Abstract  This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-silver based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also (uncontrolled) nano-silver drug intake and burn treatment of large parts of the body with wound dressings may cause risks. Main future work should focus on generating occupational and consumer exposure data, as well as toxicity data on absorption (are particles or only ions absorbed?), information on genetoxicity, and further information on the toxicity following inhalation exposure to sizes and agglomeration states as uncounted in the workplace.

Abstract  Some adjustments are needed in the European chemicals legislation REACH to assess and control the risks of nanomaterials. The information on substances to be provided under REACH is not sufficient to determine the specific properties of nanomaterials, nor to assess how these properties affect their behaviour and effects in humans and the environment. RIVM concluded this following research into the suitability of REACH for nanomaterials. RIVM therefore proposes an adapted set of minimum information requirements, to be applied to all nanomaterials to be registered under REACH, independent of their volume of production and import. These requirements allow a risk assessment of nanomaterials. Over the last years the use of nanomaterials has strongly increased. As yet, nanomaterials are defined as substances of which the discrete parts have at least one dimension smaller than one hundred nanometres. Due to their nanosize they have specific properties. Legislation should focus on controlling the potential hazards and risks of these nanomaterials. By conducting a hypothetical registration of nanosilver it was investigated whether REACH is suitable for assessing the safe use of nanomaterials. From this it appeared that no definition of a nanomaterial is present, and that a relevant measure for expressing harmfulness and exposure is as yet not known. In addition, the standard information requirements are insufficient to assess hazard and exposure. They are also insufficient for a proper characterisation of the nanomaterial. Consequently, it cannot be determined to what extent the nanoform of a substance corresponds to the non-nanoform of the same substance. Furthermore, it is unclear whether current risk reduction measures and extrapolation methods in risk assessment, as established for non-nanomaterials, are applicable to nanomaterials.

Abstract  Algal bioassays for heavy metals can detect low levels in the environment, for example, 0.01 ppm for silver. Algae respond to increasing levels of heavy metals such as copper, nickel, mercury, silver, or cadmium by reduction of growth rate. Occasionally, the response to nontoxic metals is an increase in growth rate. At very low concentrations some potentially toxic metals may be necessary micronutrients. Algal species differ quite markedly in their sensitivity to heavy metals. Combined effects of two or more metals at toxic concentrations may be synergistic (for example, copper-nickel) or antagonistic (for example, cadmium-selenium). The critical concentrations for toxicity of a particular metal may be different at different times during the growth of an algal culture, as well as being dependent upon other chemical and physical conditions. Algal cells appear to markedly concentrate metals from solution, even at concentrations of these metals in the medium which do not apparently inhibit cell division. Bioassays provide the only direct method for assessing the biological availability of metals in solution. Algae isolated from metal-polluted lakes appear to have evolved specific metal tolerances. These "tolerant" algae actually accumulate more of the metals concerned than do their "nontolerant" relatives. Correlations between fish toxicity tests and algal bioassays may allow the relatively expensive fish testing schemes to be replaced by simple and cheaper algal bioassays.

Abstract  The report was a result of an effort by experts from government, industry and the public interest community to examine the path of a number of hypothetical nanotechnology food packaging applications through the current regulatory system. The regulatory system for food packaging is scientifically rigorous and extraordinarily complex, both legally and scientifically. This first-of-its-kind analysis provides a better understanding of the potential regulatory issues on the horizon for nanotechnology-enabled packaging – an advantage for industry, consumers and regulatory agencies such as FDA and the Environmental Protection Agency (EPA).

Abstract  Exposure assessment is crucial for risk assessment for nanomaterials. We propose a framework to aid exposure assessment in consumer products. We determined the location of the nanomaterials and the chemical identify of the 580 products listed in the inventory maintained by the Woodrow Wilson International Center for Scholars, of which 37% used nanoparticles suspended in liquids, whereas <1% contained "free airborne nanoparticles". C(60) is currently only used as suspended nanoparticles in liquids and nanosilver is used more as surface bound nanoparticles than as particles suspended in liquids. Based on the location of the nanostructure we were able to further group the products into categories of: (1) expected, (2) possible, and (3) no expected exposure. Most products fall into the category of expected exposure, but we were not able to complete a quantitative exposure assessment mainly due to the lack of information on the concentration of the nanomaterial in the products--a problem that regulators and industry will have to address if we are to have realistic exposure assessment in the future. To illustrate the workability of our procedure, we applied it to four product scenarios using the best estimates available and/or worst-case assumptions. Using the best estimates available and/or worst-case assumptions we estimated the consumer exposure to be 26, 15, and 44 microg kg(-1) bw year(-1) for a facial lotion, a fluid product, and a spray product containing nanoparticles, respectively. The application of sun lotion containing 2% nanoparticles result in an exposure of 56.7 mg kg(-1) bw d(-1) for a 2-year-old child, if the amounts applied correspond to the European Commission recommendations on use of sunscreen.

Abstract  There is an emerging literature reporting toxic effects of manufactured nanomaterials (NMs) and nanoparticles (NPs) in fish, but the mechanistic basis of both exposure and effect are poorly understood. This paper critically evaluates some of the founding assumptions in fish toxicology, and likely mechanisms of absorption, distribution, metabolism and excretion (ADME) of NPs in fish compared to other chemicals. Then, using a case study approach, the paper compares these assumptions for two different NPs; TiO2 and C60 fullerenes. Adsorption of NPs onto the gill surface will involve similar processes in the gill microenvironment and mucus layer to other substances, but the uptake mechanisms for NPs by epithelial cells are more likely to occur via vesicular processes (e.g., endocytosis) than uptake on membrane transporters or by diffusion through the cell membranes. Target organs may include the gills, gut, liver and sometimes the brain. Information on metabolism and excretion of NPs in fish is limited; but hepatic excretion into the bile seems a more likely mechanism, rather than mainly by renal or branchial excretion. TiO2 and C60 share some common chemical properties that appear to be associated with some similar toxic effects, but there are also differences, that highlight the notion that chemical reactivity can inform toxic effect of NPs in a fundamentally similar way to other chemicals. In this paper we identify many knowledge gaps including the lack of field observations on fish and other wildlife species for exposure and effects of manufactured NMs. Systematic studies of the abiotic factors that influence bioavailability, and investigation of the cell biology that informs on the mechanisms of metabolism and excretion of NMs, will greatly advance our understanding of the potential for adverse effects. There are also opportunities to apply existing tools and techniques to fundamental studies of fish toxicology with NPs, such as perfused organs and fish cell culture systems.

Abstract  Environmental toxicologists, chemists and social scientists have identified three priorities for research into the impact of engineered nanoparticles on the environment.

Abstract  It is inevitable that, during their use, engineered nanoparticles will be released into soils and waters. There is therefore increasing concern over the potential impacts of engineered nanoparticles in the environment on aquatic and terrestrial organisms and on human health. Once released into the environment, engineered nanoparticles will aggregate to some degree; they might also associate with suspended solids, sediment, be accumulated by organisms and enter drinking water sources and food materials. These fate processes are dependent on the characteristics of the particle and the characteristics of the environmental system. A range of ecotoxicological effects have also been reported, including effects on microbes, plants, invertebrates and fish. Although available data indicate that current risks of engineered nanoparticles in the environment to environmental and human health are probably low, our knowledge of the potential impacts of engineered nanoparticles in the environment on human health is still limited. There is therefore a need for continued work to develop an understanding of the exposure levels for engineered nanoparticles in environmental systems and to begin to explore the implications of these levels in terms of the ecosystem and human health. This will require research in a range of areas, including detection and characterization, environmental fate and transport, ecotoxicology and toxicology.

Abstract  Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental 13C particles (CMD = 36 nm; GSD = 1.66) from [13C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 microg/m3. Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. 13C concentrations were determined by isotope ratio mass spectroscopy and compared to background 13C levels of sham-exposed controls (day 0). The background corrected pulmonary 13C added as ultrafine 13C particles on day 1 postexposure was 1.34 microg/lung. Lung 13C concentration decreased from 1.39 microg/g (day 1) to 0.59 microg/g by 7 days postexposure. There was a significant and persistent increase in added 13C in the olfactory bulb of 0.35 microg/g on day 1, which increased to 0.43 microg/g by day 7. Day 1 13C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that ~20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.

Abstract  Nano-silver (Ag) with antimicrobial activity is by far the most commercialized nano-compound. The hazards associated with human exposure to nanosized-silver should be investigated to facilitate the risk assessment process. Recent studies have shown that inflammatory, oxidative, genotoxic, and cytotoxic consequences are associated with silver particulate exposure, and are inherently linked. In the present study, the cytotoxicity and genotoxicity of nano-silver were investigated using the dye exclusion assay, the comet assay, and the mouse lymphoma thymidine kinase (tk+/−) gene mutation assay (MLA). IC20 values of nano-silver in L5178Y cells were determined the concentration of 3,769.53 μg/mL and 1,796.88 μg/mL with and without S-9, respectively. And in BEAS-2B cell, IC20 values were calculated to 1,171.88 μg/mL and 761.72 μg/mL with and without S-9, respectively. From these results, nano-silver was more cytotoxic in absence of S-9 metabolic activation system and at the BEAS-2B cells. In the comet assay, L5178Y cells and BEAS-2B cells were treated with nano-silver which significantly increased >2-fold tail moment with and without S-9. However, the mutant frequencies in the nano-silver treated L5178Y cells were slightly increased but not significant compared to the vehicle controls with and without S-9. The results of this study indicate that nano-silver can cause primary DNA damage and cytotoxicity but not mutagenicity in cultured mammalian cells.

Abstract  Silver nanoparticles (AgNPs) have emerged as an important class of nanomaterials and are currently used in a wide range of industrial and commercial applications. This has caused increasing concern about their effects on the environment and to human health. Using Japanese medaka (Oryzias latipes) at early-life stages as experimental models, the developmental toxicity of silver nanoparticles was investigated following exposure to 100–1000 μg/L homogeneously dispersed AgNPs for 70 days, and developmental endpoints were evaluated by microscopy during embryonic, larval and juvenile stages of development in medaka. Meanwhile, histopathological changes in the larval eye were evaluated. Retarded development and reduced pigmentation were observed in the treated embryos by AgNPs at high concentrations (≥400 μg/L). Maximum width of the optic tectum, as an indicator of midbrain development, decreased significantly in a dose-related manner. Furthermore, silver nanoparticles exposure at all concentrations induced a variety of morphological malformations such as edema, spinal abnormalities, finfold abnormalities, heart malformations and eye defects. Histopathological observations also confirmed the occurrence of abnormal eye development induced by AgNPs. The data showed non-linear or U-shaped dose–response patterns for growth retardation at 5 days of postfertilization, as well as the incidence of abnormalities. Preliminary results suggested that the developmental process of medaka may be affected by exposure to silver nanoparticles. Morphological abnormalities in early-life stages of medaka showed the potential developmental toxicities of silver nanoparticles. Further research should be focused on the mechanisms of developmental toxicity in fish exposed to silver nanoparticles.

Abstract  In this article, we represent a versatile and effective technique which using non-toxic chemicals to prepare stable aqueous dispersions of silver nanoparticles (NPs) via modified Tollens process. It was shown that as-prepared silver colloids consisted of finely-dispersed NPs with average diameter about 10 nm and a relatively narrow size distribution. Moreover, they could be stored very stable after several months without observation of aggregates or sedimentation. In comparison with previous works where Tollens process was being used, we for the first time applied UV-irradiation simultaneously with glucose reduction of silver salt through NPs preparation. The colloidal solutions of silver NPs were found to exhibit a high antibacterial activity against gram-negative Escherichia coli. The concentration of silver leading to a complete inhibition of bacteria growth was revealed as low as at 1.0 μg ml−1 and found much lower compared to earlier reports. These advantages of aqueous dispersions of silver NPs make them ideal for green industrial, medicinal, microbiological and other applications.

Abstract  The increasing use of manufactured nanoparticles ensures these materials will make their way into the environment. Silver nanoparticles in particular, due to use in a wide range of applications, have the potential to get into water systems, e.g., drinking water systems, ground water systems, estuaries, and/or lakes. One important question is what is the chemical and physical state of these nanoparticles in water? Are they present as isolated particles, agglomerates or dissolved ions, as this will dictate their fate and transport. Furthermore, does the chemical and physical state of the nanoparticles change as a function of size or differ from micron-sized particles of similar composition? In this study, an electrospray atomizer coupled to a scanning mobility particle sizer (ES-SMPS) is used to investigate the state of silver nanoparticles in water and aqueous nitric acid environments. Over the range of pH values investigated, 0.5–6.5, silver nanoparticles with a bimodal primary particle size distribution with the most intense peak at 5.0 ± 7.4 nm, as determined from transmission electron microscopy (TEM), show distinct size distributions indicating agglomeration between pH 6.5 and 3 and isolated nanoparticles at pH values from 2.5 to 1. At the lowest pH investigated, pH 0.5, there are no peaks detected by the SMPS, indicating complete nanoparticle dissolution. Further analysis of the solution shows dissolved Ag ions at a pH of 0.5. Interestingly, silver nanoparticle dissolution shows size dependent behavior as larger, micron-sized silver particles show no dissolution at this pH. Environmental implications of these results are discussed.

Abstract  The eco- and genotoxicity of silver nanoparticles (AgNPs) was investigated in the fourth instar larvae of the aquatic midge, Chironomus riparius. AgNPs did not have acute toxicity in C. riparius, but did exhibited chronic toxicity on development (pupation and emergence failure) and reproduction. Genotoxicity also occurred in AgNPs exposed C. riparius. Differential Display PCR (DD-PCR), based on the Annealing Control Primer (ACP) technique, was conducted to investigate the underlying toxic mechanism, which identified altered gene expression in C. riparius after treatment with AgNPs. The possible toxicity mechanism of AgNPs in C. riparius involves the down regulation of the ribosomal protein gene (CrL15) affecting the ribosomal assembly and consequently, protein synthesis. Up regulation of the gonadotrophin releasing hormone gene (CrGnRH1) might lead to the activation of gonadotrophin releasing hormone mediated signal transduction pathways and reproductive failure. Up regulation of the Balbiani ring protein gene (CrBR2.2) may be an indication of the organism's protection mechanism against the AgNPs. The overall results suggest that the toxicity of AgNPs towards aquatic organisms should be thoroughly investigated to allow for their safe use, as they seem to exhibit important toxicity towards C. riparius.

Abstract  The rapid development and potential release of engineered nanoparticles (ENPs) have raised considerable concerns due to the unique properties of nanomaterials. An important aspect of the risk assessment of ENPs is to understand the interactions of ENPs with plants, an essential base component of all ecosystems. The impact of ENPs on plant varies, depending on the composition, concentration, size and other important physical chemical properties of ENPs and plant species. Both enhancive and inhibitive effects of ENPs on plant growth at different developmental stages have been documented. ENPs could be potentially taken up by plant roots and transported to shoots through vascular systems depending upon the composition, shape, size of ENPs and plant anatomy. Despite the insights gained through many previous studies, many questions remain concerning the fate and behavior of ENPs in plant systems such as the role of surface area or surface activity of ENPs on phytotoxicity, the potential route of entrance to plant vascular tissues and the role of plant cell walls in internalization of ENPs. This article reviewed the current knowledge on the phytotoxicity and interactions of ENPs with plants at seedling and cellular levels and discussed the information gap and some immediate research needs to further our knowledge on this topic.

Abstract  Nanosilver is one nanomaterial that is currently under a lot of scrutiny. Much of the discussion is based on the assumption that nanosilver is something new that has not been seen until recently and that the advances in nanotechnology opened completely new application areas for silver. However, we show in this analysis that nanosilver in the form of colloidal silver has been used for more than 100 years and has been registered as a biocidal material in the United States since 1954. Fifty-three percent of the EPA-registered biocidal silver products likely contain nanosilver. Most of these nanosilver applications are silver-impregnated water filters, algicides, and antimicrobial additives that do not claim to contain nanoparticles. Many human health standards for silver are based on an analysis of argyria occurrence (discoloration of the skin, a cosmetic condition) from the 1930s and include studies that considered nanosilver materials. The environmental standards on the other hand are based on ionic silver and may need to be re-evaluated based on recent findings that most silver in the environment, regardless of the original silver form, is present in the form of small clusters or nanoparticles. The implications of this analysis for policy of nanosilver is that it would be a mistake for regulators to ignore the accumulated knowledge of our scientific and regulatory heritage in a bid to declare nanosilver materials as new chemicals, with unknown properties and automatically harmful simply on the basis of a change in nomenclature to the term "nano".

Abstract  Nanoparticles are small scale substances (<100 nm) used in biomedical applications, electronics, and energy production. Increased exposure to nanoparticles being produced in large-scale industry facilities elicits concerns for the toxicity of certain classes of nanoparticles. This study evaluated the effects of silver-25 nm (Ag-25) nanoparticles on gene expression in different regions of the mouse brain. Adult-male C57BL/6N mice were administered (i.p.) 100mg/kg, 500 mg/kg or 1,000 mg/kg Ag-25 and sacrificed after 24h. Regions from the brain were rapidly removed and dissected into caudate nucleus, frontal cortex and hippocampus. Total RNA was isolated from each of the three brain regions collected and real-time RT-PCR analysis was performed using Mouse Oxidative Stress and Antioxidant Defense Arrays. Array data revealed the expression of genes varied in the caudate nucleus, frontal cortex and hippocampus of mice when treated with Ag-25. The data suggest that Ag-25 nanoparticles may produce neurotoxicity by generating free radical-induced oxidative stress and by altering gene expression, producing apoptosis and neurotoxicity.

Abstract  The attention of the Council was repeatedly called to certain claims made by the firm of Schering and Glatz for the substance collargolum. These claims were of a most unusual character. If true, they would place the substance in the front rank of therapeutic agents; if unfounded, they would constitute a most reprehensible abuse of the confidence of the medical profession. In view of the importance of the matter, the Council wished to proceed with especial thoroughness. It was decided, therefore, to appoint a committee to consider the question whether exaggerated statements are contained in the pamphlets on collargol that have been distributed by the above-mentioned firm, the agents of the preparation in this country. The undersigned, being four of the five members of the committee thus appointed, beg to submit the following report:

Abstract  The magnitude of engineered nanomaterials (ENMs) being produced and potentially released to the environment is a crucial and thus far unknown input to exposure assessment. This work estimates upper and lower bound annual United States production quantities for 5 classes of ENMs. A variety of sources were culled to identify companies producing source ENM products and determine production volumes. Using refining assumptions to attribute production levels from companies with more reliable estimates to companies with little to no data, ranges of U.S. production quantities were projected for each of the 5 ENMs. The quality of data is also analyzed; the percentage of companies for which data were available (via Web sites, patents, or direct communication) or unavailable (and thus extrapolated from other companies' data) is presented.

Abstract  Silver nanoparticles (AgNPs) are gaining attention from the academic and regulatory communities, not only because of their antimicrobial effects and subsequent product applications, but also because of their potential health and environmental risks. Whereas AgNPs in the aqueous phase are under intensive study, those in the atmosphere have been largely overlooked, although it is well established that inhalation of nanoparticles is associated with adverse health effects. This review summarizes the present state of knowledge concerning airborne AgNPs to shed light on the possible environmental exposure scenarios that may accompany the production and popularization of silver nanotechnology consumer products. The current understanding of the toxicity of AgNPs points toward a potential threat via the inhalation exposure route. Nanoparticle size, chemical composition, crystal structure, surface area, and the rate of silver ion release are expected to be important variables in determining toxicity. Possible routes of aerosolization of AgNPs from the production, use, and disposal of existing consumer products are presented. It is estimated that approximately 14% of silver nanotechnology products that have been inventoried could potentially release silver particles into the air during use, whether through spraying, dry powder dispersion, or other methods. In laboratory and industrial settings, six methods of aerosolization have been used to produce airborne AgNPs: spray atomization, liquid-flame spray, thermal evaporation-condensation, chemical vaporization, dry powder dispersion, and manual handling. Fundamental uncertainties remain about the fate of AgNPs in the environment, their short- and long-term health effects, and the specific physical and chemical properties of airborne particles that are responsible for health effects. Thus, to better understand the risks associated with silver nanotechnology, it is vital to understand the conditions under which AgNPs could become airborne.

Abstract  Nanosilver has become one of the most widely used nanomaterials in consumer products because of its antimicrobial properties. Public concern over the potential adverse effects of nanosilver's environmental release has prompted discussion of federal regulation. In this paper, we assess several classes of consumer products for their silver content and potential to release nanosilver into water, air, or soil. Silver was quantified in a shirt, a medical mask and cloth, toothpaste, shampoo, detergent, a towel, a toy teddy bear, and two humidifiers. Silver concentrations ranged from 1.4 to 270,000 microg Ag g product(-1). Products were washed in 500 mL of tap water to assess the potential release of silver into aqueous environmental matrices (wastewater, surface water, saliva, etc.). Silver was released in quantities up to 45 microg Ag g product(-1), and size fractions were both larger and smaller than 100 nm. Scanning electron microscopy confirmed the presence of nanoparticle silver in most products as well as in the wash water samples. Four products were subjected to a toxicity characterization leaching procedure to assess the release of silver in a landfill. The medical cloth released an amount of silver comparable to the toxicity characterization limit. This paper presents methodologies that can be used to quantify and characterize silver and other nanomaterials in consumer products. The quantities of silver in consumer products can in turn be used to estimate real-world human and environmental exposure levels.

Abstract  Since ancient times, people have taken advantage of the antimicrobial effects of colloidal silver particles. Aside from the medical prospects, silver nanoparticles are found in a wide range of commercially available consumer products ranging from cosmetics to household cleansers. Current synthetic methods for creating silver nanoparticles typically call for potentially hazardous chemicals, extreme heat, and produce environmentally dangerous byproducts. Therefore, it is essential that novel