Advances and challenges for the use of engineered nanoparticles in food contact materials

Trends in Food Science & Technology xx (2015) 1e20

Review

Advances and challenges for the use of engineered nanoparticles in food contact materials Joseph C. Hannona, Joseph Kerryb, Malco Cruz-Romerob, Michael Morrisc and Enda Cumminsa,* a

Biosystems Engineering, School of Agriculture, Food Science and Veterinary Medicine, Agriculture and Food Science Centre, University College Dublin, Belfield, Dublin 4, Ireland (Tel.: D353 1 7167476; e-mail: [email protected]) b School of Food & Nutritional Sciences, Food Packaging Group, University College Cork, Cork, Ireland c Department of Chemistry, University College Cork, Cork, Ireland

The use of nanotechnology in the food industry has great potential, particularly in the area of food packaging. This paper looks at recent advances and industry challenges in relation to the use of metal and non-metal engineered nanoparticles (ENPs) in food packaging to grant active and intelligent properties. A particular focus will be placed on risk assessment strategies and policy developments associated with the use of nanotechnology in food contact materials (FCMs). The absence of a regulatory framework for NP FCMs has been highlighted as a drawback for the development of nanoparticle

* Corresponding author.

FCMs. To aid the understanding of nanotechnology in the area of FCMs, a NP specific exposure framework providing prompt risk assessment could be invaluable to industry, consumers and regulatory bodies.

Introduction Currently the world’s population stands at 6.47 billion, however this is expected to increase to 9.08 billion by 2050 (WPO, 2008). This creates a number of complex problems, particularly the issue of an adequate food supply. The world’s food resources are unevenly distributed globally, resulting in the difficult task of preserving food stuffs to allow for transportation to a wider geographical area. Food packaging is a common method of preserving food stuffs, combined with preservatives, temperature and pressure treatments. The advent of materials containing NPs in the size range 1e100 nm, granting improved properties, has proven advantageous in a vast number of industries such as the cosmetics, food and beverage, textile, medical, electronics and computing, appliances and cooking utensil industries (Maynard & Michelson, 2014). Emerging food packaging materials containing ENPs that possess active and intelligent properties have the potential to alleviate some of the global food supply issues. These materials may increase the shelf life of food products, improve food safety and reduce the amount of food waste due to spoilage. However, the uptake of novel food packaging materials containing ENPs has been met with concerns in relation to the risk posed to humans from consumption of ENPs which may migrate from NP food packaging into food (Kanmani & Rhim, 2014b). This issue is exacerbated by the immense uncertainty which surrounds the field of NP human oral toxicity. Advancements in the area of in vivo mouse toxicity (Park, Bae, et al., 2010; Park, Marsh, & Dawson, 2010) and in vitro human cell studies (Loh, Saunders, & Lim, 2012) presenting organ damage and inflammatory responses in mice, and extensive damage to intracellular organelles in cells have been challenged by a recent in vivo human toxicity study showing no clinically significant effects of engineered silver nanoparticles (EAgNPs) under acute oral dose conditions (Munger et al., 2014). EAgNPs are silver NPs which exist as a result of some size reducing process, whether intentional or unintentional. Additionally, contradictions exist concerning the toxicity of NPs, mainly surrounding the argument that

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Please cite this article in press as: Hannon, J. C., et al., Advances and challenges for the use of engineered nanoparticles in food contact materials, Trends in Food Science & Technology (2015), http://dx.doi.org/10.1016/j.tifs.2015.01.008

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humans are, and have been exposed to quantities of naturally occurring nanoparticles (NONPs) in food and the environment that would be considered harmful under the present conservative regulations (Sk, Jaiswal, Paul, Ghosh, & Chattopadhyay, 2012). A noteworthy distinction is the disparity between ENPs which are intentionally manufactured to possess enhanced properties and NONPs which are naturally occurring and unintentional. Currently, in the literature studies focussing on the presence of NONPs in food have been limited to a select number of foods. A study by Sk et al. (2012) confirmed the presence of carbon NONPs in food products such as bread, jaggery, corn flakes and biscuits. In their conclusions they noted that NPs existed in nature long before analytical techniques for detection of NPs were developed. Similarly, a study by Yang et al. (2014) found that food grade titanium dioxide (E171) contained between 17 and 35% nanosized particles. Another food additive which has been found to contain aggregates with particles <100 nm is silicon dioxide, also known as synthetic amorphous silica (SAS) or E551 in the EU (Bouwmeester, Brandhoff, Marvin, Weigel, & Peters, 2014). It should be noted that although NPs are naturally and unintentionally present in these foods, the processes used in their manufacture is a likely cause of their nano dimensions. Alternatively, the presence of native casein micelles with a mean diameter of 100 nm in dairy milk is an example of NONPs that are present in the raw food material before processing (Trejo, Dokland, JuratFuentes, & Harte, 2011). According to the United Kingdom Food Safety Authority (UKFSA) products found to contain NPs would include; ricotta cheese, homogenised milk and other nanoemulsion formulations of food, such as coenzyme Q10 (UKFSA, n.d.). At present, a lack of suitable methods to quantify and differentiate between ENPs and NONPs has resulted in few studies focussing on the presence of NONPs in drinking water and food (Savolainen et al., 2010). Although recent developments of nanotechnology in the food industry has been great, there are a number of issues which require attention before nano products can take the place of existing products. This review will discuss the recent developments in nanocomposite FCMs, applications and legislations. It will, more specifically, focus on the risk associated with human exposure to ENP FCMs through unintentional oral ingestion of ENPs which may have migrated from FCMs. Nanomaterials e synthesis and forms The definition of nanomaterials is constantly developing with each region having its own set of nano specific definitions. The most recent definition employed by the European Commission for a nanomaterial is a “natural, incidental or manufactured materials containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1e100 nm” ([EC] European Commission, 2011). Although

the NP upper size limit has been defined as 100 nm, some authors claim properties of nanomaterials for materials containing particles larger than 100 nm (Busolo, Fernandez, Ocio, & Lagaron, 2010). Huang et al. (2011) labelled particles in the size range 100e300 nm as “nano” due to their novel properties. Even though nanotechnology is still in its infancy with regard to research and development, new forms of ENPs are constantly being uncovered. In industry, emerging NP technologies are developed for their physicochemical properties and often gain there name from objects of similar geometry with the addition of “nano”. Some common types of NPs include; quantom dots, liposomes, carbon nanotubes, dendrimers, nanobubbles, nanoclusters, functionalized NPs (Re, Moresco, & Masserini, 2012), nanoplatelets, nanocrystals, nanofibres, nanowhiskers (Duncan, 2011), nanocubes, nanomultifacets, nanowires, nanorods (Chen & Schluesener, 2008), nanospheres, nanoplates, nanotriangles, fullerenes (Guo, Yuan, Lu, & Li, 2013) and nanocapsules (Sato, Quintas, Vincente, & Cunha, 2011). The synthesis of ENPs is a complex process dominated by two principal manufacturing categories. Firstly, a ‘Top down’ method which involves the reduction of larger particles by some physical or chemical mechanism (Cushen, Kerry, Morris, Cruz-Romero, & Cummins, 2012). Examples of the ‘Top down’ method that have been reported include mechanical milling and homogenisation (Cushen et al., 2012), laser and vaporisation followed by cooling (Brody, Bugusu, Han, Sand, & McHugh, 2008), inert-gas aggregated magnetron sputtering (Cassidy et al., 2013), etching, electro-explosion and laser ablation (Chaudhry, Boxall, Aitken, & Hull, 2005). The second known as a ‘Bottom up’ method is more complex, as it influences the assembly of molecules and ions into NPs. Examples of ‘Bottom up’ synthesis methods have been reported in the literature such as the Sol-gel method (Hatat-Fraile, Mendret, Rivallin, & Brosillon, 2013), biomass reaction (Gericke & Pinches, 2006), chemical vapour deposition (Kim, Chung, Youn, & Hwang, 2009), Plasma or flame spray synthesis (Rudin, Wegner, & Pratsinis, 2013), electromagnetic levitational gas condensation method (Kermanpur, Rizi, Vaghayenegar, & Ghasemi Yazdabadi, 2009; Mohammadi & Halali, 2014; Vaghayenegar, Kermanpur, & Abbasi, 2012), supercritical fluid synthesis (Daschner de Tercero et al., 2013), spinning (Tai, Wang, Kuo, Chang, & Liu, 2009), templating (Liu, Tao, & Zhang, 2012; de Matos & Courrol, 2014), self-assembly (Zhang & Wang, 2014), atomic layer deposition (Gould et al., 2013), crystallisation (Kong et al., 2011), solvent extraction and evaporation (Hung, Teh, Jester, & Lee, 2010), and biosynthesis (Mittal, Bhaumik, Kumar, & Banerjee, 2014). The list of ENP synthesis methods is constantly growing, with a shift towards eco-friendly synthesis methods such as the solvent reduction and stabilization of Ag colloids using starch and glucose (Cheviron, Gouanv
e, & Espuche, 2014).

Please cite this article in press as: Hannon, J. C., et al., Advances and challenges for the use of engineered nanoparticles in food contact materials, Trends in Food Science & Technology (2015), http://dx.doi.org/10.1016/j.tifs.2015.01.008

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Nanotechnology in the food industry Nanotechnology has the potential to penetrate every aspect of food production. At the farm level, targeted pesticides may increase crop yield and controlled release pharmaceuticals could improve animal health, whilst reducing the risk of disease. The efficiency of the food processing line has the potential to be revolutionised by self-cleaning antimicrobial machines and faster fluid transport systems with super hydrophobic coatings. In addition, the product packaging stage will be shortened due to container adhesives that will set quicker and at lower temperatures than conventional adhesives (Maynard & Michelson, 2014). Food contained in nano-packaging with antimicrobial ability may require less refrigeration during transport and will stay fresh over longer journeys (Rhim, Park, & Ha, 2013). In a retail outlet, nanosensor labels on packaging could inform the consumer if the product has been subject to temperature abuse during transport or if it contains an unsafe level of bacteria. When the consumer has finished with the product, waste packaging could be placed in a compost bin where it would degrade into eco-friendly constituents over a short period of time. To date, the application of ENPs in the food industry has mainly centred around four areas which include; processing food ingredients to form nanostructures, using ENPs for sensory properties and food processing, exploitation of “active” and “intelligent” properties and the direct addition of ENPs in food for supplement or nano-encapsulation (Chaudhry et al., 2008). Although there have been reports of nanotechnology being applied in the food industry in countries such as the United States and Korea (Maynard & Michelson, 2014), due to a lack of nano specific regulation it is difficult to approximate its overall use worldwide (Coles & Frewer, 2013). It is apparent from the rising number of original research papers that there has been an increased interest in the area of ENP food packaging. Nanoparticles in food packaging Due to the added and improved functions and properties of food packaging incorporating ENPs, three categories of ENP packaging can be emphasized which are “Improved”, “Active” and “Intelligent” packaging (Chaudhry et al., 2008; Silvestre, Duraccio, & Cimmino, 2011). These three categories indicate what applications the packaging material is used for. However, the use of ENPs in FCMs for active and intelligent properties in the European Union is disallowed, with the exception of certain products, such as titanium nitride (TiN) in plastic bottles (Echegoyen & Ner
ın, 2013; Simon, Chaudhry, & Bakos, 2008). Metal and non-metal nanoparticles All metals can exist in NP form. However only a small number of metals and metal-based composites have been reduced to NP form and exploited in the food industry to improve the properties of food packaging (see Table 1).

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These include silver (Ag), gold (Au), iron (Fe), iridium (Ir), zinc oxide (ZnO), silicon dioxide (SiO2), titanium dioxide (TiO2), titanium nitride (TiN), alumina (Al2O3), iron oxide (Fe3O4, Fe2O3) (Chaudhry et al., 2008; FSAI, 2008), copper (Cu), copper oxide (CuO) and palladium (Pd) (Llorens, Lloret, Picouet, Trbojevich, & Fernandez, 2012). Other metals exist which have the potential to be reduced to nanoscale and be incorporated into food packaging, but are overlooked as a result of lower antimicrobial potential. Gallium (Ga) is a good example of a rare metal element which has been overlooked as an alternative to commonly used metals in nano-particulate form (Kamat, Guin, Pillai, & Aggarwal, 2011; Youssef, Kamel, & ElSamahy, 2013). Similar to Ag, Ga shows strong antimicrobial effects against a number of pathogenic bacteria and fungi (Kelson, Carnevali, & Truong-Le, 2013). Notably, Ga is analogous to Fe and can therefore be used to starve bacteria of Fe by disrupting the bacterial Fe uptake mechanism which is necessary for bacteria to survive (Kelson et al., 2013). Ga has been considered for use in cancer medicines (Xie et al., 2014). However, due to its toxicity it has not yet been considered for use in FCMs. ENPs can also be derived from non-metals such as clays and organic materials such as protein, polymers (FSAI, 2008), chitosan and poly-lactic acid (Dev et al., 2010). Nanoclay is composed of fine-grained minerals of naturally occurring aluminium silicate having a layered sheet like geometry with sheet thicknesses <100 nm. Nanoclays such as nanoscale montmorillinite (MMT), also known as bentonite, have been incorporated in polymers with aims to increase the gas barrier properties, but have been found to also increase polymeric strength, heat resistance and thermal stability (Majeed et al., 2013). In recent years, both industry and academia have taken great interest in nanoclays for use in food packaging to combat some of these long standing issues. In addition to inorganic ENPs, ENPs are also synthesised from organic sources such as chitosan. Chitosan is a material derived from deacetylated chitin which has been shown to exhibit improved antimicrobial effects when reduced to the nanoscale (Hajipour et al., 2012). Bulk chitosan has been identified as a possible carrier matrix for antimicrobials (Ouattara et al., 2000), as an incorporated antimicrobial in polymer food packaging (Park, Marsh, et al., 2010) and as a film to be coated to surfaces (Coma, Deschamps, & Martial-Gros, 2003). However, few studies have considered the incorporation of ENP chitosan into polymer food packaging, despite its well established strong antimicrobial properties (Cruz-Romero, Murphy, Morris, Cummins, & Kerry, 2013; Kong, Chen, Xing, & Park, 2010). Although chitosan can be derived from fungi and insects, it is more commonly synthesised from food compatible sources. Food grade nanoparticles Food grade NPs are particles which exist naturally or have been manufactured in the nano size range from food

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NP type

Nanomaterial product

Manufacturer

Country

Stage

NP size

Function

Reference

Ag

Nano-silver salad bowl Nano silver baby mug cup & nurser Fresh BoxÒ food storage containers FresherLongerÔ containers & bags Nano-silver storage box

Changmin Chemicals Baby DreamÒ Co., Ltd.

Korea Korea

on market on market

not disclosed not disclosed

Antimicrobial Antimicrobial

(Maynard & Michelson, 2014) (Bouwmeester et al., 2007)

BlueMoonGoodsÔ

USA

on market

not disclosed

Antimicrobial

(Maynard & Michelson, 2014)

SharperImageÒ

USA

on market

25 nm & 1e100 nm

Antimicrobial

(von Goetz et al., 2013)

Quan Zhou Hu Zeng Nano TechnologyÒ Co., Ltd. A-Do Global

China

on market

not disclosed

Antimicrobial

(Maynard & Michelson, 2014)

Korea

on market

not disclosed

Antibacterial

(Bouwmeester et al., 2007)

Oso Fresh Kinetic Go Green

USA USA

on market on market

40-60 nm 10-20 nm

Antimicrobial Antimicrobial

(Echegoyen & Ner
ın, 2013) (Echegoyen & Ner
ın, 2013)

Lexon, Inc. SongSing Nano Technology., Ltd. Ó Mondelez International

USA Taiwan

on market on market

not disclosed not disclosed

Antmicrobial Barrier & antimicrobial

(Maynard & Michelson, 2014) (Bouwmeester et al., 2007)

USA

on market

110 nm

Colouring (E171)

Colormatrix InMatÒ Inc.

USA USA

not disclosed on market

not disclosed not disclosed

Barrier Barrier

RBC’s

USA

on market

not disclosed

Nanoencapsulation

(Weir, Westerhoff, Fabricius, Hristovski, & von Goetz, 2012) (EFSA, 2012) (Joshi, Banerjee, Prasanth, & Thakare, 2006) (Bouwmeester et al., 2007)

Bayer Honeyells NanocorÒ (distributed by Colormatrix) Aqua Nova

USA USA USA

on market on market on market

1 nm - 1 mm not disclosed not disclosed

Barrier Oxygen scavenging Barrier

(Cushen et al., 2012) (Bouwmeester et al., 2007) (Bouwmeester et al., 2007)

Germany

on market

30 nm

Nanoencapsulation

(Bouwmeester et al., 2007)

Biopharma Plantic Technologies Ltd.

USA Australia

on market on market

not disclosed not disclosed

Encapsulation Biodegradability

(Biopharma., 2012) (Han, Yu, Li, & Wang, 2011)

Au ZnO TiO2 TiN MMT SiO2 Clay

Micelle Liposome Corn starch

Plastic food containers & water bottle Fresh food containers Smartwist food Storage with nano-silver Nanorama - gold tootpaste Nano plastic wrap Trident White chewing gum (E171) PET bottles (up to 20 mg/kg) NanolokÔ NanoceuticalsÔ Slim Shake Chocolate Durethan KU2-2601 film (SiO2) AegisÒ OX Beer bottles (ImpermÔ) Nano-encapsulated CoQ-10 (NovasolÒ) Nano (gluco, greens, reds, etc.) Eco PlasticÔ

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Table 1. Applications of metal and non-metal nanoparticles in industry.

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compatible sources (Cruz-Romero et al., 2013; Sato et al., 2011). The use of food grade NPs is a solution to the inherent toxicity associated with metal and metal oxide ENPs. There should be a greater public acceptance towards food grade NPs when compared to metal ENPs due to the fact that they are more natural, whilst having a diminished toxicity (Coles & Frewer, 2013). However, concerns persist regarding the increased bioavailability and accumulation of different ENPs in the human body. As a result, there is still a need for specific human exposure assessment. Alcoholic lecithin and sodium caseinate are both food derived substances which have been reduced to nanoscale and added to chitosan for use as nanocapsules in the food sector (Sato et al., 2011). Similarly, curcumin and ascorbyl dipalmitate which are derivatives from the spice turmeric and vitamin C have been incorporated into cellulose-based packaging films as a nanoscale additive to provide antibacterial function (Sonkaew, Sane, & Suppakul, 2012). A fruit extract paprika oleoresin has been reduced to the nanoscale to improve the marinating performance and sensory properties of poultry meat (Yusop et al., 2012). There are numerous different food and plant extracts which possess antimicrobial characteristics and have the potential to be incorporated into food packaging. Spice essential oils such as oregano, garlic and rosemary are proven active antimicrobials against a range of bacteria when used in packaging films (Rhim et al., 2013; Seydim & Sarikus, 2006; Sung et al., 2013). Remarkably, none of these potential antimicrobials have been investigated at the nanoscale for use in food packaging. Incorporation and attachment in food packaging In regions that permit the use of ENP FCMs (see Table 1), two main categories of ENP incorporation exist. Independent pads or similar ENP contact materials can be included in the existing packaging or the ENPs can be immobilized within or at the surface of the packaging (de Azeredo, 2013). The addition of independent ENP FCMs in packaging has its advantages and disadvantages. A particular benefit is the increased active properties due to the close contact that can be established between the foodstuff and independent

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material. However, this benefit is overshadowed by the additional manufacturing processes and potential for significantly greater migration, which could possibly shift the food industries preference towards ENP polymer composite packaging. The method employed to produce ENP polymer composites is greatly influenced by the function of the packaging in a specific application. There are two key approaches for producing ENP packaging which include; ENP surface coatings or inclusion of ENPs within the polymer packaging. Table 2 includes a non-exhaustive list of some of the methods used to manufacture ENP composites. Due to superior ENP immobilization, direct addition of ENPs into polymer packaging has been subject to more research than ENP coating methods. Only two studies have dealt with the attachment mechanisms of ENPs to the surface of food packaging (Nobile et al., 2004; Smirnova et al., 2012). As a result, substantial gaps in knowledge exists regarding the use of surface coatings in food packaging and the associated human risk assessment. Due to the existing popularity of polymers for use in food packaging applications, polymers make a suitable substrate for the incorporation of ENPs. Moreover, polymers offer a means of ENP immobilization, preventing aggregation and uncontrollable release (Guo et al., 2013). The material properties, low cost and ease of manufacture of certain polymers make them increasingly popular for food packaging applications. Polyolefins are popular food packaging materials which include polypropylene (PP), polyethylene (PE), polyethylene terephthalate (PET), polystyrene (PS) and polyvinyl chloride (PVC) (Duncan, 2011). Adding NPs to these polymers as well as bio-polymers such as polylactic acid (PLA) has been a focus of many studies (see Table 3), with an aim of assisting the uptake of ENP food packaging on the global food market. Although research focus has mainly centred on the incorporation of ENPs into biodegradable packaging, it is important that polyolefin nanocomposites are not ignored based on their environmental impact. Incorporating ENPs into polyolefin packaging has the potential to minimize the material required for the packaging to perform successfully in use,

Table 2. Non-exhaustive list of studies reporting nanocomposite manufacturing methods. Manufacturing method Function

NP type

Size

Matrix

Electrospinning

Antimicrobial

ZnO

30 nm

Chitosan film

Improved properties

MMT

Not stated

Gelatin film

Solution casting Solvent evaporation Twin screw extrusion Spray coating Immersion/reaction Reactive magnetron sputtering Automatic spreading

Author(s)

(Y. Wang, Zhang, Zhang, & Li, 2012) Improved properties TiO2 15-30 nm Soy protein film (Z. Wang et al., 2014) Antimicrobial CNT Not stated Cellulose film (Dias et al., 2013) Barrier and migration CNC & Ag 5-10 nm & 20e80 nm PLA film (Fortunati et al., 2012) Antimicrobial Ag 10-20 nm PE (Smirnova et al., 2012) Barrier and antibacterial 3-polylysine 100-230 nm Cellulose (Gao et al., 2014) Antimicrobial Ag & Ag doped ZnO 50-100 nm PET (Carvalho et al., 2014) (Vanin et al.)

(CNT ¼ Carbon nanotubes, CNC ¼ Cellulose nanocrystals and MMT ¼ Montmorillonite).

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NPs

Packaging matrix

Detection method

Food simulant

Parameters tested

Reference

Ag/s-CNC

PLA

ICP-MS Analytical-balance

10% ethanolIsooctane

(Fortunati et al., 2014)

Ag/Zeolite

PE

ICP-AES TEM Hach lange

3% acetic acid Distilled water

Storage time Storage temperature % Fill rate Food simulant % Fill rate

Cu & Ag Ag/ZnO

PE LDPE

ICP-MS SEM ICP-MS

Ag/s-CNC

PLA

ICP-MS Analytical-balance

Chicken breast 10% ethanol 3% acetic acid Distilled water Olive oil 10% ethanol Isooctane

Ag

PVC

ICP-MS SEM

Chicken breast

Ag

PE

ICP-MS

Ag Ag

LDPE PP PE

ICP-MS SEM ICP-MS TEM AFM

Ag Ag

PE PE

ICP-MS RSD AAS SEM (EDX capabilities)

Ag

PP

ICP-MS

Ag/MMT MMT Ag

PLA Starch based biopolymers PP HDPE

Strip- Voltammetry EDX-RF AAS Analytical-balance AF4-ICP-MS SEM

10% ethanol 3% acetic acid Distilled water Olive oil 50% ethanol 3% acetic acid Distilled water Alcohol/ ethanolSunflower oil 95% ethanol 3% acetic acid 95% ethanol 4% acetic acid Ultra pure water Hexane Tap water Deionized water 5% acetic acid Water/HNO3 Lettuce Spinach Distilled water 3% acetic acid

Ag & Zn

LDPE

TEM AAS

Orange juice

% Fill rate

Al & Si Cu

PET PLA-acetone

TEM XRD ICP-MS ET-AAS

3% acetic acid Saline solution

Storage time Storage temperature Storage time% Fill rate

Storage time Storage temperature Storage time Storage temperature Storage time Storage temperature % Fill rate Storage time Storage temperature % Fill rate Particle diameter Storage time Storage temperature Storage time Storage temperature No. of coatings

(Cushen, Kerry, Morris, CruzRomero, & Cummins, 2014b) (Cushen et al., 2014a) (Panea et al., 2014) (Fortunati et al., 2013) (Cushen et al., 2013) (von Goetz et al., 2013)

Storage time Storage temperature Storage temperature

(Echegoyen & Ner
ın, 2013) (Smirnova et al., 2012) (Ag coatings) (Song et al., 2011) (Huang et al., 2011)

Storage time Storage temperature

(Hauri & Niece, 2011)

Storage time % Fill rate

(Busolo et al., 2010) (Avella et al., 2005) (Artiaga, Ramos, Ramos, C
amara, & G
omez-G
omez, ) (Emamifar, Kadivar, Shahedi, & Soleimanian-Zad, 2010, 2011) (Farhoodi et al., 2014) (Conte et al., 2013)

Storage time Storage temperature

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Table 3. Nanoparticle migration studies.

J.C. Hannon et al. / Trends in Food Science & Technology xx (2015) 1e20

due to the improved structural and thermal properties imparted by the ENPs (Silvestre et al., 2011). ENPs are commonly immobilized within polymer packaging using two methods; formation of particles and/or polymer in situ or attachment of particles and polymer in their final state (Yang, 2003). In situ methods that involve incorporation of ENPs into liquid polymers, include spin coating and casting methods. When the polymer is a solid, ENPs can be formed by a reduction of ions. An example of this reduction process may be the formation of EAgNPs using silver nitrate (AgNO3) as a precursor (Cushen, Kerry, Morris, Cruz-Romero, & Cummins, 2014a). Attaching the ENPs and polymer in their solid state is a more complex process. Nanocomposites can be formed using a combination of casting followed by solvent evaporation. Alternatively, ENPs in powder form can be added to an extrusion process. More complex methods of creating nanocomposites include diffusion and synthesis of ENPs and polymer in situ. The method employed often determines the concentration and distribution of the ENPs within the polymer. ENP surface coatings for food packaging applications is an area which has, until recently, been neglected as a result of intensified ENP migration and the absence of commercially viable manufacturing methods. Nevertheless, due to the substantial benefits linked to ENP surface coatings, there needs to be a greater emphasis on research and development in this area. Applying ENPs to a packaging surface has an advantage of increasing the antimicrobial function of the ENPs as there is more reactive surface area in contact with foodstuff allowing greater Ag ion migration. However, the ENPs position makes them more susceptible to migration. Guo et al. (2013) reviewed methods of applying polymer coatings containing ENPs to surfaces in order to benefit from antibacterial properties. The inclusion of a polymer in the coating process highlights the poor attachment characteristics of certain ENPs. Further methods of ENP attachment with improved immobilization exist and have been considered for other industries such as the biomedical (Roguska, Pisarek, Andrzejczuk, & Lewandowska, 2014), energy and electronic industries (Kim, Lee, & Maeng, 2009). Therefore, it would be counter-productive to reject surface coating methods based on factors such as attachment which can be improved. A simple method of creating nanocomposites for antimicrobial application is via spray coating. Currently, the only study which has used spray coatings to coat ENPs to food packaging was carried out by Smirnova et al. (2012). A study by Nobile et al. (2004) used a plasma technique to coat EAgNPs in a polyethylenoxide-like coating on polyethylene food/beverage packaging. Despite this technique being considered for biomedical applications (Favia et al., 2000), this is the first time it has been proposed for application in food packaging. An emerging technology for incorporation of ENPs onto surfaces with improved immobilization is by means of a Self-Assembling Block Copolymer. The process involves self-assembly of uniform

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nanostructures using an anionic polymerization process. Once the nanostructure is in place, ENPs which have an affinity for the polymer substrate are attached to the nanostructure in a process called templating. The block copolymer is then exposed to some chemical reaction which leaves a nanoscale pattern. A major limiting factor of the process is the restricted number of organic monomers which can be used, such as PS, PB, PI and PMMA (Yang, 2003). Furthermore, only certain ENPs have an affinity for the polymer substrates which can be used for selfassembling block copolymers. Self-assembling block copolymers have been considered for use in the pharmaceutical industry as a means of drug delivery (Vauthier, Persson, Lindner, & Cabane, 2011), however, no studies have suggested this mechanism for attachment of ENPs in food packaging materials. Similarly, the use of Atomic Layer Deposition (ALD) methods have not been considered for use in food packaging applications. Unlike other methods, ALD provides an industrially viable and scalable method for coating food packaging. The “line-of-site” independent nature of ALD allows a pinhole-free film of ENPs to be coated to any surface that is exposed, including internal surfaces (King, Liang, & Weimer, 2012). ALD has the ability to deposit oxides, non-oxides, metals and hybridpolymer based materials on surfaces. Properties of nanoparticle food packaging For NP packaging to be embraced by the public there must be a seamless transition from existing packaging to nanopackaging. Certain functional and aesthetic characteristics of food packaging materials are generally recognised as necessary for a food product to be successfully marketed. Characteristics such as the transparency, structural integrity, gas barrier, antibacterial, product texture and in the case of re-usable storage containers washability, could be considered important. The transparency of food packaging is a desirable characteristic as it allows the consumer to view the content of the product before it is purchased. High percentages of well distributed fine NPs have been found to produce relatively transparent polymers (Nazarov, Khaydukov, Sokolov, Panchenko, & Shkurinov, 2013). However, small percentages of large size particles can cause a loss in transparency. Kanmani and Rhim (2014b) reported the linear decrease in transparency of gelatin films with increasing EAgNP content. The protein content of food has been shown to affect the transparency of packaging containing ENPs. Martinez-Abad, Lagaron, and Ocio (2012) observed varied changes in transparency and colour of NP packaging in contact with two food media, chicken and apple. The high protein sample, chicken was found to cause the greatest loss of transparency in comparison to the apple samples. Considering the most likely application of nanopackaging is for high value meat products, this is an important finding as loss in transparency would hinder the marketability of such a high protein product. In addition to the basic requirements of conventional

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packaging that nanocomposites must satisfy, there must also be clear benefits in terms of existing and novel packaging properties. Properties such as; barrier characteristics, oxygen scavenging, antimicrobial, thermal, biosensing and material strength. On examination of products that are commercially available, two areas which have seen increased interest can be recognised; gas barrier and antimicrobial nanocomposites (see Table 1). Gas and moisture barrier properties A particularly important function of food packaging is to maintain the sensory properties of the enclosed food product, as well as the freshness through transport and storage. A barrier to the outside environment should be established to prevent the movement of moisture and gases through the walls of the packaging (Simon et al., 2008). Nanoscale materials having large aspect ratios have the ability to improve gas barrier properties dramatically when incorporated as a filler into the walls of packaging. The increased aspect ratio creates an obstacle for gas and moisture passing through the packaging walls by increasing the path that the gas/moisture must travel. One particular type of nanomaterial which has been investigated to provide gas barrier properties to food packaging is nanoclay. It is evident that industry has taken an interest in nanoclays due to the range of food packaging products containing nanoclay which have been developed (see Table 1). A company called Voridan in association with Nanocor has developed a nanocomposite containing clay nanoparticles called Imperm. Imperm has been used by a number of companies, such as Honeywell (AegisÒ), Hite Brewery Co. and Bayer AG (Durethan KU2-2601) to produce their own nanocomposite packaging materials having improved material and gas barrier properties (Handford et al., n.d.). Ever since the pioneering work by Avella et al. (2005) on MMT ENPs in starch biodegradable films, research in the area of nanoclay composite packaging has evolved and diversified to include alternative packaging materials in combination with multiple types of NPs (Busolo et al., 2010; Farhoodi, Mousavi, SotudehGharebagh, Emam-Djomeh, & Oromiehie, 2014). Antibacterial properties The antimicrobial properties of packaging containing NPs has been attributed to the ENPs capacity to prevent the attachment and growth of bacteria at the surface of packaging (Lichter, VanVliet, & Rubner, 2009), as well as the release of ions to preserve food against microbial growth (Fortunati et al., 2014). One factor linked to the antibacterial efficacy of NPs which has been the subject of significant debate in the scientific community is the effect of NP size (Hajipour et al., 2012). The debate surrounds the question of whether NP size has an effect on antibacterial activity. Small well dispersed ENPs in the nano scale range of between 1 and 10 nm were shown to produce improved antimicrobial properties (Fern
andez et al., 2009). In a study concentrating on the size dependant

antimicrobial activity of Ag colloid NPs it was found that the smallest particles with a mean size of 25 nm had the greatest antimicrobial activity (Pan
acek et al., 2006). However, a recent study by Xiu, Zhang, Puppala, Colvin, and Alvarez (2012) stipulated that ENP size had an indirect effect on antibacterial activity. Under strictly anaerobic conditions EAgNPs were found to have a lack of antimicrobial activity. This implies that Ag ions are the source of antimicrobial properties. Therefore, ENP size does not increase cell toxicity but alternatively increases the reactive surface area for oxidation of Ag into Ag ions, increasing antimicrobial activity. Consequently, ENP aggregation is a factor that can dramatically reduce the antimicrobial activity of NPs by reducing the reactive surface area (Zook, Halter, Cleveland, & Long, 2012). Zook et al. (2012) demonstrated the effects that polymer coatings had on the agglomeration, dissolution and toxicity of EAgNPs. The application of coatings was found to decrease agglomeration and consequently increase toxicity. Improved antimicrobial properties can be exibited by a number of ENPs such as Ag, ZnO, TiO2 and MMT (Cushen et al., 2012). However, due to the superior antimicrobial properties of EAgNPs, there has been growing interest regarding the incorporation of EAgNPs and EAgNP hybrids in food packaging. Significantly improved antimicrobial properties have been observed for Ag-chitosan nanocomposites (Rhim, Hong, Park, & Ng, 2006; Sanpui, Murugadoss, Prasad, Ghosh, & Chattopadhyay, 2008). Ag ions released from EAgNPs in absorbent pads were found to be an efficient antimicrobial against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (Fern
andez et al., 2009). Similarly, Ghosh et al. (2010) demonstrated antimicrobial activity for EAgNP/agar nanocomposite thin films in the order C. albicans > E. coli > S. aureus. Contradictory studies can be found which present mild inhibition of S. aureus in comparison to the satisfactory inhibition of E. coli using EAgNPs of mean diameter 13.5 nm in an aqueous solution (Kim et al., 2007). When comparing antimicrobial studies it is important to consider the media in which the ENPs are restrained. Many antimicrobial studies deal with EAgNPs mobilized in aqueous solutions. The antimicrobial activity of ENPs contained in such a state could be considered a poor representation of ENPs immobilized in food packaging as the ionisation potential of ENPs is increased in a liquid medium. Thus it is important that antimicrobial studies be available for NPs incorporated in food packaging. Despite the considerable research focus on nanocomposites containing EAgNPs to provide antimicrobial activity, there has been instances of non-metal, metal-oxide and metal-hybrids being used to provide antimicrobial function. In particular, nanoclays such as MMT which would be conventionally exploited for barrier properties have been incorporated in food packaging as an antimicrobial. Rhim et al. (2006) observed greatly improved antimicrobial activity for four different chitosan-based nanocomposites

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containing unmodified MMT, organically modified MMT, Ag and Ag-zeolite ENPs. In later work, particular attention was paid to two chitosan/organoclay nanocomposites (CloisiteÒ 30B and CloisiteÒ 20A) which increased gas barrier properties in linear low density polyethylene (LLDPE) and gave antimicrobial properties against grampositive bacterium (Hong & Rhim, 2008, 2012). Other ENPs which have been found to be effective antimicrobials against food pathogens include ZnO (Akbar & Anal, 2014) and TiO2 (Bodaghi et al., 2013). Examples of materials containing natural antibacterial properties can also be found, which include protective nanostructured coatings on animals and insects. It has been shown that insects coat themselves with antibacterial substances to form a protective coating from predators and the environment. The surface of Cicada insect wings possess natural bactericidal characteristics attributed to their nanopillar surface coating (Hasan, Crawford, & Ivanova, 2013). A number of naturally occurring antioxidants have been studied for use in food packaging applications such as a-tocepherol, plant extracts and essential oil extracts from herbs and spices (Woranuch & Yoksan, 2013). For NPs to be adopted in industry for use in packaging to provide antimicrobial properties the benefits must be clear and substantial. A significantly increased antimicrobial activity must be observed for materials containing NPs which can compete with alternative antimicrobial materials which are already in use such as chitosan. Chitosan has been shown to be affective against a wide range of bacteria, is biodegradable and does not have the same regulatory barriers as nanocomposites due to its non-toxicity (Aider, 2010). The manufacture of nanocomposites such as biodegradable food packaging (e.g. chitosan) containing EAgNPs (Kanmani & Rhim, 2014a) providing synergistic improvements in terms of mechanical and antimicrobial activity could provide an alternative to conventional packaging. More attention is required for applications were NP combinations in packaging can present synergistic improvements and thus tackle some of the world’s current packaging problems (Busolo et al., 2010). Risk assessment strategies for nanoparticles in food packaging ENPs have the potential to cause harm to humans and the environment through increased toxicity, mobility and bioaccumulation. For nanotechnology to be accepted by consumers, all associated risks should be clearly communicated in such a way that consumers can make an informed decision. Furthermore, the level of risk posed to humans should be investigated under the worst case conditions of exposure. If an unacceptable level of risk is presented, a risk management strategy should be developed to mitigate the risk. Risk assessment is a methodology commonly used to assess the risk posed to humans and the environment from exposure to a substance or process. When

9

applied to ENP food packaging, the level of exposure to humans from ingestion of NPs is determined via migration studies and in vivo toxicity studies. If an acceptable level of risk is observed it is then the responsibility of the governing authority to allow or disallow the use of the product. A recent success of this process was the acceptance on TiN ENPs by the European Food Safety Authority (EFSA) for use in PET bottles in concentrations up to 20 mg/kg (EFSA, 2012). The function of TiN ENPs is to improve the oxygen barrier properties of the walls of the PET container that they are incorporated into. Excellent containment of the TiN NPs within the walls of the PET containers may be a unique aspect of the migration mechanism which is not shared by other NPs which require some level of migration to carry out their function. NPs such as EAgNPs must migrate in the form of Ag ions to allow for their antimicrobial function, while complying with the migration limits set out by the European Commission (EFSA, 2008; European Commission, 2011). Therefore a compromise must be made between the level of migration and antimicrobial activity. Exposure assessment models Frequently, substances that are considered harmful to humans may not exist in high enough doses to pose any real risk to humans. Mathematical exposure models provide a method for quantifying the risk posed to humans from NPs. Using the results from NP migration studies as an input to an exposure model, the associated risk from NPs can be predicted based on the scenario surrounding their use. Two common scenarios are often identified for human exposure to ENPs, the worst case scenario (wcs) and the most likely scenario (mls) (Cushen, Kerry, Morris, CruzRomero, & Cummins, 2013). The mls is an exposure value based on the most probable intake of a substance obtained from migration studies and survey data. The wcs involves the greatest exposure to ENPs possible, based on exaggerated migration and consumption data. To produce a human exposure model suitable toxicity studies, migration studies and consumer data must be available. Given the lack of in vivo toxicity studies for exposure to ENPs, it is necessary to adapt non-nano rodent oral toxicity studies and apply a safety factor. Only four human exposure models are currently available in the literature that quantifies the risk posed to humans from oral exposure to ENPs which have migrated from food packaging (Bachler, von Goetz, & Hungerb€uhler, 2013; Cushen et al., 2013, 2014a; von Goetz et al., 2013; Smirnova et al., 2012). In each study a mathematical model is generated to predict the potential migration and resulting migrant amounts are compared to actual migration results. The resulting migrant quantities are then coupled with consumer data to generate a model that predicts the risk posed to humans from oral exposure. von Goetz et al. (2013) observed worst case acute exposure of 4.2 mg EAgNPs caused by storage of 100 ml of food simulant in an EAgNP food container. Although this could be

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considered a large quantity of migrating particles it was noted that other potential sources of EAgNPs are present in nature which can contain comparably large quantities, such as drinking water (Akaighe et al., 2011). Weaknesses in the model were attributed to the uncertainties surrounding the toxicological effects of EAgNPs and the possibility of a “Trojan horse mechanism” (Kreuter, 2004). In the model no link was made to food consumption data and alternatively it was stated that a given amount of liquid food would cause worst case acute exposure for humans. A particular strength of the exposure model formulated by Cushen et al. (2013) was the use of chicken consumption data from an Irish survey to predict the exposure to an individual consuming the average quantity of chicken per day. In addition, when determining the toxicity of ENPs to humans the surface area of the dosage was considered alongside the weight of the dose when calculating the Provisional Ingestion Limit (PIL) which was adapted from O’Brien and Cummins (2010). It was found that the worst case conditions would cause migration of 8.85 mg/kg of EAgNPs, considerably lower than the conservative 60 mg/kg overall migration limit allowed by the European Union (European Commission (EU), 2002). This value far exceeds the specific migration limit of 0.01 mg/kg for unauthorized substances outlined in Directive 10/2011/EEC (European Commission (EU), 2011). Migration limits have been set by the European Commission for products that are used in applications involving particularly susceptible persons, such as infants (Commission Regulation (EU), 2009). Given the number of applications for nanocomposites in the infant food storage industry it is surprising that few studies have specialized in the area. In a recent study by Bachler et al. (2013) a physiologically based pharmacokinetic model was generated for ionic and NP silver for five exposure scenarios. Oral exposure was quantified for EAgNPs from two sources; dietary intake and from food which has been stored in ENP food storage boxes. The pharmacokinetic model was validated by comparing simulated organ concentrations to those obtained from in vivo experimental studies. It was demonstrated that for EAgNPs size and coating did not show a significant effect on biodistribution. Furthermore, in vivo studies suggested that EAgNPs are more likely to be stored as insoluble salt particles than dissolve into silver ions. Interestingly, in all exposure scenarios the Ag levels in most organs were below or around the background levels of dietary intake and lower than levels which would cause adverse effects in vitro. The results indicate that outside of an occupational setting, the level of risk to adults from exposure to nanosilver consumer products is low. O’Brien and Cummins (2011) presented a risk assessment framework on three nanomaterials; EAgNPs, cerium oxide NPs and TiO2 NPs which have the potential to accumulate in surface and waste water in the environment (O’Brien & Cummins, 2011). The framework utilized uncertainty and variability principles, alongside qualitative

risk assessment principles to generate a ranking system for metallic NP concentration, transport and persistence in aquatic environments. Nanomaterial characteristics as well as aquatic environmental characteristics were compiled to rank risk of exposure under three scenarios. The study highlights were data critical to NP exposure are lacking and suggests research needs in order to populate the qualitative framework with quantitative exposure data. Although, the risk assessment of human exposure to ENPs was not featured in the study, the structure of the framework was very applicable to food packaging risk assessments. Such a qualitative risk ranking framework for human exposure to nano FCMs would give a preliminary indication of human exposure and help prioritise quantitative exposure assessments to populate a nano food packaging exposure model. The NanoRelease Food Additives Expert Group (NanoRelease Food Additives Expert Group, 2015) has focused on the uptake of ENPs in the alimentary tract (Alger, Momcilovic, Carlander, & Duncan, 2014), characterisation methods and related risk management aspects. The expert group have published a number of papers, particularly in the area of characterisation of NPs released from FCMs (Noonan, Whelton, Carlander, & Duncan, 2014) and the use of gastro intestinal models to assess the digestion and absorption of ENPs release from FCMs (Lefebvre et al., 2014). A particular strength of the review carried out by Lefebvre et al. (2014) is the presence of an example approach for the assessment of the uptake of NMs in the human gastro intestinal tract (GIT). The model accounts for In vivo animal models, Ex vivo tissue models, In vitro cell culture models, In vitro non-cellular fluid models and In silico computational models. Each of these elements can be used to strengthen an overall methodology for the assessment of NP release from FCMs and subsequent human exposure. A comprehensive human exposure framework for flavours, additives and FCMs has recently been published under the FACET project (European Commission (EU), 2012). The framework combines European consumer surveys with toxicity studies to allow for the risk assessment of existing and emerging materials. A major downfall of the framework is the exclusion of nanomaterials in the list of contaminants. However, the project has the potential to be used as a methodology for the human risk assessment of nanomaterials. There is a growing need for a framework dealing with human exposure to NPs in FCMs. Barriers to such a framework being established include; gaps in knowledge related to ENP migration, ENP physicochemical properties, human toxicity and the fate of ENPs in the GIT. Fate of nanoparticles in the GIT In the human body there are three main routes of exposure from ENPs, these are dermal contact, inhalation and ingestion. Other uncommon routes of exposure which have recently become applicable, due to emerging ENP medicines

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and hygiene products, are through rectal administration, through the female genital tract and by direct administration into the blood by injection (Chen & Schluesener, 2008). There are numerous scenarios in which humans can be exposed to NPs through any of aforementioned routes. For example, a study on the levels of vinyl chloride from PVC in a domestic water supply found that the vinyl chloride could be ingested and also inhaled from shower water due to the formation of aerosols (Lee et al., 2002). In this review the principal focus is on ENP exposure via the oral route of exposure. It should be noted that although the possible risk to humans from oral exposure to ENPs are great, studies that focus on oral exposure and the fate of ENPs in the GIT are limited (Silvestre et al., 2011). At present there are no in vivo studies related to the toxicity of ENPs to the human body through the ingestion route. Therefore, the toxicity of ENPs in the GIT has been investigated by means of in vivo studies of rodents (Kim et al., 2008; Park, Bae, et al., 2010; Park, Marsh, et al., 2010), in vitro studies on representative human GIT cells (Aueviriyavit, Phummiratch, & Maniratanachote, 2014) and in vitro studies of ENPs when exposed to a synthetic human stomach (Rogers et al., 2012). Each independent study has the potential to contribute to a broader investigation into the toxicity of ENPs for humans. However, few studies have linked the numerous fragmented studies to build a general human exposure model for ENPs in food packaging materials. The ambiguous nature of ENP fate in the GIT has not aided the acceptance of ENPs in food packaging applications. Recent studies presenting data on important GIT mechanisms have shown similarities concerning ENP behaviour. Rogers et al. (2012) carried out in vitro studies on the exposure of EAgNPs to a synthetic human stomach and the effects of synthetic human stomach fluid on the agglomeration of NPs (Rogers et al., 2012). Following a 1 h exposure period it was noted that EAgNPs agglomerated and reacted with the synthetic stomach fluid to form silver chloride (AgCl). It was noted that the results may not have been representative of a human stomachs exposure to NPs due to the effects of some of the coating compounds used during the preparation of the EAgNPs. Similarly, Mwilu et al. (2013) carried out an in vitro study on the influence of synthetic stomach fluid on EAgNPs with different sizes and capping agents. Significant aggregation was noticed, particularly in relation to the smaller ENPs (<10 nm) in comparison to the larger particles (75 nm). A significant difference was also observed between the agglomeration of EAgNPs prepared in house (pvp-stabilized) to those obtained from a commercial source. Another important factor influencing the uptake of NPs into the GIT is the transit time of food after ingestion. In a review of different models of the human gastric and small intestinal digestion system, Guerra et al. (2012) gives a detailed break-down of the time required for food to pass through the GIT. When food passes into the stomach

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it is exposed to hydrochloric acid (HCL), pepsin and gastric lipase at a pH of between 1 and 5 for approximately 15 min to 3 h. It is then discharged to the small intestines where it is exposed to a higher pH of between 6 and 7.5 for 2 to 5 h. Lastly it is passed to the colon were it is exposed to a pH of 5e7 for 12e24 h before being removed from the body (Guerra et al., 2012). Both the time and pH that the food is exposed to while passing through the GIT generates a number of questions in relation to the fate of ENPs passing through the GIT. Time, ionic strength, pH and increased temperature are known to cause aggregation of ENPs as well as increased aggregate diameters (Liu, Surawanvijit, Rallo, Orkoulas, & Cohen, 2011; Majedi, Kelly, & Lee, 2014). This could possibly affect the toxicity or even migration of ENPs within the human body. Furthermore, it was suggested that the digestion of foodstuffs may take place in the nanoscale implicating that the human body has the potential to process such ENP substances (Chaudhry et al., 2008). Regardless of the ability of ENPs to aggregate and cause harm within the GIT, there are further worries in relation to the fate of NPs in the GIT such as the ability of ENPs to penetrate the natural barrier in the GIT and accumulate in organs potentially forming harmful doses. Fr€ohlich and Roblegg (2012) presented a review of human exposure to ENPs from consumer products through oral ingestion, with a focus on models demonstrating the ability of NPs to penetrate the natural barrier within the GIT. Most notably, ENP size is investigated as a major factor influencing the permeation of natural mucus layers in the GIT. From existing studies, it can be deduced that the toxicity to humans from exposure to ENPs will remain the subject of scepticism until In vivo studies are available. Another aspect which effects the toxicity of ENPs to humans is the ability or inability of ENPs to migrate from food packaging to food.

Nanoparticle migration Migration refers to the release of a substance from one medium to another. Following Fick’s first law of diffusion, the substance will migrate due to a concentration gradient between both mediums (Simon et al., 2008). If there are no ENPs present in the food, any ENPs that are loosely bound in the food packaging will migrate from the packaging to the food. This occurs due to the lower concentration of ENPs in the food which drives migration. Factors that affect migration include temperature, time, concentration gradient, material properties, migrant position in the material and the interaction between the migrant and material. The migration potential and diffusion mechanisms for ENPs from food packaging materials is an area of nanotechnology which has not received the same attention as such areas as nano-aerosols (Savolainen et al., 2010), nano-fluids (Mohammed, Al-aswadi, Shuaib, & Saidur, 2011) and nano-medicines (Lehner, Wang, Marsch, & Hunziker, 2013).

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Experimental migration studies Until recently, numerous nanocomposite food packaging related articles (de Azeredo, 2013; Echegoyen & Ner
ın, 2013; Rhim et al., 2013) have been unsuccessful in highlighting the increasing number of ENP migration studies (see Table 3). Several studies are present in the literature assessing the migration of ENPs from polymer food packaging to real food matrices and simulants. For example, the migration of EAgNPs and Ag-based ENP combinations are the most widely studied from packaging materials such as PVC (Cushen et al., 2013), PE (Huang et al., 2011; Song, Li, Lin, Wu, & Chen, 2011; von Goetz et al., 2013), low density polyethylene (LDPE) (Echegoyen & Ner
ın, 2013; Panea, Ripoll, Gonz
alez, Fern
andez-Cuello, & Albert
ı, 2014), PP (Echegoyen & Ner
ın, 2013; Hauri & Niece, 2011) and also biodegradable materials such as modified PLA (Busolo et al., 2010; Fortunati, Peltzer, Armentano, Jim
enez, & Kenny, 2013; Fortunati et al., 2014) and starch based biopolymers (Avella et al., 2005). The majority of studies have concentrated on the incorporation of ENPs into food packaging materials to avail of improved antimicrobial effects. In contrast, Avella et al. (2005) focussed on the improved biodegradability of starch based polymers containing MMT ENPs and Fortunati et al. (2013) examined the improved oxygen barrier properties of PLA containing pristine s-CNC and EAgNPs. Although the focus of migration studies is to assess the risk posed to humans through unintentional ingestion of ENPs from FCMs, two of the studies (Huang et al., 2011; Song et al., 2011) don’t compare the low levels of migration observed, to migration limits set by the European Commission (European Commission (EU), 2011) or another regulatory body. Furthermore, only four of the studies (Cushen et al., 2013, 2014a; von Goetz et al., 2013; Smirnova et al., 2012) included models for human exposure to ENPs. Even though different approaches were employed for each migration study certain aspects are similar. The use of food simulants is a commonality between almost all of the migration studies. A major benefit of using food simulants is that they cover a wide range of food types which allows for a comprehensive human exposure assessment when coupled with consumption data. Additionally, increased migration from using fatty or acidic food simulants produces a worst case scenario, adding a safety factor to human exposure assessment. Real food matrices such as chicken and turkey meat have been used to test the antimicrobial effect of active packaging (Contini et al., 2012; Cushen et al., 2013), however, it was pointed out by Contini et al. (2012) that the lower fat content of the turkey meat reduces the diffusion of antioxidants into the meat. In a migration study both chicken and turkey meat would not be a model food matrices for testing, as reduced diffusion could possibly cause the overall migration to be underestimated. A benefit of pairing real food matrices with the packaging in which they are sold, is that a human exposure assessment can be carried out for that particular food application.

Depending on the desired outcome of the study, migration can be determined in terms of an overall migration limit (OML) or a specific migration limit (SML). An overall migration study is used to clarify that no packaging additive or contaminant migrates from the packaging to food. Specific migration studies involve the analysis of a particular migrant from packaging. With a focus on presenting a worst case migration scenario as well as a most likely scenario, multiple packaging and environmental factors have been investigated; mainly storage time, storage temperature, ENP percentage fill and ENP size. Natural light has the potential to degrade polymers via photo-oxidation and increase migration of substances from those polymers in applications involving long term exposure (Kumar, Depan, Singh Tomer, & Singh, 2009). However, due to the short exposure period for food packaging in service it is unlikely that natural light will cause significant deterioration and have any effect on migration. Few studies have considered the increased migration from packaging in scenarios of repeated use (von Goetz et al., 2013). This is surprising given the number of studies which have determined the migration from reusable food storage containers such as lunch boxes and re-sealable bags. Directive 10/2011/EEC (European Commission (EU), 2011) states that for articles destined for repeated use, three repeated migration tests should be carried out using a fresh food simulant sample after each repetition. Disregarding such conditions could potentially lead to underestimated migration levels. The use of combinations of ENPs in packaging films has been found to affect the migratability of substances. In studies on PLA modified with pristine CNC and including EAgNPs, it was found that the migration of Ag was faster in the samples that had been modified with the CNC nanocrystals (Fortunati et al., 2013). The inclusion of the modified nanofiller with a high affinity for PLA consequently resulted in higher Ag ion mobility and increased migration. Studies are also available which focus on the detection of Ag ion migration specifically and not ENP migration (Kumar, Howdle, & M€unstedt, 2005; Mart
ınez-Abad, Ocio, Lagar
on, & S
anchez, 2013; Fernandez, Soriano, Hernandez-Munoz, & Gavara, 2010). Given the number of migration studies to date, it is remarkable that no framework has been generated to deal with the migration of ENPs from food packaging materials. This could be attributed to a lack of applicable numerical models or the rapid development of ENP polymer composites for food packaging applications. Mathematical migration models In terms of migration modelling, a mathematical model provides an analytical formula containing a compact relationship between relevant variables in a system. Numerical models are applied in situations where mathematical models cannot be solved analytically and involve an iterative computational procedure (Barnes & Chu, 2010). Mathematical and numerical models can be highly beneficial

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when used for ENP migration modelling as they can produce comparable migration results, for a range of different system conditions. There is the potential for mathematical and numerical models to be used as an alternative for costly and time consuming migration studies. Currently there is only one mathematical model (Simon et al., 2008) which focusses specifically on ENP migration from polymer food packaging to food. Simon et al. (2008) presented general equations for the migratability, diffusion rate and amount of migrating particles. The type of ENP was not accounted for. Instead the size of the ENP and the viscous properties of the polymer were used. The interphase between the packaging and food was assumed to present no obstacle to the migration of ENPs. The wide-ranging applications of the mathematical model are a significant advantage, giving an insight into the probability of ENPs migrating from popular polyolefin packaging materials. However, neglecting specific characteristics of ENPs on a case-by-case basis has the potential to cause errors in the results. There are a number of mathematical models which deal with migrants which are of nanoscale dimensions such as monomers (Helmroth, Rijik, Dekker, & Jongen, 2002; Lickly, Rainey, Burgert, Breder, & Borodinsky, 1997). Helmroth et al. (2002) presents a critical review of existing migration models for regulatory purposes. ENPs are not specifically mentioned in the review, however, certain polymer monomers are listed as possible migrants which are of nanoscale size. Deterministic, stochastic and worst case mathematical models were critically reviewed on the basis of migration prediction. They concluded that although mathematical models allowed for cost and time saving when compared to experimental migration studies, it is still necessary to confirm migration quantities with experimental studies. Similarly, Lickly et al. (1997) examines the limitations of mathematical models dealing with the migration of acrylonitrile and styrene monomers from food packaging materials (Lickly et al., 1997). From the migration predictions an estimate of US consumer exposure to both monomers was created. Assuming that ENPs follow the laws of Fickian diffusion, models generally dealing with the diffusion of additives and contaminants could be applied to ENP diffusion. Mathematical models have been used to model the migration of phenolic antioxidants from polypropylene (Hamdani, Feigenbaum, & Vergnaud, 1997) and general food additives and contaminants from food packaging films (Chung, Papadakis, & Yam, 2002). Fortunati et al. (2013) calculated the diffusion coefficients for PLA modified with s-CNC nanocrystals with nanosilver using the migration model described by Chung et al. (2002) showing the broad applicability of the model. Numerical migration models Numerical models dealing with ENP migration from packaging to food are lacking. To date, a numerical model presented by von Goetz et al. (2013) is the only model which deals with ENP migration from food packaging.

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The numerical model is a 2D Lagrangian Particle Tracking Model (LPTM) which was adapted from a model predicting the “Influence of Dead-Water Zones on the Dispersive Mass Transport in Rivers” (Weitbrecht, 2004). The model assumes Fickian diffusion and takes account of the ENP diffusion from within the polymer to the plastic/liquid interphase. What occurs beyond the interface as well as leaching effects of liquid food matrices are excluded from the model. The affect that the penetration of food has on migration of particles from food packaging is a major factor that has been intentionally neglected in all the aforementioned migration models (Hamdani et al., 1997). Regulation due to possible migration Due to uncertainties in relation to ENP migration, a number of regulatory bodies have placed strict regulation on the use of ENPs in FCMs. In each region, regulatory authorities have taken their own approach to manage the commercialisation of ENP FCMs, whether it is in the form of a guidance document, specific FCM regulation or amendment to existing FCM regulations. Regions such as Australia, New Zealand, United States of America, European Union and Canada have made amendments to current FCM legislation and have provided general guidance documents for nanomaterials. For countries such as Brazil, Argentina, China, Japan and Mexico there has been limited regulation related to nanomaterials. None of the aforementioned countries have established regulations specific to ENPs in FCMs (Magnuson et al., 2013). In Australia and New Zealand the Food Standards Australia New Zealand has amended its Application Handbook (Food Standards Australia New Zealand [FSANZ], 2013) to include FCMs containing substances in the nanoscale. Health Canada has provided a guidance document for nanomaterials in general (Health Canada [HC], 2011). Prior to 2004, European Union regulations related to the application of nanomaterials in FCMs were limited. Regulation No. 1935/ 2004 of the European Parliament was the first regulation to deal with active and intelligent materials intended to come into contact with foodstuff. ENPs were not mentioned specifically, but were instead accounted for under the terms ‘active’ and ‘intelligent’ materials. European Commission Regulation No. 10/2011 (European Commission (EU), 2011) was brought about amending and consolidating EU Directive 82/711/EEC (European Commission (EU), 1982) and 85/572/EEC dealing with migration studies and food simulants. In Regulation No. 10/2011 it is stated that any substance which can migrate from food packaging to food must not exceed the limit of 10 mg/dm2 of the FCM. Included among the list of substances for use in FCMs are active and intelligent materials which includes nanomaterials (European Commission (EU), 2011). The limit of migration for a specific substance can be altered in the event that a risk assessment is carried out which shows a higher overall level of migration. The current status

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of NP FCM regulation is outlined in Fig. 1. The United States Food and Drug Administration (USFDA) regulate the use of nanomaterials in FCMs in the United States of America. According to the USFDA in a recent guidance document (United States Food and Drugs Association [USFDA], 2014), for a new FCM to be made commercially available the product manufacturer must provide a safety assessment which includes studies on humans and animals evaluating its safety under the worst case conditions of use. Furthermore, studies must also distinguish the food substances identity, stability, purity, potency, performance and usefulness. Throughout the document it is stressed that the reduction of any substance to the nanoscale is considered a significant deviation from conventional manufacturing processes and consequently merits particular examination. In such cases, safety evaluations should be accompanied by toxicity studies specific to the substance and should not use data extrapolated from conventionally

manufactured substances. An important point is that the USFDA states that it does not make generalisations related to the harmfulness of all products containing nanotechnology but instead encourages industry to provide specific risk assessment so that products can be assessed on a case-by-case basis. When dealing with polymer food packaging including nanomaterials, an important argument is that although agglomeration of ENPs during synthesis can be problematic, once the polymer has been formed the ENPs are practically immobilized (Yang, 2003). This characteristic can be beneficial in terms of reducing the risk to humans from exposure to NPs which have migrated from food packaging to foodstuffs (Savolainen et al., 2010). Immobilization can also hinder the antimicrobial properties that are migration dependant. It is the basis for the recent acceptance of TiN ENPs for use in PET bottles up to 20 mg/kg by the European Food Safety Authority (EFSA). This is

Fig. 1. Schematic illustration of the current status of food contact material legislation in the European Union.

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as a result of a specific risk assessment on the novel food packaging material conducted by ColorMatrix group (EFSA, 2012). The study found that TiN ENPs did not migrate from PET bottles in any harmful amount under a range of time and temperature conditions. As a result of the positive outlook from the risk assessment, TiN ENPs were added to the EFSA 21st list of substances for FCMs (EFSA, 2008). The acceptance of TiN ENPs in PET bottles shows promise for the acceptance of other nanomaterials for food contact applications in the future. Conclusion In recent years, ENP food packaging technologies have been the focus of attention due to their associated benefits. Development has increased exponentially with industry, academia and regulatory bodies contributing to the uptake of the technology in the food industry. However, the increased use of ENP food packaging is being impeded by uncertainty surrounding ENP toxicity and bioaccumulation. For society to accept ENP technologies human risk assessment must indicate an acceptable level of risk for the technology in question under the worst case scenario of use. The level of risk should then be clearly communicated to regulatory bodies and the consumer to allow them to make an informed decision on the use of the product. In light of the increasing numbers of ENP migration studies, only three studies have presented human exposure assessment models for unintentional uptake of ENPs from active food packaging (Cushen et al., 2013, 2014a; von Goetz et al., 2013; Smirnova et al., 2012). Given the uneven ratio of migration studies (19) to human exposure assessments (4) it can be seen that more emphasis needs to be placed on presenting comprehensive exposure data that could be informative to regulatory bodies and the consumer. In the area of ENP food packaging, developments have materialized at a relentless rate. Methodologies for ENP synthesis are emerging with higher yields, greater size control, decreased environmental impact and improved industrial viability. Additionally, novel antimicrobial nanocomposites are being developed using bioavailable materials from food and plant extracts which eliminate some of the toxic and regulatory issues related to metal and metal oxide nanocomposites. New sources of NPs from food and plants are being investigated which are readily available in large quantities and may not have the same public perception and toxicity as metal derived ENPs. There is presently no migration study or human risk assessment that deal with food and plant derived ENPs incorporated into food packaging. In the literature, knowledge gaps are present in a number of areas. The majority of studies have had an undeviating focus on packaging with ENPs incorporated within polymer substrates. Presently, only two studies have assessed the migration of ENPs from antimicrobial food packaging coatings (Nobile et al., 2004; Smirnova et al., 2012). Given the clear benefits of using surface coatings it is surprising that limited studies are available. Currently there are no

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mathematical or numerical models for NP migration prediction from the surface of packaging. Similarly, no human exposure models or frameworks exists for packaging ENP surface coatings. Although the European Commission have imposed strict regulations on the migration of unauthorized contaminants from FCMs in applications involving particularly susceptible persons, no studies have focused on applications such as infant FCMs. Following the recent release of the FACET exposure tool it has become apparent that a similar framework specific to ENPs would be highly beneficial to industry, consumers and regulatory bodies. A framework would allow for the amalgamation of data from the multiple fragmented migration and toxicity studies, establishing a footing for the safe uptake of ENP polymer composites in the food packaging industry. Acknowledgements This work was funded under the Food Institutional Research Measure (FIRM) as administered by the Irish Department of Agriculture, Food and the Marine (Project no. 11/F/038). References Aider, M. (2010). Chitosan application for active bio-based films production and potential in the food industry: review. LWT e Food Science and Technology, 43(6), 837e842. http://dx.doi.org/10. 1016/j.lwt.2010.01.021. Akaighe, N., MacCuspie, R. I., Navarro, D. A., Aga, D. S., Banerjee, S., Sohn, M., et al. (2011). Humic acid-induced silver nanoparticle formation under environmentally relevant conditions. Environmental Science & Technology, 45(9), 3895e3901. http://dx.doi.org/10.1021/es103946g. Akbar, A., & Anal, A. K. (2014). Zinc oxide nanoparticles loaded active packaging, a challenge study against Salmonella typhimurium and Staphylococcus aureus in ready-to-eat poultry meat. Food Control, 38(0), 88e95. http://dx.doi.org/10.1016/j. foodcont.2013.09.065. Alger, H., Momcilovic, D., Carlander, D., & Duncan, T. V. (2014). Methods to evaluate uptake of engineered nanomaterials by the alimentary tract. Comprehensive Reviews in Food Science and Food Safety, 13(4), 705e729. http://dx.doi.org/10.1111/15414337.12077. Artiaga, G., Ramos, K., Ramos, L., C
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Please cite this article in press as: Hannon, J. C., et al., Advances and challenges for the use of engineered nanoparticles in food contact materials, Trends in Food Science & Technology (2015), http://dx.doi.org/10.1016/j.tifs.2015.01.008