aspect-ratio metal oxide titania ENM has also been shown in cells in culture and in vivo [ ]. Studies such as these have raised questions and concern about the long-term adverse effects of ENM exposure.
Translocation of ENMs from the lung has been shown. After MWCNT inhalation or aspiration they were observed in subpleural tissue, the site of mesotheliomas, where they caused fibrosis [ , ]. Once ENMs enter the circulatory system across the 0. Thirty to 40 nm insoluble 13 C particles translocated, primarily to the liver, following inhalation exposure [ ].
Similarly 15 and 80 nm iridium particles translocated from lung to liver, spleen, heart, and brain. ENMs have also been shown to translocate following injection. Indirect evidence was shown of fullerene distribution into, and adverse effects in, the fetus 18 h after its injection into the peritoneal cavity of pregnant mice on day 10 of gestation [ ]. Following subcutaneous injection of commercial 25 to 70 nm titania particles into pregnant mice 3, 7, 10, and 14 days post coitum, aggregates of to nm titania were seen in the testes of offspring at 4 days and 6 weeks post-partum and in brain at 6 weeks post-partum.
Abnormal testicular morphology and evidence of apoptosis in the brain indicated fetal titania exposure had adverse effects on development. The authors attribute these effects to ENM translocation across the placenta [ ]. ENM excretion into milk and oral absorption post-partum might contribute to ENM presence in the offspring, but we are unaware of any studies assessing ENM translocation into milk. Non-protein bound substances generally enter milk by diffusion, and reach an equilibrium between milk and blood based on their pKa and the pH difference between blood and milk, described by the Henderson-Hasselbalch equation.
Given the size of most ENMs, it is unlikely they would diffuse across the mammary epithelium. Within 40 weeks after a single intrascrotal injection of MWCNTs most rats died or were moribund with intraperitoneal disseminated mesothelioma, which were invasive to adjacent tissue, including the pleura. The distribution of carbon-, metal- and metal oxide-based ENMs after translocation from the lung, skin or intestine is similar to that seen after their iv administration. They generally appear as agglomerates in the liver and spleen [ 23 , 93 , , , - ].
The ENMs are usually in the cytoplasm, with little indication that they enter the nucleus [ , , - ]. Due to their small size ENMs may gain access to regions of the body that are normally protected from xenobiotics sanctuaries , such as the brain. This feature has suggested their potential application for drug delivery to the brain, which is being extensively pursued [ - ], but at the same time it raises concern about central nervous system distribution of ENMs when exposure is not intended. Anionic polymer ENMs entered the brain more readily than neutral or cationic ones.
Both anionic and cationic ENMs altered blood-brain barrier integrity [ ]. The persistence of ENMs may be a major factor contributing to their effects. Many ENMs are designed to be mechanically strong and resist degradation [ 22 ]. Referring to nanoscale fiber-like structures, it has been stated: The analogy of high-aspect-ratio ENMs to asbestos is one of the contributors to this concern. The prolonged physical presence of ENMs, that are not metabolized or cleared by macrophages or other defense mechanisms, appears to elicit ongoing cell responses. The majority of CNTs are assumed to be biopersistent.
For example, two months after the intratracheal instillation of 0. Following oral administration, nm non-ionic polystyrene ENMs were seen in mesenteric lymphatic tissues, liver, and spleen 10 days later [ ]. Following iv administration, carboxylated-MWCNTs were cleared from circulation and translocated to lung and liver; by day 28 they were cleared from the liver, but not from the lung [ ]. No significant decrease of the amount mass of cerium was seen in the liver or spleen of rats up to 30 days after iv administration of 5 or 30 nm ceria.
Hepatic granuloma and giant cells containing agglomerates in the cytoplasm of the red pulp and thickened arterioles in white pulp were seen in the spleen unpublished data, R. Yokel [ , ].
In summary, the persistence of ENMs in tissue raises justifiable concerns about their potential to cause long-term or delayed toxicity. Many surface coatings have been investigated in order to develop ENMs as carriers for drug delivery. Surface modifications can prolong ENM circulation in blood, enhance uptake at a target site, affect translocation, and alter excretion.
When ENMs enter a biological milieu they rapidly become surface coated with substances such as fulvic and humic acids and proteins, all of which can alter their effects [ , , ]. The abundance of plasma proteins on gold approximated their abundance in plasma, whereas some proteins were highly enriched on titania [ ]. Metal oxide and carbon-based ENMs rapidly adsorb proteins [ 66 ], resulting in changes in their zeta potential electrical potential at the ENM surface and toxicity [ , ].
For circulating ENMs, the surface coating is extremely important, because this is what contacts cells [ ]. Although it is understood that ENMs will be surface coated with proteins, lipids or other materials, which may or may not persist on the ENM surface when they enter cells, little is known about the surface associated molecules on ENMs within cells. It is likely, however, that surface coatings profoundly influence ENM effects within cells. Although surface functional groups are known to modify ENM physico-chemical and biological effects, there is little information on the influence of functional groups on health effects.
This further complicates the prediction of ENM toxicity in humans from in vitro , and perhaps in vivo , studies. Reported systemic effects of pulmonary-originating CNTs include acute mitochondrial DNA damage, atherosclerosis, distressed aortic mitochondrial homeostasis, accelerated atherogenesis, increased serum inflammatory proteins, blood coagulation, hepatotoxicity, eosinophil activation suggesting an allergic response , release of IL-6 the main inducer of the acute phase inflammatory response , and an increase of plasminogen activator inhibitor-1 a pro-coagulant acute phase protein [ ].
The translocation of ENMs and their release of cytokines and other factors could potentially affect all organ systems, including the brain. For example, daily ip injection of titania for 14 days resulted in a dose-dependent increase of titanium and oxidative stress and a decrease of anti-oxidative enzymes in the brain of rats [ ]. As particle size decreases and surface area increases, the ease of ignition and the likelihood of a dust explosion increase.
The latter may create a second hazard due to increased ENM release. There are no reports that ENMs have been used intentionally, e. Not much is known about the extent of occupational exposure to ENMs. There is obvious value in conducting exposure assessments in the workplace to identify the routes, extent, and frequency of ENM exposure. In assessing worker exposure, the traditional industrial hygiene sampling method of collecting samples in the breathing zone of the worker personal sampling is preferred over area sampling.
Only a few of the studies cited [ 51 ] conducted breathing zone measurements. On the other hand, area samples e. When monitoring potential workplace exposure to ENMs it is critical that background nanoscale particle measurements be conducted before their production, processing, or handling in order to obtain baseline data.
Engineered nanomaterials: exposures, hazards, and risk prevention
Nanosize particles frequently come from non-ENM sources, such as ultrafines from internal combustion engines and welding [ , ]. An early study of SWCNT release during its handling in the workplace showed very low airborne concentrations of agglomerated material [ ]. The rapid agglomeration of ENMs in air has been repeatedly shown [ 55 , , ]. Airborne ENMs associate with other airborne materials when present, or self-associate in their absence. Once formed there was little decrease in the resultant airborne agglomerations for up to 4 h [ 55 ]. Surface samples had up to fold more total carbon than the office floor [ ].
Another study showed that wet cutting of a hybrid CNT in an epoxy resin or in a woven alumina fiber cloth using a cutting wheel with water to flush dust particles produced no significant increase of airborne 5- to nm particles in the operator breathing zone, whereas dry machining did [ ]. Production of a nanocomposite containing alumina in a polymer by a twin-screw extrusion process caused release of 5- to nm and to nm alumina in the worker's breathing zone [ ].
Covering the top of the feeding throat and the open mouth of the particle feeder, thorough cleaning by washing the floor, and water-based removal of residual dust on all equipment significantly decreased airborne particles [ , ]. These results suggest that some engineering controls may be appropriate to safely remove some airborne ENMs, including maintaining the room at negative pressure relative to the outside, avoiding the handling of dry ENMs, adequate ventilation, and containment of the ENM material during its use.
They used the technique to determine particle number concentrations using two hand-held, direct-reading, particle number concentration-measuring instruments, a condensation and an optical particle counter, to survey 12 sites working with ENMs. This was complemented by collection of particles on filters and transmission electron microscopic visualization.
The results demonstrated the utility of NEAT and, in some cases, the source of ENM release and efficacy of engineering controls [ ]. Engineering controls are discussed in more detail below. There are numerous reports of adverse lung effects, and some reports of human deaths, from nanosized polymer fumes [ 26 ]. Two deaths were reported among seven to year-old female workers exposed to polyacrylate nanoparticles for 5 to 13 months. Cotton gauze masks were the only PPE used, and were used only occasionally. The workplace had one door, no windows, and no exhaust ventilation for the prior 5 months [ ].
Workers presented with dyspnea on exertion, pericardial and pleural effusions, and rash with intense itching. Spirometry showed that all suffered from small airway injury and restrictive ventilatory function; three had severe lung damage. Non-specific pulmonary inflammation, fibrosis, and foreign-body granulomas of the pleura were seen. Two workers died of respiratory failure. Although presented as the first report of clinical toxicity in humans associated with long-term ENM exposure, many experts have expressed uncertainty that ENMs contributed to these outcomes [ 22 , , ].
Given the poor environmental conditions of the workplace and lack of effective PPE use, these outcomes could probably have been prevented. The giant insurance firm Lloyd's of London conducted a risk assessment and concluded "Our exposure to nanotechnology must therefore be considered and examined very carefully" [ http: Japan's Ministry of Health, Labour and Welfare funded studies starting in to establish health risk assessment methodology of manufactured nanomaterials.
However, a new study incorporated a physiologically-based lung model and data of particle sizes of airborne titania ENM during manufacturing to estimate anatase and rutile titania ENM burdens and adverse effects in lung cells.
1. Introduction
The authors concluded that workers exposed to relatively high airborne to nm anatase titania are unlikely to have substantial risk for lung inflammatory responses, but are at risk for cytotoxicity [ ]. Risk characterization and assessment and gap analysis case studies were conducted with fullerenes, CNTs, silver as a example of a metal, and titania as an example of a metal oxide ENM [ ].
Numerous additional data gaps were identified for each. There are no existing regulations or standards for ENMs within the three jurisdictions that have the largest nanotechnology funding, the U. The respiratory protection standard requires employers provide workers with NIOSH-certified respirators or other PPE when engineering controls are not adequate to protect health. Suggested implementation includes many of the primary prevention measures discussed in this review and an occupational health surveillance program of exposure and medical monitoring.
The goal in managing the potential risks from ENMs is to minimize exposure. In the absence of specific information on ENMs, the extensive scientific literature on airborne, respirable aerosols and fibers has been used to develop interim guidance for working safely with ENMs [ ] [ http: Occupational health surveillance, which includes hazard and medical surveillance, is the process whereby information from any of these activities is collected and used to support or modify what is done at a higher step in the hierachy, as shown by the upward pointing arrow [ ].
Those steps in the hierachy that have been investigated for ENMs are further discussed below. Elements of occupational health protection. The continuum of prevention and the heirarchy of exposure control left arrow and occupational health surveillance right arrow. Adapted from [ ] and [ ]. ENM exposure can be reduced through the use of engineering controls, such as process changes, material containment, and enclosures operating at negative pressure compared to the worker's breathing zone; worker isolation; separated rooms; the use of robots; and local exhaust ventilation LEV.
Given the lack of occupational exposure standards to provide guidance, the most prudent approach is to minimize exposure. A survey found that engineering controls in Switzerland were more commonly used in the production of powder than liquid ENMs. It is anticipated that as this industry matures and knowledge is gained, control will more commonly include superior methods in the hierarchy of exposure control [ ].
Some companies a minority were using inappropriate occupational environmental clean-up methods, such as sweeping and compressed air [ ]. These results suggest more widespread adoption of nano-specific environmental health and safety programs and the use of PPE in the absence of superior controls are appropriate. However, one should also consider that these methods can release ENMs into the environment, potentially creating environmental pollution and loss of costly material.
ENM handling is often conducted in fume hoods. Field sampling conducted to determine fume hood, work zone, and background concentrations of PM 2. Monitoring aerosolized particles during chemical vapor deposition CVD SWCNT synthesis and aerosol-assisted CVD MWCNT synthesis in a fume hood showed significant release at the source, but not outside of the hood, suggesting fume hood use did not create fugitive airborne emissions and was necessary to protect workers [ ].
These authors also determined the release of dry powder alumina 27 to 56 nm primary particle size, nm agglomerates and 60 nm silver ENM into the researcher's breathing zone and laboratory environment when poured or transferred in 3 fume hoods; 1 a conventional hood that has a constant air flow with velocity inversely related to sash height, 2 a by-pass hood which attempts to maintain a constant velocity by use of a by-pass grill above the hood which becomes uncovered, allowing more air flow through it rather than the hood face as the sash is lowered, and 3 a constant velocity variable air volume hood that uses a motor to vary fan speed as the sash is moved.
The results showed significant release of ENMs into the researcher's breathing zone and laboratory environment and identified the variables affecting release. The constant velocity hood performed better than the by-pass hood, which in turn performed better than the conventional hood [ ]. The newly developed air-curtain hood is evidently not commercially available. The results showed much lower levels with the air curtain hood [ ]. Sash height, which affected hood face velocity, affected ENM release.
Worker motion and body size affected ENM release from a traditional, but not the air-curtain, hood. The authors found that ENM handling in traditional fume hoods with a face velocity of 0. In the Center for High Rate Manufacturing recommended locating equipment at least 6 inches 15 cm behind the sash, minimizing hood clutter, and avoiding rapid or violent motions while working in the hood [ ].
In a study conducted in an industrial setting, use of an exhaust hood during procedures that are more likely to release ENMs their production, handling, measurement, and reactor cleanout resulted in no significant increase of ENMs in the workplace [ ]. These studies show that significant reduction of worker exposure to ENMs can be achieved using available fume hoods and consideration of worker activities within these hoods.
It has an all stainless steel interior for ease of cleaning, perforated rear baffle to reduce turbulence, and a replaceable HEPA filter. It is available with a built-in ionizer to attract particles to the interior surface of the hood, and an external exhaust for volatiles. Air-displacement ventilation in an industrial setting was accomplished by introduction of supply air that entered at low velocity at the floor level and was cooler than room air.
As the air rose it became warmer and was exhausted close to the ceiling. This provided efficient clearing of ENMs from the breathing zone [ ]. A well-designed exhaust ventilation system with a HEPA filter should effectively capture airborne nanoparticles. A "down flow" booth, "elephant trunk", or fume hood may not provide sufficient protection because they may cause turbulence, spinning the ENM out of the airflow [ ].
The effectiveness of engineering controls in ENM production and research facilities has been demonstrated in a few cases. Prior to use of engineering-control measures, total airborne mass concentrations of MWCNTs, measured by area sampling, were 0. After enclosing and ventilating the blending equipment and re-locating another piece of equipment that produced considerable vibration, the concentration decreased to below the limit of detection [ ]. In another study, the effectiveness of LEV was assessed during clean-out of slag and waste, which used brushes and scrapers, of reactors that produced 15 to 50 nm diameter ENMs.
A portable LEV unit was used that had been shown to reduce welding fume exposure [ ]. The poor performance of the custom fume hood may have been due to the lack of a front sash and rear baffles, and to low face velocity 0. Respirable particles were an order of magnitude lower when the work was conducted in a BSC than on a work table [ ]. These results illustrate the importance of good exhaust hood design as well as the worker protection provided by a BSC.
When engineering controls are not feasible for reducing exposure, administrative controls should be implemented. These are policies and procedures aimed at limiting worker exposure to a hazard [ ]. These could include a nanoscale material hygiene plan; preparation, training in, and monitoring use of standard operating procedures; reduction of exposure time; modification of work practices; and good workplace and housekeeping practices. For example, one laboratory was thoroughly cleaned after high air concentrations of nanoscale materials were measured in a facility engaged in the commercial compounding of nanocomposites [ ].
A large decrease of airborne 30 to nm particles resulted. Subsequent routine maintenance kept the particles below those originally observed, leading the authors to conclude that this administrative control was beneficial in reducing potential exposure. It is discussed below. The last line of defense in the hierarchy of exposure control is the use of PPE, such as respirators, protective clothing, and gloves. The filter's resistance to oil is designated as N, R, and P; N not resistant to oil , R resistant to oil , and P oil proof.
Some industrial oils can remove electrostatic charges from filter media, reducing filter efficiency. Airborne nanoparticles behave much like gas particles. Charged particles are trapped by electrostatic attraction, which involves an electrically charged particle and an electrically charged electret fiber. Electret filters are constructed from charged fibers.
This appears to be a significant mechanism for respirator trapping of ENMs [ ]. Neutral particles that pass through a charged fiber can be polarized by the electric field, thereby inducing charge to the particle. In dry conditions, ENM penetration decreases with time. With continued use, however, ENM penetration through an electrostatic filter increases; this was suggested to be due to the humidity of exhalation [ ].
Soaking fiber filters in isopropanol removes electrostatic charge. The mechanisms of ENM association with fiber materials. Each panel shows particles carried by airstreams, indicated by the bands with right pointing arrows. Some particles are retained by the fiber. Those that are not continue on the airstream past the fiber. The upper panel shows a large particle that is unable to follow the airstream around the fiber and collides with the fiber due to inertial impaction. The particle trapped by interception comes close enough to the fiber within the particle radius that it is captured by the fiber.
Electrostatic attraction is discussed in the text VI, C, 1. Small particles collide with each other, gas molecules, and other suspended matter in the air stream, resulting in Brownian motion and a random zigzagging path of movement, which may cause the particle to hit the fiber, as shown in the diffusion panel. Most of the studies were conducted with different sizes of NaCl, but a few used silver, graphite or titania.
The results show that dust masks purchased at hardware or home improvement stores would not be expected to protect the wearer. Increasing flow rate increased penetration.
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This highest flow rate was intended to model an instantaneous peak inspiratory flow during moderate to strenuous work. A similar result of ENM penetration positively correlating with air flow rate is shown in Panel F, where 5. Particle penetration through dust masks and facepiece respirators. Circle Results from 6 3M Engineered nanoparticles and particulate respirators [ http: N95 respirators at two flow rates.
Panel G shows greater penetration of titania than graphite through FFP3 respirators under the same experimental conditions. These results suggest further work is warranted to understand the influence of the physico-chemical properties of ENMs, particularly size, charge, and shape, on their penetration through filtering facepiece respirators.
An issue that significantly impacts filtering facepiece respirator effectiveness is its seal around the face. Shaffer quoted in [ ]. This underscores the importance of a proper fit for face mask respirators. There is a particle size that maximally penetrates each filter material; the most penetrating particle size MPPS. This is approximately the same size of spherical ENMs that appear to contribute to their greatest differences in biological systems from solution and bulk forms of the same materials, as discussed in II, A, 2.
This feature raises concern because the size of ENMs that may have the greatest effects in people are those that are best able to penetrate filtering facepiece respirators.
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Until results are obtained from clinical-laboratory or work-place studies, traditional respirator selection guidelines should be used. Recommendations for selection, use, care and maintenance. No guidelines are available on the selection of clothing or other apparel e. This is due in part to the minimal data available on the efficacy of existing protective clothing, including gloves.
Pore structure of the various fabrics greatly influenced penetration [ ]. Although nonwoven fabrics were much more effective to protect workers from ENM exposure than woven fabrics, they are much less comfortable to wear, suggesting improvements in fabric design or selection are needed to address this disincentive to use more effective PPE.
The selection of laboratory coat materials can greatly influence the potential penetration of ENMs, which may end up on or penetrating street clothing, resulting in worker absorption or their even greater dispersion into the environment. An unpublished study reported in the interaction of alumina and organoclay ENMs with powder-free natural rubber latex, powder-free synthetic latex nitrile, and cotton gloves [ ]. Although these surface imperfections were not complete holes, they may serve as pathways for the penetration of nanoparticles under unfavorable conditions, such as stretching and tearing.
The surface pores may be important if they collect nanoparticles and the user does not remove the gloves when going to another location, thereby transporting the ENMs. Not surprisingly, there were wider gaps between the fibers in cotton gloves. The authors pointed out that ENMs may be treated with special coatings to enhance their dispersion characteristics, which may alter their permeability through glove materials. This study, however, did not determine the penetration of ENMs through gloves.
Double gloving has been suggested [ ], which should reduce material penetration when there is glove perforation as well as dermal contamination when removing a contaminated outer glove. However, double gloving has not been shown to significantly decrease material penetration [ ]. Occupational health surveillance is the ongoing systematic collection, analysis, and dissemination of exposure and health data on groups of workers for the purpose of early detection and injury.
It includes hazard surveillence, the periodic identification of potentially hazardous practices or exposures in the workplace, assessing the extent to which they can be linked to workers, the effectiveness of controls, and the reliability of exposure measures. A goal is to help define effective elements of the risk management program for exposed workers.
Occupational health surveillance also includes medical surveillance, which examines health status to determine whether an employee is able to perform essential job functions [ ]. This is different than medical screening or monitoring, a form of medical surveillance designed to detect early signs of work-related illness by administering tests to apparently healthy persons to detect those with early stages of disease or those at risk of disease. The third level in the continuum of prevention and heirarchy of exposure control, tertiary prevention, includes diagnosis, therapy, and rehabilitation.
Owing to the lack of documented episodes of ENM exposure in humans that have resulted in adverse outcome, there is little experience with treatments of ENM exposure. One example that illustrates clever application of the knowledge of ENM properties was the use of UV light to visualize and treat the accidental dermal exposure of a human to quantum dots suspended in solution [ ]. Based on the current knowledge of ENM exposure risks, some good workplace practices have been suggested.
They are shown in Appendix 1. The investigators established a measure of risk for each potential hazard and suggested improvement actions. These were then addressed with administrative controls, environmental monitoring, PPE and good workplace practices. The following are some published guidelines, not regulations, for safe handling and use of ENMs. Guidelines for safe research practices" as their Safety Net guidelines [ http: