Nanotechnology and nanoparticles

Nanotechnology involves the deliberate production and application of nanoparticles (NPs) between 1 and 100 nm.^[1] The emergence of nanotechnology began in the 1980s,^[2] and currently, applied nanotechnology is a sharply growing market producing various engineered NPs (ENPs) with different chemical composition, size, crystal structure, shape, surface chemistry, and charge.^[3,4] These ENPs can be classified by their dimensionality, morphology, composition, and uniformity and agglomeration state.^[5] The physical, optical, thermal, chemical, and biological properties of ENPs are different and yield more effective performance compared to their respective bulk substances.^[6] Hence, ENPs are now being used in various commercial products ranging from electronics to medical and health care products, food, textiles, and household products.^[7] As of January 2014, the publicly available online inventory of ENP-based consumer products contained 1682 products (Fig. 1), and by 2015, the market for nanoproducts will reach the $1 trillion milestone.^[8]

Environmental, health, and safety concerns of ENPs

As applications of nanotechnology expand and nanoproducts are used more frequently, ENPs are released into the air, soil, and water and become "emerging pollutants". Their small size and high reactivity have raised environmental health and safety concerns about their transport, fate, and toxicity in the environment and risks to human health.^[9,10]

Possible scenarios of infants and children exposure to ENPs

Exposure of children to ENPs can occur through inhalation, ingestion, and/or dermal exposure, from contaminated air, food or drinking water, or directly from nanoproducts (Figs. 1 and 2).^[11-13] Children's consumer products were ranked based on their bioavailability of silver NPs (AgNPs). Products from greatest to least were: plush toy and fabric products, cleaning products, sippy cups, humidifiers, breast milk storage bags, and kitchen scrubbers.^[11] However, the extent of ENP exposure is unknown.

Inhalation

Exposure near manufacturing or construction sites

Because of greater concentrations and exposure frequency of ENPs in occupational settings, the production of ENPs poses risks to workers in the manufacturing facilities.^[14] Over 100 nanoproducts mainly containing silicon dioxide (SiO₂)-, zinc oxide (ZnO)-, aluminium oxide-, Ag-, and titanium dioxide (TiO₂)-NPs are used in the construction industry, with measurements from European workplaces confirming a modest exposure of workers to ENPs.^[15] In Bangkok, Thailand, there are 400 000 children, aged 0-3, who play in and near those construction sites.^[16] Since airborne ENPs can remain suspended over extended time periods and traverse long distances from the point source, children who live or play around manufacturing or construction sites could encounter elevated levels of ENPs.

Exposure by use of nanosprays

Children can be exposed to nanosprays or nanopowder products for anti-microbial or personal hygiene as the evaporation from the sprayed droplets can form clusters of ENPs which can be inhaled.^[12,17,18] These products, including antiodor spray for hunters, surface disinfectant, and throat spray, can emit 0.24 to 56 ng Ag in aerosol-form with a diameter range of 1 to 2.5 μm.^[12]

Exposure by playing on synthetic turfs

Artificial surfaces are commonly installed in playgrounds and stadiums.^[19] Most synthetic turfs and rubber mulches use pulverized and recycled vehicle tires as padding and grit material, which contain carbon black NPs and carbon nanotubes (CNTs).^[20,21] As children crawl, sit, and play on these surfaces, ENPs can be disrupted and released into the atmosphere, where they can be inhaled. Unfortunately to date, there are no studies investigating potential risks and health consequences from this unprecedented, often chronic exposure of ENPs in children playing on tire crumb surfaces and facilities.

Dermal

Exposure through sunscreens and cosmetics

Mainly C₆₀-, TiO₂- and ZnO-NPs are now accepted as additives in pharmaceutical and cosmetic formulations to enhance drug delivery, treat skin disease, or facilitate systemic access.^[22,23] Approximately 21 to 60 μg/L of Ti has been found in children's swimming pools, most likely from sunscreen.^[24]

Exposure through textiles and clothing

Fabric and textile industries employ ENPs, mainly AgNPs, as an antimicrobial agent.^[25] In general, clothing has a moderate Ag content of 30 to 45 μg Ag per gram product.^[25] About 13.8 and 23 μg/m2 of Ag were transferred from the surface of plush toys and baby blankets onto dermal wipes, respectively, which was an initial estimate of the amount of dermal exposure to infants or children.^[11,26] The use of AgNPs in wound bandages renders another exposure potential because the product will be in contact with compromised skin.^[26,27] Children have been thereby exposed to ENPs through direct contact with the skin, or indirectly when ENPs contained in cloths, fabrics, and sunscreen are released into the aquatic environment.^[25,28]

Ingestion

Exposure through nanofoods

ENPs are being added into food and food supplements (nanofood) or food packaging to improve texture, structure, sensory appeal, and extend shelf life.^[3,29] According to the inventory of ENP-based consumer products, 205 foods contained ENPs in 2014 (Fig. 1), and 150-600 nanofoods and 400-500 nanofood packaging applications are currently on the market.^[30] Foods containing TiO₂-NPs include candies, sweets, cookies, and gums, with gum containing the greatest concentrations.^[31] Further intake estimation indicated that 95% of TiO₂-NPs were swallowed by gum consumers after chewing for 10 minutes.^[13] For US children under the age of 10, the simulated exposure to TiO₂-NPs was 1-2 mg/kg body weight per day,^[31] highlighting the need for the development of methods to study the size distributions and elemental compositions of food-relevant NPs.

Exposure through food chain

Beyond direct exposure, ENPs can translocate into higher orders of the food chain. Certain ENPs end up in the soil with the potential to enter food sources. The absorption, translocation, accumulation, and biotransformation of metal (ZnO and cerium dioxide)-NPs and carbon-based ENPs have been identified in edible plants.^[32,33] It is important to identify whether various sizes, types, and chemical compositions of ENPs can be absorbed by soil and transformed or metabolized by different plant species.

Maternal-fetal transmission

Prenatal exposure

Many ENPs [gold-NPs, TiO₂-NPs, SiO₂-NPs, single­walled-CNTs (SWCNTs), and quantum dots (QDs)] can penetrate the placental barrier and concentrate in the fetus.[34-36] The chemical composition, size, charge, dose, and capping materials of ENPs contribute to their ability to translocate from mother to pups across the placental barrier, allowing to induce embryo-fetal toxicity.^[36,37] In fact, it has been suggested that ENPs might cross the human placenta because of the transplacental capability of NPs demonstrated in a human ex vivo model.^[38]

Postnatal exposure via breast milk

ENPs can also transfer from lactating mother to offspring through breast milk. This has been investigated in female rats, showing the total accumulation of polyvinylpyrrolidone coated AgNPs in milk was greater than 1.94% of the intragastrically administered dose after 48-hour lactation.^[39] Greater than 25% of AgNPs was absorbed by the digestive tract of infant rats, and 17.9% and 0.9% of the total amount in infant rats was distributed to the liver and kidney, respectively.^[39]

Nanopediatrics

Lipid-based nanocarriers have the ability to effectively deliver therapeutic and imaging agents, and are outstanding in nanomedicine applications.^[40] In fact, the global nanomedicine market is expected to grow to $96.9 billion by 2016.^[41] Nanopediatrics is a newly emerged branch of pediatrics, which focuses on the development and use of nanomedicine to promote children's health in various areas, including disease diagnosis and treatment.^[42] Despite the great promise in these applications, they create additional exposure routes to children.

Special aspects of physiology and toxicology in infants and children

Differences in exposure between children and adults

Children, a generally vulnerable and high-risk population for a multitude of toxicants, interact in and with the environment in various ways that differ from adults.^[43] Children eat more food, drink more water, and inhale more air than adults based on body weight.^[44] Children also have greater dermal exposure to ENPs in sunscreens/cosmetics than adults as they have lower body weights but an increased ratio of body surface area to weight.^[4] Additionally, three typical characteristics of infants and children further magnify exposure: 1) regular hand-to-mouth behaviors; 2) unique food consumption patterns,^[45,46] for example, a child consumes 2-4 times as many TiO₂-NPs as an adult from the consumption of sweet products;^[31] and 3) being closer to the ground where aerosolized ENPs in nanosprays with a greater density than air become closer in proximity. Therefore, infants and children are at greater risk of exposure to ENPs compared with adults.^[43]

Differences in developmental biology between children and adults

Children are not simply little adults. Anatomy, physiology, and organ function of children all differ from those of adults. The thinner and under-keratinized epidermis of children may increase the absorption of ENPs through the skin. Infants and children are prone to enhanced deposition of inhaled ENPs in the lung because of the relative smaller caliber airway and higher ventilation requirements.^[43] Moreover, their immature alveolar epithelium has reduced function, which allows ENPs to pass through blood-air barrier more easily.^[43,47] The respiratory rate, heart rate, metabolism, and excretion of children are notably different.^[45,48] Infants and children are biologically susceptible and at an increased risk of toxicant injury. This vulnerability arises from developmental immaturities of vital organs, which present unique targets not accessible in adults.^[48,49] Particularly in the first months of infancy, the inability to metabolize, detoxify, and excrete toxicants can increase the risk of toxicant injury.^[44]

Differences in health effect between children and adults

Toxicological data showed no adverse effect between adults and children because of developmental differences.^[43,50] Based on reproductive and developmental toxicology data, timing of exposure, duration, dose and susceptibility, or genotype of parents and fetuses or children plays critical roles in the pattern of injury, with periods of significant vulnerability at both the fetal and early post-natal life stages.^[43,50,51] Certain ENPs are able to induce different health risks at different ages. A comparative toxicity study has reported the different responses of TiO₂-NPs on youth and adult rats after 30 days oral exposure.^[52] In youths, liver edema, heart injuries and non-allergic mast cell activation in the stomach were observed, with only slight injuries of the liver and kidney, whereas, in adults, reduced intestinal permeability and molybdenum contents were detected.^[52]

In infants and children, the growth and development of organ systems are not well adept at repairing damage caused by toxicants, increasing vulnerability where the resulting dysfunction in development can be permanent.^[44,46,48] Hence, the delicate developmental processes of fetuses or children may be easily altered by ENPs; if their central nervous system (CNS) is injured, respiratory system damaged, reproductive development disrupted, or immune system development destroyed, the consequential dysfunction could be irreparable. Furthermore, numerous diseases initiated by toxicants require many years to develop, thus toxic exposures that occur early in life are more likely to cause lasting effects than exposures that occur later in life.^[45,46,48]

Adverse health effects and potential risks of ENPs

The toxicities of ENPs are a matter of various mechanisms, including: 1) size;^[53] 2) charge; 3) shape; 4) surface chemistry/coating;^[54] and 5) reactive oxygen species (ROS) generation.^[55] Currently, toxicokinetic and toxicodynamic data, as well as the potential health hazards for infants and children are limited and remain under investigation (Fig. 3).

Skin

ENPs such as iron (5 nm),^[56] TiO₂,^[57] QDs,^[58] and AgNPs (25 nm)^[27] have previously demonstrated an ability to penetrate the skin barrier, and pose risk of ROS-mediated skin aging.^[59] Porcine skin after 14 days of exposure to AgNPs demonstrated intercellular epidermal edema with focal dermal inflammation (spongiosis), epidermal hyperplasia, and parakeratosis in a dose dependent manner.^[60,61]

Skin penetration can lead to systemic exposure and development of lesions by ENPs.^[62,63] It was reported that that a 17-year-old boy with 30% burned skin developed hepatotoxicity and argyria-like symptoms after treatment with an Ag-containing wound dressings.^[62] The different systemic toxicities of AgNPs via acute (3 days) and subchronic (13 weeks) dermal exposure were detected in 5-6 week old male guinea pigs.^[64,65] Subchronic exposure resulted in greater tissue abnormalities than acute exposure.^[64] Uptake of AgNPs by tissue is ranked in the sequence of kidney>muscle>bone>skin>liver> heart>spleen.^[65] Therefore, evidence suggests certain ENPs are able to penetrate children's skin and distribute to tissues after prolonged dermal exposure.

Respiratory system

ENP deposition, as an indispensable step for adverse effects, strongly depends on size and shape.^[17] Inhaled airborne NPs between 5 to 50 nm are efficiently deposited in the alveoli where risks for toxic effects are the greatest.^[17] Childhood exposure to particulate matter of air pollution has been associated with decreased lung function, wheezing, cough, and exacerbation of asthma.^[66,67] Because of a large surface area in the lung and the small size of NPs, airborne NPs can penetrate the thin blood-air barrier to reach systemic circulation and efficiently transfer and translocate to other organs.^[43,68]

Regarding AgNPs-containing nanosprays, the exposure modeling estimates 70 ng of Ag deposits in the respiratory tract, with 82% falling in the nasopharyngeal region, 2% in the tracheobronchial region, and 16% in the alveolar region, if 1 to 2 throat sprays occurred per day.^[12] As nanotechnology-related consumer products develop in popularity and necessity, simultaneous exposure from various types of AgNPs­containing products would be possible and might result in additive exposure levels in children.

Human epidemiological studies and case reports revealed that long-term exposure to NPs might cause lung damage. The first "nano scare" was reported in March of 2006.^[69] About 100 German consumers had symptoms including coughing, headache, sleep disruption and vomiting after using aerosols like bathroom cleaning Magic-Nano products (Kleinmann GmbH; Sonnenbuehl, Germany), though the illness was not linked to the nano­component (ZnO) of the aerosols.^[69] A 26-year-old female chemist handling nickel NPs developed throat irritation, nasal congestion, "post nasal drip", facial flushing, and skin symptoms,^[70] whereas a 38-year-old healthy man died 13 days after inhaling nickel NPs (<25 nm found in lung macrophages) due to adult respiratory distress syndrome.^[71] Another patient reported a 33-year­old woman inhaling carbon NPs from toner dust; she developed weight loss and diarrhea.^[72] Case reports confirmed that inhaled ENPs can travel systemically via lymphatic and blood vessels and affect other organs.^[71] Published results have illustrated that further research is necessary to better understand the possible biomarkers that could be used for surveillance of ENPs exposure, and to explore nanotoxicological mechanisms by which NPs can cause adverse health effects and most effective ways to protect children.^[73]

The gastrointestinal tract (GIT) and liver

Absorption via the GIT is a significant route of ENPs exposure after ingestion of food and pharmaceuticals.^[29] GIT is covered by a protective mucosal layer, which is a mixture of highly branched glycoproteins and macromolecules and is a barrier for ENP uptake.^[74] After translocation across the intestinal epithelium, ENPs enter the blood stream by hepatic portal circulation to the liver and systemic circulation or by mesenteric lymph nodes to the lymphoid circulation.^[74,75] Uptake and distribution can be affected by composition, size, surface coating, surface charge, shape (aspect ratio), and flexibility.^[74,75] ENPs can result in hepatic damage and toxicity, as AgNPs can induce a higher incidence of bile-duct hyperplasia, with necrosis, fibrosis, and pigmentation in rats.^[76] TiO₂-NPs can cause hepatic injury, thrombus, tachycardia, systolic hypertension,^[77,78] nephrotoxicity and pathological changes in mice kidneys.^[79] Exposed rats demonstrated reduced liver weight, hepatocyte enlargement, sinusoidal dilatation, and accumulation of granular material.^[80,81]

Brain

ENPs have the potential to penetrate the blood-brain barrier and contribute to damage of brain tissues. In vivo studies revealed ENPs (metallic NPs, QDs, and CNTs) can be translocated to the brain from the skin, blood, and respiratory pathways.^[82] In a cross-sectional study, workers handling ENPs showed a decrease in capability of backward memory in neurobehavioral tests.^[83] In children, motor, cognitive, and behavioral changes are observed after particulate metal exposure.^[84] These evidences support concerns regarding the neurotoxicity of ENPs, and indicate that children, in particular, may be at an elevated health risk post-NP exposure, since childhood and adolescence are quite crucial periods of neurodevelopment.^[84]

Immune and circulation systems

ENPs can interact with complex networks of immune cells located within and beneath epithelial surfaces.^[43] ENPs can act as allergens during the neonatal period, triggering the immune system to induce allergic inflammation in later life stages.^[43,85] Detrimental cardiovascular consequences due to NPs exposure have been reported in epidemiological studies.^[83,86] Cardiovascular disease markers fibrinogen, vascular cell adhesion molecule levels, and interleukin-6 were significantly higher in workers handing ENPs than in unexposed controls, which were consistent with cardiotoxicity of NPs.^[83,87] Cationic dendrimers can exhibit significant hemolytic and hematological toxicities.^[88] To circumvent toxicity, there is a great need to adopt various strategies, including masking of cationic charge of dendrimers through surface engineering by neutralization of charge.^[88]

Reproductive and developmental systems

Pre-pregnancy, pregnancy, prenatal, and postnatal toxicants exposures are avenues offering critical windows of opportunity for adverse reproductive and developmental outcomes,^[46] which can be manifested at different phases within the life span of the organism. Both in vitro and in vivo studies have displayed that metallic NPs, carbon-based NPs, and dendrimers are able to induce adverse effects including reproductive failure, metabolic syndrome, and cancer.^[89] Certain ENPs may also have effects on human reproduction by altering testicular and ovarian structure and function.^[90,91]

ENPs can induce adverse effects on developing fetuses due to maternal NP exposure and transfer during pregnancy.^[34] Early miscarriages and fetal malformations were also detected in pregnant mice 10 days after SWCNTs injection, and teratogenicity was observed at a dosage as low as 100 ng/mouse.^[35] Additionally, intragastric administration of ENPs to lactating mothers can affect CNS development of offspring, which was shown in rats orally exposed to TiO₂-NPs during lactation from day 2 post-delivery to 21 days.^[92] However, the current literature on ENPs exposure in developing animals has limitations in analytical methodology that stem from deficiencies in selectivity, sensitivity, or both, and these have obscured researchers' complete understanding of fetal exposure to ENPs. Thus, it is important to systematically assess potential reproductive and developmental toxicities of common ENPs in model organisms. 

Conclusions and recommendations

Health risk assessment remarks

As new technology and innovation emerge, pros and cons need to be carefully analyzed, especially the use of ENPs. ENPs are of considerable importance, because global businesses and companies continue to invest heavily in nanotechnology for a wide range of nanoproducts. Although certain ENPs have great promise in the treatment of pediatric diseases and the development of potent nanomedicine and nanovaccines for young children, we need to ensure there are no hidden dangers in the applications. As highlighted above, our knowledge about actual ENPs exposure and nanotoxicity in infants and children largely remains unknown, and many unsolved questions remain (Fig. 3). Specifically, 1) what size(s), type(s), and degree(s) are ENPs released from consumer products or contained in nanofoods? 2) how much of a certain ENP a child may be exposed to via normal or recommended use of nanoproducts or consumption of nanofoods? 3) are there any exposure scenarios for infants and children that must be deemed as particularly critical? 4) how and to what degree(s) do ENPs cause health hazards to infants and children? Are they different from adults in response to ENPs? 5) what are the most critical or sensitive periods during development when exposure to ENPs can induce adverse effects in infants and children? 6) are there any differences in toxic effects between prenatal and postnatal exposure to a certain ENP?

It is indispensable to utilize state-of-the-art approaches that combine environmental risk assessment and biologic monitoring with the exposure patterns and developmental stages of children. Because of the aggregation or degradation of ENPs in the environment, they are no longer at the nanosized level. As some health effects of ENP exposure might not be apparent for decades, long-term studies investigating ENP safety are crucial. It will be particularly important to conduct these toxicity-testing studies with ENPs that are more widely used due to their various sizes, shapes, and surface chemistry. In addition, comparative studies to explore the toxicity differences of ENPs among different life stages are essential to help infer the health risks to children and assist with regulations and policies for ENPs.

Regulation perspectives

To date, the nanotechnology industry has generally not been regulated. Manufacturers are not required to report the use of ENPs except for SWNTs and multi-walled NTs, or label products containing ENPs,^[3] giving regulatory and legislative agencies limited authority to access ENP-containing product information for exposure assessments.^[4] There should be greater disclosure on what types and how many ENPs are in products and foods, and manufacturers should improve their processes to minimize potential dangers of ENPs in their products in consideration of the increased vulnerability of children and the precautionary principle. Moreover, companies engaged in nanotechnology research and development program, as well as government agencies such as the Food and Drug Administration and Environmental Protection Agency should ensure products and foods containing ENPs be safety tested and labeled for consumers. With increasing awareness of environmental exposures and detrimental effects of ENPs, newly prudent policies, laws, and guidelines for nanotechnology-related innovation must be designed and implemented as soon as possible to protect and improve human health, safety, and the environment. This research can ensure public confidence in the safety of nanotechnology research, manufacturing, and application.

 

---

Funding: This study was supported by a grant from the National Natural Science Foundation of China (No: 81102097).

Ethical approval: Not needed.

Competing interest: All authors disclosed no conflict of interest.

Contributors: Each of the authors wrote at least one section of this review. Tang S and Wang M contributed equally to this work. Tang S and Sun WJ were conceived and responsible for final editing of this review.

References

1  Bhushan B. Springer handbook of nanotechnology. Berlin: Springer, 2007.

2  Scientific American. Understanding nanotechnology. New York: Warner Books, 2002.

3  Kessler R. Engineered nanoparticles in consumer products: understanding a new ingredient. Environ Health Perspect 2011;119:a120-a125.

4  Hansen SF, Michelson ES, Kamper A, Borling P, Stuer-Lauridsen F, Baun A. Categorization framework to aid exposure assessment of nanomaterials in consumer products. Ecotoxicology 2008;17:438-447.

5  Buzea C, Pacheco II, Robbie K. Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2007;2:MR17-MR71.

6  Service RF. Nanotoxicology. Nanotechnology grows up. Science 2004;304:1732-1734.

7  Hood E. Nanotechnology: looking as we leap. Environ Health Perspect 2004;112:A740-A749.

8  Sargent JF. Nanotechnology: a policy primer. CRS Report for Congress, 2013.

9  Teow Y, Asharani PV, Hande MP, Valiyaveettil S. Health impact and safety of engineered nanomaterials. Chem Commun (Camb) 2011;47:7025-7038.

10 Garcia-Reyero N, Kennedy AJ, Escalon BL, Habib T, Laird JG, Rawat A, et al. Differential effects and potential adverse outcomes of ionic silver and silver nanoparticles in vivo and in vitro. Environ Sci Technol 2014;48:4546-4555.

11 Quadros ME, Pierson R 4th, Tulve NS, Willis R, Rogers K, Thomas TA, et al. Release of silver from nanotechnology-based consumer products for children. Environ Sci Technol 2013;47:8894-8901.

12 Quadros ME, Marr LC. Silver nanoparticles and total aerosols emitted by nanotechnology-related consumer spray products. Environ Sci Technol 2011;45:10713-10719.

13 Chen XX, Cheng B, Yang YX, Cao A, Liu JH, Du LJ, et al. Characterization and preliminary toxicity assay of nano-titanium dioxide additive in sugar-coated chewing gum. Small 2013;9:1765­1774.

14 Kuhlbusch TA, Asbach C, Fissan H, Göhler D, Stintz M. Nanoparticle exposure at nanotechnology workplaces: a review. Part Fibre Toxicol 2011;8:22.

15 van Broekhuizen P, van Broekhuizen F, Cornelissen R, Reijnders L. Use of nanomaterials in the European construction industry and some occupational health aspects thereof. J Nanopart Res 2011;13:447-462.

16 Musikaphan W, Kitisriworaphan T. Possible impacts of nanoparticles on children of Thai construction industry. In: Bittnar Z, Bartos PJ, eds. Nanotechnology in Construction 3. Berlin: Springer, 2009: 329-336.

17 Biskos G, Schmidt-Ott A. Airborne engineered nanoparticles: potential risks and monitoring challenges for assessing their impacts on children. Paediatr Respir Rev 2012;13:79-83.

18 Losert S, von Goetz N, Bekker C, Fransman W, Wijnhoven SW, Delmaar C, et al. Human exposure to conventional and nanoparticle-containing sprays-a critical review. Environ Sci Technol 2014;48:5366-5378.

19 Claudio L. Synthetic turf: health debate takes root. Environ Health Perspect 2008;116:A116-A122.

20 Novak J. Exposure to crumb rubber nanoparticles could lead to serious health issues: researchers. http://www.turfandrec.com/ index.php?option=com_content&task=view&id=2986&Itemid= 139 (accessed October 1, 2009)

21 Walquist S. Children's bodies are not landfills. http://www. oakpark.com/News/Articles/5-14-2013/Children's-bodies-are­not-landfills/ (accessed May 14, 2013)

22 Papakostas D, Rancan F, Sterry W, Blume-Peytavi U, Vogt A. Nanoparticles in dermatology. Arch Dermatol Res 2011;303:533­-550.

23 Neubert RH. Potentials of new nanocarriers for dermal and transdermal drug delivery. Eur J Pharm Biopharm 2011;77:1-2.

24 David Holbrook R, Motabar D, Quiñones O, Stanford B, Vanderford B, Moss D. Titanium distribution in swimming pool water is dominated by dissolved species. Environ Pollut 2013;181:68-74.

25 Benn T, Cavanagh B, Hristovski K, Posner JD, Westerhoff P. The release of nanosilver from consumer products used in the home. J Environ Qual 2010;39:1875-1882.

26 Stefaniak AB, Duling MG, Lawrence RB, Thomas TA, LeBouf RF, Wade EE, et al. Dermal exposure potential from textiles that contain silver nanoparticles. Int J Occup Environ Health 2014;20:220-234.

27 Larese FF, D'Agostin F, Crosera M, Adami G, Renzi N, Bovenzi M, et al. Human skin penetration of silver nanoparticles through intact and damaged skin. Toxicology 2009;255:33-37.

28 Benn TM, Westerhoff P. Nanoparticle silver released into water from commercially available sock fabrics. Environ Sci Technol 2008;42:4133-4139.

29 Mahler GJ, Esch MB, Tako E, Southard TL, Archer SD, Glahn RP, et al. Oral exposure to polystyrene nanoparticles affects iron absorption. Nat Nanotechnol 2012;7:264-271.

30 Martirosyan A, Schneider YJ. Engineered nanomaterials in food: implications for food safety and consumer health. Int J Environ Res Public Health 2014;11:5720-5750.

31 Weir A, Westerhoff P, Fabricius L, Hristovski K, von Goetz N. Titanium dioxide nanoparticles in food and personal care products. Environ Sci Technol 2012;46:2242-2250.

32 Rico CM, Majumdar S, Duarte-Gardea M, Peralta-Videa JR, Gardea-Torresdey JL. Interaction of nanoparticles with edible plants and their possible implications in the food chain. J Agric Food Chem 2011;59:3485-3498.

33 Hernandez-Viezcas JA, Castillo-Michel H, Andrews JC, Cotte M, Rico C, Peralta-Videa JR, et al. In situ synchrotron X-ray fluorescence mapping and speciation of CeO2 and ZnO nanoparticles in soil cultivated soybean (Glycine max). ACS Nano 2013;7:1415-1423.

34 Sun J, Zhang Q, Wang Z, Yan B. Effects of nanotoxicity on female reproductivity and fetal development in animal models. Int J Mol Sci 2013;14:9319-9337.

35 Pietroiusti A, Massimiani M, Fenoglio I, Colonna M, Valentini F, Palleschi G, et al. Low doses of pristine and oxidized single-wall carbon nanotubes affect mammalian embryonic development. ACS Nano 2011;5:4624-4633.

36 Chu M, Wu Q, Yang H, Yuan R, Hou S, Yang Y, et al. Transfer of quantum dots from pregnant mice to pups across the placental barrier. Small 2010;6:670-678.

37 Campagnolo L, Massimiani M, Magrini A, Camaioni A, Pietroiusti A. Physico-chemical properties mediating reproductive and developmental toxicity of engineered nanomaterials. Curr Med Chem 2012;19:4488-4494.

38 Wick P, Malek A, Manser P, Meili D, Maeder-Althaus X, Diener L, et al. Barrier capacity of human placenta for nanosized materials. Environ Health Perspect 2010;118:432-436.

39 Melnik EA, Buzulukov YP, Demin VF, Demin VA, Gmoshinski IV, Tyshko NV, et al. Transfer of silver nanoparticles through the placenta and breast milk during in vivo experiments on rats. Acta Naturae 2013;5:107-115.

40 Machado MC, Cheng D, Tarquinio KM, Webster TJ. Nanotechnology: pediatric applications. Pediatr Res 2010;67:500-504.

41 Nanotechnology in medical applications: the global market. http://www.bccresearch.com/market-research/healthcare/ nanotechnology-medical-applications-global-market-hlc069b. html (accessed January 1, 2010)

42 McCabe ER. Nanopediatrics: enabling personalized medicine for children. Pediatr Res 2010;67:453-457.

43 Sly PD, Schüepp K. Nanoparticles and children's lungs: is there a need for caution? Paediatr Respir Rev 2012;13:71-72.

44 Landrigan PJ. Children as a vulnerable population. Int J Occup Med Environ Health 2004;17:175-177.

45 Bearer CF. How are children different from adults? Environ Health Perspect 1995;103:7-12.

46 Garry VF. Pesticides and children. Toxicol Appl Pharmacol 2004;198:152-163.

47 Heinrich J, Slama R. Fine particles, a major threat to children. Int J Hyg Environ Health 2007;210:617-622.

48 Landrigan PJ, Claudio L, Markowitz SB, Berkowitz GS, Brenner BL, Romero H, et al. Pesticides and inner-city children: exposures, risks, and prevention. Environ Health Perspect 1999;107 Suppl 3:431-437.

49 Schuepp KG. The potential harmful and beneficial effects of nanoparticles in children. In: Marijnissen JC, Gradon L, eds. Nanoparticles in Medicine and Environment. Netherlands: Springer, 2010: 211-226.

50 Fanucchi MV, Buckpitt AR, Murphy ME, Plopper CG. Naphthalene cytotoxicity of differentiating Clara cells in neonatal mice. Toxicol Appl Pharmacol 1997;144:96-104.

51 Pinkerton KE, Joad JP. Influence of air pollution on respiratory health during perinatal development. Clin Exp Pharmacol Physiol 2006;33:269-272.

52 Wang Y, Chen Z, Ba T, Pu J, Chen T, Song Y, et al. Susceptibility of young and adult rats to the oral toxicity of titanium dioxide nanoparticles. Small 2013;9:1742-1752.

53 Tang S, Allagadda V, Chibli H, Nadeau JL, Mayer GD. Comparison of cytotoxicity and expression of metal regulatory genes in zebrafish (Danio rerio) liver cells exposed to cadmium sulfate, zinc sulfate and quantum dots. Metallomics 2013;5:1411-­1422.

54 Hoshino A, Fujioka K, Oku T, Suga M, Sasaki YF, Ohta T, et al. Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification. Nano Lett 2004;4:2163-2169.

55 Tang S, Cai Q, Chibli H, Allagadda V, Nadeau JL, Mayer GD. Cadmium sulfate and CdTe-quantum dots alter DNA repair in zebrafish (Danio rerio) liver cells. Toxicol Appl Pharmacol 2013;272:443-452.

56 Baroli B, Ennas MG, Loffredo F, Isola M, Pinna R, López-Quintela MA. Penetration of metallic nanoparticles in human full-thickness skin. J Invest Dermatol 2007;127:1701-1712.

57 Sadrieh N, Wokovich AM, Gopee NV, Zheng J, Haines D, Parmiter D, et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulationscontaining nano­and submicron-size TiO2 particles. Toxicol Sci 2010;115:156­-166.

58 Prow TW, Monteiro-Riviere NA, Inman AO, Grice JE, Chen X, Zhao X, et al. Quantum dot penetration into viable human skin. Nanotoxicology 2012;6:173-185.

59 Wu J, Liu W, Xue C, Zhou S, Lan F, Bi L, et al. Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett 2009;191:1­8.

60 Samberg ME, Oldenburg SJ, Monteiro-Riviere NA. Evaluation of silver nanoparticle toxicity in skin in vivo and keratinocytes in vitro. Environ Health Perspect 2010;118:407-413.

61 Surekha P, Kishore AS, Srinivas A, Selvam G, Goparaju A, Reddy PN, et al. Repeated dose dermal toxicity study of nano zinc oxide with Sprague-Dawley rats. Cutan Ocul Toxicol 2012;31:26-32.

62 Trop M, Novak M, Rodl S, Hellbom B, Kroell W, Goessler W. Silver-coated dressing acticoat caused raised liver enzymes and argyria-like symptoms in burn patient. J Trauma 2006;60:648­-652.

63 Vlachou E, Chipp E, Shale E, Wilson YT, Papini R, Moiemen NS. The safety of nanocrystalline silver dressings on burns: a study of systemic silver absorption. Burns 2007;33:979-985.

64 Korani M, Rezayat SM, Gilani K, Arbabi Bidgoli S, Adeli S. Acute and subchronic dermal toxicity of nanosilver in guinea pig. Int J Nanomedicine 2011;6:855-862.

65 Korani M, Rezayat SM, Arbabi Bidgoli S. Sub-chronic dermal toxicity of silver nanoparticles in Guinea pig: special emphasis to heart, bone and kidney toxicities. Iran J Pharm Res 2013;12:511­-519.

66 Gehring U, Cyrys J, Sedlmeir G, Brunekreef B, Bellander T, Fischer P, et al. Traffic-related air pollution and respiratory health during the first 2 yrs of life. Eur Respir J 2002;19:690-698.

67 Hertz-Picciotto I, Baker RJ, Yap PS, Dostál M, Joad JP, Lipsett M, et al. Early childhood lower respiratory illness and air pollution. Environ Health Perspect 2007;115:1510-1518.

68 Bur M, Henning A, Hein S, Schneider M, Lehr CM. Inhalative nanomedicine-opportunities and challenges. Inhal Toxicol 2009;21 Suppl 1:137-143.

69 Wolinsky H. Nanoregulation: a recent scare involving nanotech products reveals that the technology is not yet properly regulated. EMBO Rep 2006;7:858-861.

70 Journeay WS, Goldman RH. Occupational handling of nickel nanoparticles: a case report. Am J Ind Med 2014;57:1073-1076.

71 Phillips JI, Green FY, Davies JC, Murray J. Pulmonary and systemic toxicity following exposure to nickel nanoparticles. Am J Ind Med 2010;53:763-767.

72 Theegarten D, Boukercha S, Philippou S, Anhenn O. Submesothelial deposition of carbon nanoparticles after toner exposition: case report. Diagn Pathol 2010;5:77.

73 Kumar A, Dhawan A. Genotoxic and carcinogenic potential of engineered nanoparticles: an update. Arch Toxicol 2013;87:1883­1900.

74 Cockburn A, Bradford R, Buck N, Constable A, Edwards G, Haber B, et al. Approaches to the safety assessment of engineered nanomaterials (ENM) in food. Food Chem Toxicol 2012;50:2224-2242.

75 Schleh C, Semmler-Behnke M, Lipka J, Wenk A, Hirn S, Schäffler M, et al. Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology 2012;6:36-46.

76 Kim YS, Song MY, Park JD, Song KS, Ryu HR, Chung YH, et al. Subchronic oral toxicity of silver nanoparticles. Part Fibre Toxicol 2010;7:20.

77 Nemmar A, Melghit K, Al-Salam S, Zia S, Dhanasekaran S, Attoub S, et al. Acute respiratory and systemic toxicity of pulmonary exposure to rutile Fe-doped TiO(2) nanorods. Toxicology 2011;279:167-175.

78 Cui Y, Gong X, Duan Y, Li N, Hu R, Liu H, et al. Hepatocyte apoptosis and its molecular mechanisms in mice caused by titanium dioxide nanoparticles. J Hazard Mater 2010;183:874­-880.

79 Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, et al. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 2007;168:176-185.

80 Nalabotu SK, Kolli MB, Triest WE, Ma JY, Manne ND, Katta A, et al. Intratracheal instillation of cerium oxide nanoparticles induces hepatic toxicity in male Sprague-Dawley rats. Int J Nanomedicine 2011;6:2327-2335.

81 Vesterdal LK, Danielsen PH, Folkmann JK, Jespersen LF, Aguilar-Pelaez K, Roursgaard M, et al. Accumulation of lipids and oxidatively damaged DNA in hepatocytes exposed to particles. Toxicol Appl Pharmacol 2014;274:350-360.