Direct ENP exposures
Humans are constantly exposed to NP. Modern human exposures to atmospheric particles and NP were well described. (D. Tinker et al. unpubl.data) 167,168 An estimate for the number of atmospheric NP depositing daily in the human lung is 5 × 1012.169 In the UK, about 40 mg (1012) of exogenous microparticles (mainly silicates and TiO2) are ingested orally per person per day as food additives, pharmaceutical/supplements or toothpaste.163 Experiments on European drinking water have shown that 1 L contains typically 7 × 1011 natural NP, averaging 15 nm diameter, which have passed through the normal filtration and treatment processes.170
Inhalation is a key exposure route for ENPs in consumer, occupational and environmental settings, and significant efforts are active in this area of research. The increasing utilization of ENPs in nanomedicine for drug delivery, selective imaging, dentistry and wound treatment has increased ENP interactions with circulatory components. ENPs are also found in an increasing range of products, leading to direct and indirect human exposures to specific nanomaterials.171 Between 2005–2010 a steady growth in products claiming to be nano-based have been reported;2 >1300 products were listed in this inventory in 2010 compared with 54 in 2005, even though a ‘nano-claim’ was no guarantee of nanomaterial inclusion in the product, and lack of claim was no guarantee of absence.172 Such inventories provide a clear indication of market growth and establish a list of materials to conduct exposure assessments. Perhaps of particular significance to the lung of consumers are sprays (e.g. deodorants, suncreams, medicinal or for coatings) and ENPs in direct contact with humans such as silver used in clothing or food containers.
ENP toxicity in humans is dependent on exposures and their systemic bioavailability, not just toxicity or hazard. Exposure assessments attempt to define human exposures by identifying nano-enabled products using inventories (e.g. Woodrow Wilson2), through the application of mass flow models to calculate risks from current production volumes173 and predicting releases during the product life cycle. Because the toxicokinetic profiles of each type are expected to differ, we now consider selected ENPs which dominate the market in terms of their current production volumes or are expected to result in human lung exposures via medical and consumer products especially nano-silver, gold, titantium dioxide, polystyrene, silica, polystyrene and iron oxide. Direct human exposures are expected principally through medical/dentistry, food and consumer products.174
Silver ENPs are now being utilized extensively for antimicrobial purposes, and increasingly in clinical practice. Debate continues as to whether the nano-form per se is active as a microbicide or whether it is the release of silver ions within bacteria that provides the toxic effects. Nano-silver is also found in a wide range of consumer products.172 Colloidal silver (silver hydrosol) is advertised as an ‘alternative therapy’ and can be purchased from health food outlets. It is also found in clinical wound dressings (e.g. Acticoat (NUCRYST Pharmaceuticals, Fort Saskatchewan, AB, Canada)), socks and towels (to reduce bacteria and odour), toothpaste and cosmetics. Kitchen utensils and household appliances employ the microcidal effect of nano-silver (e.g. inner surfaces of refrigerators, air purifiers, vacuum cleaners, hair trimmers and food containers). It is also being considered for incorporation into food packaging to reduce food decay.15 Antimicrobial paint containing nano-silver is proposed for hospitals, schools and offices. The World Health Organization only considers silver to be a toxic at very high doses, and maximal concentrations are defined for water and air that currently cover nano-silver, despite the fact that ENPs may exhibit significantly different properties. Investigations in an in vitro diffusion cell system demonstrated the detection of nano-silver in the stratum corneum and outermost layer of the epidermis in intact and damaged human skin.175 To date, no studies have investigated the long-term effect on normal and damaged skin of nano-silver. As with most ENPs, nano-silver can be employed in drug delivery, specifically carry anti-cancer therapeutics, protein and DNA, and serum levels of silver were increased following use of silver-coated wound dressings.176 Several clinical trials of nano-silver enabled therapeutic agents are registered as on-going in the US including silver central venous catheters, nano-silver bacterial gel and silver biomaterial nanotoxicity: no current clinical trials are registered in the UK.
Nano-gold is found in tens of consumer products including cosmetics, toothpaste and a variety of antibacterial products. They are used in durable paint, water purification, faster computers, tougher shoe soles, and lighter and cheaper televisions. Gold ENPs are also employed in biodiagnostic applications, enabling the identification of a number of infectious diseases via colorimetry,177 and under investigation for drug delivery and in the detection of cancers.178 US clinical control trials using gold ENPs include treatment of atherosclerosis, anti-cancer agent vectors and investigation of the potential of gold NP as an anti-cancer agent.179
Nano-TiO2 is commonly found in sunscreens and cosmetic products due to its ability to provide barrier ultraviolet protection. In the UK, the Boots' (Nottingham, UK) product Soltan sun care range is one of the market leaders and contains TiO2 ENPs, and in 2003, this range comprised approximately 49% of the market projected to be worth approximately 290m USD. Penetration of TiO2 is negligible for healthy skin.175,180 Other commercially available TiO2 products include cleaning products, coatings for self-cleaning surfaces and car waxes and polishes (e.g. Turtlewax (Chicago, IL, USA)). Clinical applications of nano-TiO2 are limited, but in vitro and preclinical studies have suggested a therapeutic role in the treatment of a variety of tumours.84,181
Silica ENPs are produced on an industrial scale as additives to food, cosmetics (including some of the Lancome range and Leorex), car tyres, drugs, printer toners and varnish. Highly luminescent silica ENPs have been developed for the selective tagging of a wide range of biomedically important targets, such as cancer cells, bacteria (enabling identification of infectious diseases) and individual biomolecules. Nano-silica is also proposed as drug delivery vectors. Drug molecules loaded into surface-modified silica ENPs with bio-recognition entities (antibodies or proteins) allow specific cells or receptors in the body to be located.61,182 However, the toxicity of these ENPs has not been fully established. In the US, a clinical control trial is investigating silica NP in the treatment of atherosclerosis and as dentures containing silica NP to improve durability. Silica NP are already found in dental fillings (nanofillers) that are now employed commercially (Filtek; 3M, Berkshire, UK).
Polystyrene ENPs are the most widely used polymeric ENPs owing to their low cost and commercial availability. Commercially, they are found in disposable coffee cups and cutlery, food containers and CD cases. They also have a role in drug delivery systems,70 fluorescence imaging,182 in cancer diagnosis and in identifying trace amounts of infectious diseases (including anthrax, adenovirus and malaria).177
Applications of iron oxide ENPs include multi-tera bit storage devices, catalysis, sensors and a platform for high-sensitivity biomolecular magnetic resonance imaging for medical diagnosis and therapeutics. Recently, iron ENPs have been widely used in coal industry to produce clean fuels due to their catalytic activities that facilitate the chemical reactions to form and cleave carbon–carbon bonds. One key application of iron oxide ENPs is in human biomedical applications, such as labelling and magnetic separation of biological materials, imaging and diagnostic applications in human, site-directed drug delivery and anti-cancer hyperthermia therapy.183 Iron ENPs enhance the permeability of cells through the production of reactive oxygen species and the destabilization of microtubules.184
The incorporation of ENPs into medical products appears to be one of the largest non-occupational exposure routes for humans. Systemic delivery of therapeutic agents via inhalation of ENPs for organ, tissue or tumour targeting remains an attractive, non-invasive means of administration.185 Metal oxide NP are used for non-invasive vascular and tumour imaging.186 Dental materials also increasingly contain ENPs for infection control, improved material lifetimes and properties and improved biocompatibility.187
In line with other environmental contaminants, foetal exposures remain a growing concern. Intravenous and inhalation exposure studies, plus cell model exposures, have demonstrated placental transfer,188 complications in pregnancy and damage in the foetus.189 Damage mechanisms of intravenous nano-silica in mice included increased coagulation, inflammation and/or through oxidative stress.190 Finally, in mice, pregnancy enhances lung inflammatory responses to otherwise relatively innocuous inert particles such as TiO2, and exposures of non-allergic pregnant female mice to inert or toxic environmental air particles can cause increased allergic susceptibility in the offspring.190 While few of these materials tested would lead to maternal exposures or be circulating at these concentrations, the evidence suggests that some material effects are likely, and caution may be applied to particular maternal exposures.
Occupational nanomaterial release scenarios are always at the upper end of exposure ranges, and ENP exposures at work are being newly established. Measurements of occupational exposures (e.g. in the workplace191 and from product testing171) and models of exposure191 establish likely upper levels. Some lessons on how small particles behave on entering the body of humans and animals can be obtained from experience gained over the last 100 years in occupational dust exposures, but it is many years before effects may be observed observed, for example mesothelioma resulting from asbestos exposures.192,193 Currently, research scientists, medical and dental professionals often work with nanomaterials without assessment. Occupational exposures in manufacturing facilities tend to be more stringent, although elevated concentrations are associated with materials handling and even small production facilities.194 As demonstrated in accident or emergency situations, ENP exposures to combustion products from burning nanomaterials lead to first responder or fire victim exposures.17 In China, seven young female workers, exposed to NP for 5–13 months, all with shortness of breath and pleural effusions were exposed to NP consisting of polyacrylate and had lung tissue displaying non-specific pulmonary inflammation, pulmonary fibrosis and foreign-body granulomas of pleura.16 Transmission electron microscopy revealed NP observed in the cytoplasm and karyoplasms of pulmonary epithelial and mesothelial cells, but are also located in the pleural fluid. Such cases arouse concern that long-term exposure to some NP without protective measures may be related to serious damage to human lungs. Clearly, in some countries, regulation may not be so careful, and higher worker and environmental exposures may occur.
Environmental exposures via air, soil and water
Some engineered nanomaterials will be released to the environment in significant quantities.94,194 This may give rise to chronic, complex, multi-component ENP exposures that are generally not considered in toxicological exposure studies. Once in the environment, some ENPs will remain in circulation and lead to human exposures and certain materials in particular are being studied: nano-sized silver, TiO2, silica, zinc oxide, alumina, carbon black and carbon nanotubes. Modification of ENP size distribution and surface may also occur in the environment, affecting the way ENPs interact with the human body and influencing toxicity, in some cases, reducing, and in some cases, increasing effects. In terms of dose, these exposures are expected to be much lower than in the direct exposures to medical or consumer products.