Nanotechnology includes a set of disciplines, techniques, and devices to manipulate, restructure, and design matter at a nanoscale level (one billionth of a meter). The material containing particles, aggregates, or filaments of dimensions smaller than 100 nm is now called nanomaterial. Therefore, nanotechnology results in the formation of a diverse range of new structures and systems now called nanoparticles, nanodispersions, nanolaminates, nanotubes, nanowires, buckyballs, quantum dots, and other terms . The modification and fabrication of materials at nanoscale creates small-sized particles with a very large ratio of surface area to volume. This has led to improved optical, electrical, mechanical, and functional characteristics of matter and is responsible for the successful current and future applications of this new interdisciplinary technology . The size of nanoparticles, their distribution, number of interfaces or grain boundaries, the chemical composition of the constituent phases, and their interactions are the basic factors governing the unique properties of nanomaterials. These naturally occurring or engineered particles of the 21st century can be termed “magic bullets” because they can be targeted to deliver in a specific manner and thereby have high potential in various applications, including the manufacture of drug, textile, and food.
Agriculture and food production have been directly associated with human development and welfare as well as ecosystem maintenance. With the constant rise in world population, current environmental hazards, global climatic change, shortage of energy sources, and shrinkage of arable land, the use of modern technologies to increase and improve food production and food quality is imperative. The use of nanotechnology in food and feed processing is applicable at all stages of production, packaging, storage, transportation, and value addition. Nanotechnology has many beneficial effects in the food sector, including the costs involved, environmental hazards, disease detection to prevent losses, and management of farm practices. The enormous potential and ability of this powerful technology to combat various problems have already shown successes in the agroindustrial sector, and many more applications are under research and are yet to be commercialized . The use of nanoparticles, as in crop disease detection and protection, smart delivery systems for bioactives, fertilizers, pesticides, and fungicides, less use of harsh chemicals in the food chain, encapsulation of enzymes for various processes, use of nanosensors in food packaging and transportation, and use of nanoparticles to detect food contamination and food adulteration, has revolutionized the food industry worldwide . The most promising use of nanotechnology in food technology is the functionality that can be achieved by the relatively small amounts of these engineered nanoparticles, their increased interfacial reactions that enhance the effectiveness of their use, and their easy formulation, better handling, and lesser impact on the environment.
Food technology combines all the unit operations that take place from the farm to the time food reaches the fork. The use of lightweight sophisticated machinery and the design of nanoprocessor chips are the benefits of this powerful technology at the farm level of agriculture. Good agricultural produce depends on the adequate use of fertilizers, pesticides, and fungicides and their excessive amount that poses threat to human health and the ecosystem. The targeted release of nanofertilizers and encapsulated pesticides and herbicides offers the benefits of controlled release and prevent the excessive lumps of these chemicals to be dumped into the soil . The use of nanolaminates and various functional ingredients, such as antioxidants, flavor enhancers, browning inhibitors, and enzymes in food packaging, plays an important role to prevent the deterioration of food from excessive ingress of moisture, dust, light, off-flavors, and off-odors. The combination of information technology and nanotechnology has led to the development of nanosensors. Nanosensors have effective applications in packaging, storage, and transit operations of food products as they can sense and signal the information regarding freshness, quality, and physical, chemical, and microbiological changes that are important parameters of food quality and safety. The incorporation of nanoparticles (silicates) in the packaging material can improve the mechanical properties and can be used to make biodegradable packaging material with improved barrier properties. The safety and quality of food products are of utmost importance to consumers nowadays and the sensitivity of nanosensors to detect minute concentrations of heavy metals, pathogens, and toxins in food items is another promising aspect of this nanoscale science in the food sector. The combination of nanobiosensors with intelligent packaging systems (active and smart packaging) is an extremely sensitive and rapid technique for food pathogen detection and food quality maintenance . The advancement in nanofabricated tools has facilitated better detection of plant and animal diseases and the development of novel disease control approaches such as nanostructures to study the mechanism of bacterial colonization in plants and target drug delivery systems . Nanosized functional ingredients manufactured as nutraceuticals and functional food have greater nutrient retention and absorption and are made as nanoemulsions for better bioavailability in the body. Nanotechnology provides an opportunity to modify the structure, properties, and interaction between various food components to design novel food with improved taste, texture, flavor, freshness, and stability .
The last decade has seen tremendous growth in the study of the adverse effects of nanoparticles. Most of these reported studies are in vitro studies performed primarily by dosing a specific amount of nanomaterial to cells that are growing at the bottom of the plate. Further, the response of the cells is monitored to conclude what effect does that particular nanomaterial has on the cells. Different studies cannot be compared to each other for these are often carried out with arbitrary conditions and nanomaterials that are not well characterized. For now, we can make out that there are only a few studies that offer consistent results and are of value. Large-scale progress in the field of nanotoxicology has been seen, but there still is a void between validation and evidence-based studies. There is a need for high-throughput methods such as metabolomics along with evidence-based studies.
2 Nanotechnology usage in food – current scenario and public opinion
Food business stakeholders and research scientists have realized all the potential applications of nanotechnology in food, although the success of any emerging technology depends much on its cost-effectiveness as well as on the public perception of its risks and benefits . Nanotechnology has numerous advantages to benefit agriculture and food industry, but its market usage is still marginal and uncertain in the food industry while it is used rapidly in other industrial sectors of medicine, biotechnology, information technology, and physical sciences. This limited market coverage of nanoagrotech products is due to the lack of adequate returns in comparison to the huge initial investment involved, scarcity of regulatory framework, and varied public perception. Large companies are busy patenting various applications to seek the security of their future operations, but industrialists do not identify any large economic gains due to the limited field usage. Various regulatory agencies are assessing the safety issues of the nanotechnology products and are putting up more consensus and harmonized approach toward the improvised food sector applications of nanotechnology .
Many studies in this regard have shown that public response toward the awareness of nanotechnology is neutral, but there is more deflection toward those applications where nanoscience is not directly applied to food. The use of natural food constituents is preferred more than nanostructured additives, so this dynamic technology has identified commercial applications in food packaging market with good consumer acceptance than the nanotechnology food themselves , . The study conducted by Matin et al.  examined the perception of the general public toward the acceptance of nanotechnology in food science, which showed that 30% of the respondents supported the benefits of nanotechnology over risks, 44% were of the opinion that risks are coincident with benefits, and 26% perceived that risks are more than overall benefits. Consumer acceptance towards any novel food item is governed by individual preference or choice and by the knowledge of the science that is behind its production. The focus of nanotechnology toward sustainable environment and society is appreciable but not complementary with the risks perceived to health by the use of this technology . It has been observed that people perceive nanotechnology risks similar to genetically modified food, thus reducing the consumption of such food. Also, government regulations and trust issues influence individual responses .
3 Nanotechnology applications in the food industry
3.1 Food packaging sector
The proper packaging of any food item is critical to prevent food spoilage and deterioration from environmental effects and for the maintenance of safety during storage and transportation. The commercial market for nanotechnology in the food and beverage sector was about $6.5 billion in 2013 with an annual growth rate of 12.7% and is likely to reach $15.0 billion by 2020 . Distinct functional and novel properties of packaging material have been achieved by the inclusion of nanoparticles with different physical and chemical characteristics . Nanocomposites using nanoclays and layered silicates for food packaging have been made by introducing inorganic and hybrid organic-inorganic systems in packaging materials that elicit multiple functions, improve barrier and mechanical properties, and are more biodegradable and stable than conventional packaging materials . The incorporation of silver, zinc oxide, titanium oxide, and titanium nitride as nanoparticles have been done in various packaging systems for antimicrobial properties, with zinc oxide being relatively more efficient and cost-effective than others. The antimicrobial effect is attributed to the lysis of the bacterial membrane due to photocatalytic reactions of nanostructured particles. Titanium nitride has been generally used to improve the mechanical strength of packaging materials such as polyethylene terephthalate (PET). Clay nanoparticles have been used to manufacture PET bottles for beverages, reducing the gas permeation rate and ingress of oxygen and thus maintaining the carbonation of beverages, especially beer, for about 30 weeks , , .
Nanolaminates prepared from polysaccharides, proteins, lipids, and colloidal particles help to preserve the overall acceptability of food and extend the shelf life of various agrofood. These laminates are being used as edible coatings to encase food as these films are active barriers to oxygen and carbon dioxide exchange and have high mechanical strength in terms of rigidity and flexibility. Edible films have application in different types of food such as fruits, vegetables, chocolate, candies, baked goods, and meat .
Nanocomposites made from starch with poly-β-hydroxyl octanoate and starch with nanoclay showed higher strength and a higher barrier against water vapor. The incorporation of active functional substances such as antimicrobials, antioxidants, browning inhibitors, flavor promoters, and enzymes into the nanolaminates improve the quality of food; for instance, ethylene-absorbing nanoparticles have been reported to enhance the shelf life of various perishable fruits and vegetables by absorbing the ethylene gas produced by the respiratory food , .
Nanoscience has been used to make biodegradable plastic packaging materials lighter in weight and thermally more stable with improved barrier protection. The use of montmorillonite, polylactic acid, polycaprolactone, and polyhydroxybutyrate containing nanoclays as fillers has shown to extend the shelf life of fast food, bakery products, fruits, and vegetables by improving the mechanical strength and thermal stability of nanocomposite films , . Biodegradable plastic films can be formed by using zein (prominent corn protein) nanoparticles after treatment with acetic acid, ethanol, or formaldehyde and various silicates, with the resulting material being chemically inert and possessing high tensile strength, microbial resistance, and barrier properties against moisture, oxygen, and volatiles. This is attributed to the unique structure of the zein molecule forming a mesh of tubular structures and to the locking of nanocomplexes in polymeric materials that are able to control the diffusion rate . Durethan KU2-2601 is a packaging film containing nanosilicates to prevent food spoilage developed by Bayer Polymers (Pittsburg, USA) and is currently available commercially . Natural bionanopackaging polymers have been prepared from starch and protein molecules with the advantage of better stability for particulate food and ability to deliver functional ingredients. Such biodegradable and innovative nanocomposites have been developed by Plantic Technologies Ltd. (Victoria, Australia) using cornstarch. Chitin, a natural polymer found in crustaceans, can be drawn into nanofibers having antimicrobial properties, and such natural nanopackaging materials have great potential to improve food safety, stability, and food quality , .
Active and intelligent packaging systems are used to sense the changes in the food package and signal those changes to consumers while at the same time being capable of releasing active functional ingredients that preserve the food. Active packaging applications of nanotechnology have the largest share in the market and produced about USD 4.35 billion sales in 2014. The polymer packaging material with nanoclay addition has 70% market coverage and has shown 100% efficiency to prevent permeability in PET due to the layered structure of the polymeric material and exfoliated clay platelets . The efficacy of silver-polyamide 6 nanocomposites has been studied against Escherichia coli and has shown persistent and longer antibacterial activity. Packaging films coated with titanium dioxide (TiO2) have been found active against contamination of food contact surfaces . Various companies, such as The Sharper Image (Fresher Longer, USA) and Blue Moon Goods (Fisher Scientific, USA) and A-DO Global (South Korea), have developed plastic food boxes with silver nanoparticles incorporated in them, and silver zeolites have been used in commercial active packaging systems by Agion Technologies permitted for use by the European Food Safety Authority . Antimicrobial nanoparticles are impregnated on nanolaminates or kept in sachets or dispersed into the package or coated on the surface matrix of packaging material to reduce the microbial growth. Nanoparticles of TiO2 as oxygen scavengers and enzymes to control off-odors have been successfully developed for processed meat, ready-to-eat food, pasta, and fish products by Sealed Air Corporation (Saddle Brook, NJ, USA) using the nanotechnology approach , .
3.2 Nanosensors for food quality evaluation
Food preservation has a great importance to prevent food spoilage by retarding microbial growth rate. The rapid detection of physical, chemical, and microbial contamination in food is enabled by nanosensors . Low-cost nanosensors can be introduced in food packages to sense the changes in the quality of food at various stages of storage and transportation. These sensors signal these changes by some visible, optical, or electrical outputs.
Nanosensors to detect the presence of insects or pests inside storage systems of grains have been developed in Canada and have the advantage of low power requirement, lightness, and easy installation . The electronic tongue has been successfully incorporated into packaging materials having the ability to show a visible color change when the package environment changes. Electronic tongue used in smart packaging of food and beverages, developed by Kraft Foods, has a large number of nanoparticles that are sensitive to the changes associated with the staling of fresh food. Such devices have shown much higher sensitivity to recognize different tastes compared to human tongue , . Electronic nose with gas sensors is made of nanowires and is able to detect and signal different types of odors in food packages. An electronic nose has been used to sense the quality change in grain samples in response to fungal contamination , .
Nanofabricated glucose biosensor and liposome nanoparticles have been employed for the detection and quantification of glucose and allergenic proteins in food, respectively , . A glucose-sensitive enzyme with gold nanoparticles has been reported to successfully quantify the amount of glucose in beverages and the detection of aflatoxin B1 to a limit of 0.01 ng/ml has been achieved by nanoimmunosensors . Microfluidic nanosensor, a chip made of silicon, is a rapid device and can detect pathogenic contamination with low sample volumes being used , . Polychromix (Wilmington, MA, USA) produced a digital transformer using the nanoelectromechanical system to perform food analysis by estimating trans-fat content in food. These quality-control devices respond through different frequencies using transducers that are capable of detecting biochemical signals produced by any kind of adulteration in food and storage areas. These devices are portable, low cost, and easy to interpret. A nanocantilever developed by Bio-Finger (the European Union funded the project) is an innovative silicon biosensor that detects the antigen-antibody and enzyme-substrate reactions and produces electromechanical signals of various frequencies to detect the pathogens, various proteins, chemical toxins, and residual contaminants in food. One such nanocantilever has been developed to detect pathogenic microorganisms in food and water .
The optical detection of pathogens in a food sample by reflective interferometry using nanoscience works on the principle of measuring light scattered by mitochondria of cells when a known pathogen protein on the silicon nanochip binds to any other similar pathogen protein present in a food sample. Fluorescent dyes to detect pathogens such as Salmonella in food are more rapid than the conventional laboratory methods with less incubation time. An anti-Salmonella antibody with nanodye particles attached to silver nanorods is a sensor that produces visible color when food is contaminated with Salmonella. The optical detection of microorganisms such as E. coli and Salmonella in food due to the interaction with nanosensors has been developed by Agromicron Ltd. (Harbor Road, Wanchi Hong Kong) and named as Nano Bioluminescent Spray. The denser the microbial load present in a food product is, the more the intensity of light produced will be , , . The detection of pesticides and heavy metal residues is very important in food due to the acute toxicity and adverse effects they pose to human health and the environment. For instance, the optical properties of quantum dots have been studied to detect pesticide residues in food . A highly sensitive and accurate optical sensor made of gold nanoparticles has been used to detect the adulteration of pet food and infant food. The sensor binds to melamine and produces a color change from red to blue based on analyte concentration and thus measures the melamine content of raw milk and infant formula. The detection of cyanide in drinking water can be efficiently achieved by fluorescent assay of gold nanoparticles used as aggregates and luminescent quantum dots with specific antibodies are able to detect botulinum toxins to picomolar levels to ensure food safety .
The presence of excess moisture and oxygen inside food packages triggers undesirable changes causing food spoilage and the use of nanosensors to detect changes in gas concentration inside package headspace is valuable. Nanosized particles of TiO2 and a dye (methylene blue) have been used to produce a fluorescent indicator ink to detect oxygen concentration inside packages and thus help to control the modified atmosphere package conditions . Copper nanoparticles coated with carbon are able to detect excess moisture condition inside packages that induce a color change in sensor strips due to the separation and swelling of nanoparticles in the humid environment . Carbon dioxide detection in modified atmosphere packaging is made possible by fluorescent dyes incorporated in nanobeads .
Pathogen detection methods developed by nanoscience are gaining importance in food analysis as they offer benefits of sensitivity, speed, reproducibility, and high efficiency with less measurement time. The microbial detection of bacteria, viruses, and toxins becomes convenient due to easily observable optical signals and electrical signals produced by the binding of nanoparticles to antibodies of the target microorganism. Nanotechnology uses magnetic separation assays in combination with antigen-antibody interaction to separate the target pathogen from complex food substrate and then detects it by near or mid-infrared spectroscopy. For instance, the use of magnetic iron oxide nanoparticles can be used to separate Listeria monocytogenes from contaminated milk. A similar approach detects Brucella antibodies in infected blood serum of cows .
3.3 Carbon nanotubes (CNTs)
CNTs are hollow tubes made of graphite carbon with an additional atom group attached to their peculiar hexagonal shape, hence becoming low resistance conductors . The use of nanotubes in food applications is accounted for the unique thermal, chemical, mechanical, optical, and electrical properties of these single-walled or multiwalled nanotubes. The use of these carbon tubes in nanosensors has increased the antimicrobial property of the sensor, which can be attributed to the penetration into microbial cell walls by these tubes leading to irreversible damage and cell death . For the rapid detection of E. coli in food, a CNT with perfluorosulfonated polymer sensor has been developed by Cheng et al. . Similarly, an antibody-specific CNT sensor has been used to monitor food quality by identifying Salmonella infections in nutrient solutions. Multiwalled CNT-containing enzyme cholesterol oxidase on carbon electrode has been designed for cholesterol detection in high-fat food and has shown excellent performance , .
Electrochemical detection using CNTs can be used to detect vitamin content, flavor-producing compounds, and antioxidants in food such as beans and apples as well as the presence of food colorants such as Ponceau 4R and Allura Red in beverages and Sudan-1 in ketchup , . Various nanosensors are designed using CNTs for the binding of specific antibody and produce a significant change in the conductivity of sensor, which is easily detectable than traditional methods . The addition of CNTs (single walled or multiwalled) as fillers to packaging materials resulted in extremely high tensile strength, toughness, and barrier properties in materials such as polypropylene, polyamide, polyvinyl alcohol, and others . Nanotubes obtained by the hydrolysis of the α-lactalbumin present in milk proteins are highly dense and stable protein nanotubes with large aspect ratio and high elasticity. These food-grade nanotubes can serve as carriers of nutrients, supplements, and aroma compounds , . The CNT gas sensor used in active packaging is able to monitor carbon dioxide and ammonia levels to maintain the requisite gaseous environmental conditions .
3.4 Use of nanobarcodes for product tracking and anticounterfeiting
Packaging is a coordinated system that ensures the marketing and delivery of goods to consumers in a condition that is safe, acceptable, and without any product modification, typically associated with counterfeiting . Nanotechnology has helped food business industries to track and trace a food product, to prevent package tampering, and to ensure brand protection. To avoid the recall of a product from the market, advances in nanotechnology have the potential to improve the traceability and authenticity of the product in the market supply chain .
The use of nanobarcodes on the packages that contain all the necessary product-related information enables the producers to have a look at the product supply chain and to track the product in case of any infringement. Intelligent and disposable label developed by Timestrip is used to measure the time in minutes for which the food product was exposed to abnormal environmental conditions such as higher or lower temperatures than the normal required temperature. These labels contain nanomembranes that carry the diffused liquid from the food product under different temperature conditions . Radiofrequency identification (RFID) chips are nanotag devices that are used to record all the conditions in terms of temperature, humidity, and ambient gas concentration during the transit and storage of product, helping all the players (manufacturers, retailers, distributors, and consumers) of the supply chain about the freshness, food quality, and food safety. RFIDs are cheaper and versatile tags that have been successful in detecting whether the product has been distributed timely, especially perishable food products, by providing an accurate report on the quality parameters of these food .
Nanobarcodes developed by Oxonica (CA, USA) are made from gold, silver, and platinum nanoparticles, each strip coded with biological fingerprint and quality characteristics of the specific food product. These barcodes, when attached to food products, offer the advantage of brand protection and easy tracking in the supply chain to avoid counterfeiting . In a similar approach, nanodisks of gold and nickel incorporating chromophores that function by reflecting a light spectrum when hit by a laser beam have been used as biological tags for the detection of DNA and food adulteration . “Dip pen nanolithography” is a technique in which a scanning probe is dipped in some modified ink to encrypt information related to batch number or processing conditions on food product or package itself. Information about the soil and climatic conditions can also be encrypted on the product to have a greater security if product recall from the market is due to issues related to the agricultural origin of the product , . Nanoscale markers have been marketed by Authentix (Addison, TX, USA). For the issues of food safety, various pathogens such as E. coli, anthrax bacteria, and some potent viruses such as Ebola can be detected using nanobarcode technology by fluorescent detection under ultraviolet light .
3.5 Development of functional food and smart delivery systems using nanoencapsulation technology
The encapsulation of functional bioactive compounds, flavors, antioxidants, probiotics, ω-3 and ω-6 fatty acids, and phytochemicals using nanoengineered materials has increased the pace of the processing and development of functional food and nutraceuticals. Such products possess enhanced potency, taste, texture, and aesthetical appeal and the technology also helps in maintaining the integrity and stability of these sensitive compounds against degradation during processing and storage. The growing awareness about the health benefits of natural bioactive compounds has paved an enormous market for functional food and nutraceuticals with a many-fold increase in the efficiency, solubility, bioavailability, and stability of encapsulated active ingredients using nanostructured materials and techniques. Some examples of nanoencapsulated components in food include lycopene nanoparticles incorporated in tomato juice and jam to increase the antioxidant activity, casein encapsulation as nanomicelles to deliver health-promoting proteins and vitamin D2 in the food substrate, enzyme encapsulation in plant-based nanosilicates with applications in industrial processes and smart delivery systems, and fortification of iron nanoparticles in functional drinks and breakfast cereals , . “Chinese nanotea” fortified with nanosized selenium increases mineral uptake . Fish oil rich in ω-3 fatty acids has been successfully delivered in food such as bread as capsule or powder by encapsulating in natural polymers using suitable encapsulating techniques , .
Kraft, Unilever, and Nestle are some food industries involved in commercializing novel food fortified with proteins, vitamins, minerals, and fiber as a functional ingredient but reduced calorie and sugar content. Probiotic microorganisms, including Bifidobacteria, have been successfully incorporated in yogurt with a controlled-release mechanism using starch as a nanoencapsulant .
Lipid-based nanoencapsulation has higher bioavailability in the gastrointestinal tract and stability against environmental stress compared to other biomaterials such as proteins, collagen, gelatin, chitosan, and polysaccharides. Increased activity and target delivery have been studied for antioxidants encapsulated in lipid-based systems . Functional beverages containing lycopene, lutein, β-carotene, phytosterols, and vitamins A, D, D3, and K have been developed by Nutralease and Aquanova with added benefits and improved shelf life . Liposomes are closed single-layer or multilayer vesicles made of lipids/phospholipids and the aqueous phase that have been used as carriers of functional ingredients in food. Liposomes have the advantage of entrapping and delivering both hydrophilic and lipophilic bioactive components due to their amphiphilic nature and have shown efficacy to deliver α-tocopherol and glutathione simultaneously in food matrices , .
Nanoencapsulation of lipophilic compounds such as β-carotene, citral, flaxseed oil, oil-soluble vitamins, and coenzyme Q has shown better digestibility because small-sized nanoparticles are transported rapidly through the epithelial cells and facilitate higher absorption due to enhanced solubility .
Nanotechnology-based delivery systems such as nanoemulsions, associated colloids, dispersions, nanocochleates, and micelles have the advantage of delivering the encapsulated ingredients directly onto the site of action, controlling the rate of release under specific environmental triggers (such as a change in pH, solubility, and charge). Such a system also offers protection from physical and chemical degradation and above all is compatible with the organoleptic attributes of food systems. The novel delivery system named “Nanodrop” has been successfully used to deliver functional components with better absorption . Emulsions formulated using nanoscience are more stable and have novel delivery properties in food systems due to reduced size and increased surface area compared to conventional emulsions . The nanoencapsulation of various flavor and sensory nanocomponents or microcomponents provides benefits of masking and improving the color, taste, and desirability of various food. Nanoemulsions are developed with a high-pressure homogenization process to form an adsorbed film of surfactant (which is generally protein or phospholipid) at the liquid-liquid interface of dispersed and continuous phase. These nanoemulsions have dispersed phase droplets of diameter between 50 and 100 nm and are regarded as true emulsion . Multiple emulsions are of two types: oil-water-oil and water-oil-water nanoemulsions, which are formed by the electrostatic deposition of layers of polyelectrolyte (shell) on the surface of lipid droplets (core) and act as economical carriers of functional ingredients in the food industry. The rate of release of functional components from the multiple layers of nanoemulsions in food matrix is determined in response to change in pH, electrostatic charge, and porosity of the shell material .
Associated colloids have been used in encapsulating nonpolar ingredients into the hydrophobic core formed from surfactant micelles or vesicles . Another delivery system of nanocochleates is used to encapsulate hydrophobic, positively and negatively charged compounds into lipid bilayers , . Micelles (5–100 nm in diameter) are also used to encapsulate bioactive compounds with efficiency in release mechanisms .
Applications of nanoemulsions in food include low-fat ice cream, mayonnaise, spreads, and others developed without any change in the viscosity, mouthfeel, and textural properties , . Increased bioavailability of curcumin (bioactive compound in turmeric) has been found when encapsulated as nanoemulsion in processed food . Antimicrobial nanoemulsion is another application of nanotechnology in food processing and packaging; for instance, antimicrobials such as soyabean oil and tributylphosphate have been found effective as nanoemulsions when they come in contact with contaminated food surfaces based on the electrostatic interaction between the cationic-nanosized ingredient and anionic pathogens .
The application of nanotechnology in the food industry has become prevalent in the last decade or so. However, the use of nanoparticles in food comes with unforeseen harmful effects. We need to analyze the factors that may hamper human health and the environment. Before we discuss how nanotech in food hampers health, we must have an insight into nanotoxicity and the mechanisms by which it may deteriorate human/animal health.
Choose any model organism and any nanoparticle and you will find contrasting or slightly different studies about the toxicological effect of the same nanomaterial. After years of research, we have only come to the conclusion that materials at nanoscale show drastically different properties and unexpected behavior. This unexpected behavior is what leads to our concerns about its toxicity. The interaction between engineered nanoparticles and various living organisms and the environment is still to be explored at large.
The last decade has seen a growth of about 600% in the number of papers published in the field of nanotoxicology, the study of adverse effects of nanomaterials on health and the environment . Most of these reported studies are in vitro studies performed primarily by dosing a specific amount of nanomaterial to cells that are growing at the bottom of the plate. Further, the response of the cells is monitored to conclude what effect does that particular nanomaterial has on the cells. Different studies cannot be compared to each other for these are often carried out with arbitrary conditions and nanomaterials that are not well characterized. For now, we can make out that there are only a few studies that offer consistent results and are of value. Large-scale progress in the field of nanotoxicology has been seen, but there still is a void between validation and evidence-based studies. There are complaints about the misconceptions  and slow progress in the field .
Nanoparticles have the unique property of increased surface area per unit volume. This renders them to behave completely different from their bulk counterparts. For instance, bulk gold is normally inert, but as soon as we transform this macroscopic gold to nanoparticles, it shows high reactivity and unique properties . It is due to these unique properties that gold nanoparticles find vast applications from drug delivery to medical imaging. However, nanoparticles are more likely to react with various biological entities such as lipids and proteins or cells as a whole. Nanoparticles may cross the cell membrane entering various organs and activate inflammatory or other immune responses , .
To foresee the unknown consequences of nanoparticle usage, nanotoxicological studies are performed. A typical toxicity test involves cells or organisms subjected to a specific dose of chemicals (nanoparticles, in the case of nanotoxicological studies) and measuring the response of the cells over a period of time. The dose-response relationship from these experiments determines the optimum dose and acceptable limits for chemicals. However, unlike conventional chemicals and their toxicology studies, nanoparticles, as stated earlier have shapes, surface area, and surface electrical charge completely different from bulk counterparts. These might diffuse, aggregate, sediment, and change the physical and chemical properties of the media they are kept in. The major inference that we draw is that the conventional in vitro assays may misinterpret the results and the dose-response regimes. These conventional assays do not take into account the anomalous behavior of nanoparticles in the environment and their cellular uptake .
Most of the toxicity studies have been done at a much higher dose than the realistic dose , and as Paracelsus has rightly said, “the dose makes the poison”, these experiments exemplify the same . Most of the substances considered toxic today are harmless in small quantities and are poisonous only when overly consumed. The exact quantification of the release of nanoparticles in the environment and occupational exposure is quite a challenge. The half-life and life cycle of nanomaterials based on modeling studies have been reported. These studies need improvements as data relevant to the industrial production of nanoparticles have not yet been much included in studies, such as the amount that is released at different life cycle stages of these materials and the forms in which these are released into the environment . Nanomaterials may acquire different chemical and physical forms once released into the environment for they have remarkably different physical and chemical properties with respect to their bulk counterparts. These novel chemical and physical properties have a huge impact on various ways through which these may interact with biological components, their uptake, accumulation, and clearance through the body, and interaction with the environment at large. There is more than one factor that governs the toxicity of nanoparticles as shown in Figure 1.
It is for sure that due to the highly reactive surfaces nanoparticles in the environment cannot exist as bare particles. It has been observed that a corona of protein is acquired by a nanoparticle surface that decides the pathway through which cell uptake, accumulation, and clearance will proceed . Further, the interaction between the nanoparticle and the biological membrane can be either physical or chemical. Physical interactions mainly result in the disruption of membranes and its activity, protein folding, aggregation, and various transport processes . In contrast, chemical interactions mainly lead to reactive oxygen species (ROS) generation and oxidative damage . The environmental interactions also add complexity to the determination of nanoparticle toxicity .
Human exposure to nanoparticles that are airborne cannot be avoided. Intentionally via nanotherapeutics or unintentionally via natural/anthropogenic particles, we are exposed to nanoparticles. The high reactivity of nanoparticles and the multiple entry routes aggravate the problem (Figure 2). These particles can travel large distances facilitated by Brownian motion and are likely to get deposited into our air sacs .
Nanoparticle toxicity has been dealt with approaches similar to conventional toxicity analysis. Most of the studies have suggested oxidative stress as a major parameter for nanotoxicity analysis.
As discussed earlier, nanoparticles may have varied shape, size, charge, solubility, and chemistry as a whole. CNTs, for example, have been extensively studied for its toxicological impact on living beings . The toxicity potential of these nanotubes has come to light due to its striking similarity to different carcinogens such as asbestos.
However, when considering the toxicity, it is not only the nanoparticle but also the various other factors one should consider. CNTs, for instance, can be single walled or multiwalled, functionalized or nonfunctionalized, may or may not be conjugated with the metal catalyst, or may be hydrophobic or hydrophilic depending on the functional group attached and many more such factors need to be considered . As it would become cumbersome to test each and every parameter for toxicity, toxicologists have identified key parameters or tests that allow scientists to screen safer nanomaterials.
A major step in the direction was taken by Xia et al. by carrying out a systematic study on how nanomaterials can induce oxidative damage to cells . The basic idea of the study was to know the mechanism and thus compare the toxicity potential of various nanomaterials. This can be done simply by looking at the generation of reactive species within the cell. Oxidative stress results from the imbalance between oxidants (ROS, peroxide, etc.) and antioxidants (vitamin C, glutathione, etc.).
An increase in the number of oxidants in the cell can have damaging effects on the cell. There is abundant literature on pollution particles such as carbon soot and other nanosized pollutants that lead to the generation of ROS and can lead to oxidative stress (Figure 3) . With the study conducted by Nel et al. we can now compare the oxidative stress profiles of conventional particles to those of particles that are being newly synthesized every day. The data can be further extrapolated to newer materials . If carefully thought out, this and other similar studies can serve as an important building block toward a more efficient screening system for nanotoxicology. Although the study provides insights into the oxidative damage that can be caused by different nanomaterials, a few avenues were left unexplored. First, the experiments should be conducted on more than one cell line; also, primary cell culture (such as human macrophages) should also be used to make sure that the cell culture model is foolproof. Second, different dose regimes should be considered and doses used should be comparable to the dose of the nanomaterial being released into the environment. Third, different media formulations need to be tested as most of the studies have been carried out with fetal calf serum (FCS). FCS contains high levels of different antioxidants. These antioxidants may mask the oxidative damage caused by nanomaterials. Last but not the least, some supplementary assays need to be done to complete the picture. For example, both intracellular and extracellular oxidative stress need to be monitored.
The field is in its early days and there is so much to explore. The fact that their particles can distort lipid organization and overall membrane structure  is an evidence in itself that the nanoparticles may affect biology as a whole. There is an urgent need for information to better understand the nanoparticle-biological interactions and processes. These interactions primarily involve biomolecules such as proteins, but there are studies that show us different routes to monitor the same. Granick et al. have emphasized on physical interactions of nanoparticles and found that nanoparticles can modulate the lipid membrane phase structuring (Figure 4) , .
Therefore, it would be too early to jump to conclusions or to prefer a single field of study. For now, we can say that understanding the manner in which nanoparticles interact (physical or chemical) with biological molecules or living matter can open up loads of opportunities to the field of toxicology. The knowledge and mechanism of oxidative stress seem to be the aptest parameter and appeal maximally to discriminate between toxic and nontoxic materials. The near-future goal of nanotoxicologists seems to develop more studies based on the works of Nel et al. and other similar groups. This will help us learn about the mechanism responsible for nanomaterial-induced toxicity and lead us to safe and profitable nanotechnology.
The National Academy of Sciences report entitled “Toxicity testing in the 21st century: A vision and strategy” emphasizes on new technologies from biotechnology and bioinformatics to revolutionize the toxicity testing . It also emphasizes on learning lessons from alternative methods and their validation. New problems should be dealt with new solutions, and nanotoxicity is one big example. Most of the toxicology tools that are being used for the assessment of toxicity potential of products, mainly nanoparticles, rely on high concentration or dose regime animal studies. These methods have remained unchanged for years. Knowledge in biological sciences doubles really quickly. We now have tons of knowledge and data as we had 60–70 years back. We cannot fuel our cars with a more advanced fuel if we do not change its engine. Similarly, what we need today are better predictive models and tools to minimize time and costs.
Studying the properties of individual nanoparticles, their exposure route, exposure time, the right dose and the right model system can be time-consuming, tedious and expensive. It is here, where high throughput screening methods and computational approaches slide in to save our day. These can rapidly screen and prioritize nanoparticles for toxicology assays and thus accelerating the process of establishing a relationship between material and its biological behavior . Quantitative nanostructure-activity relationship  can help us predict the cytotoxicity of a number of metal nanoparticles . Another important aspect to be considered for the field to progress is a detailed characterization of the nanomaterial in question, this would help researchers to use that data to design toxicology assays, properly interpret the results obtained and ensure that data can be reproduced and compared by others. Although researchers have initiated the knowhow of material properties, interactions, and toxicity mechanism, the coming years still have a big challenge to understand the physical and chemical properties, interactions and responses.
Most of the modern toxicology studies are animal based in vitro or in silico; however, there is a need for evidence-based toxicology. With such vast knowledge and advancements, the current toxicological assays need to be revamped and new tools, such as proteomics, functional genomics, high-throughput screening, and metabolomics, to name a few, should be incorporated more and more to these studies. Incorporation of these advanced tools will lead to the minimization of a number of false positives and accelerate and validate the evaluation of toxicity of nanoparticles. The onus of nanotechnology and its safe applications is on the shoulders of scientists and the public must be well informed on the benefits and risks associated with the field.
5 Harmful effects of nanoparticles on humans
The use of nanotechnology in food irrespective of its wide benefits confers the possible adverse environmental, social, and health risks as these particles are believed to enter the ecosystem through the delivery of pesticides in agriculture or through application in processed food such as the packaging sector, thus raising the toxicity concerns about their usage . The enhanced risk of nanoengineered particles is due to the higher reactivity of these nanoparticles and increased bioavailability of smaller particles to our bodies leading to long-term pathological effects. Nanomaterials can enter the food chain through:
Direct incorporation of nanoparticles in novel food as nanoemulsions, nanocapsules, and nanoantimicrobial films.
By use of nanomaterials in food manufacturing, processing, preservation, and trackings such as the use of nanolaminates, nanosensors, and CNTs.
The level of human exposure to nanoparticles greatly depends on the specific area where it is used in the food industry and the concentration of usage with exposure risk being higher in the fields where nanomaterials are added directly to food products as carriers of novel food ingredients. Some of the toxic effects of nanoparticles used in food are presented in Table 1. The migration of nanoparticles from food packaging materials and the behavior of nanoparticles upon entering the body are still being evaluated at an extensive level .
As discussed earlier, nanoparticles can cause oxidative stress to human body cells and can traverse from lungs to blood, cell nuclei, and central nervous system leading to the inflammation of the gastrointestinal tract, Parkinson’s syndrome, Alzheimer’s disease, as well as the impairment of the DNA. Adverse effects on kidney, liver, and other vital organs have been reported due to long-term exposure to nanoparticles .
6 Migration issues of nanoparticles
Recent studies have documented the migration of silver nanoparticles into food products with an amount below the permissible limits and there is a lack of safety assessment data in this regard. The result of a study conducted by the National Packaging Products Quality Supervision and Inspection Centre showed that silver migration from fresh nanosilver bags increased in all the food solutions with an increase in time and temperature, suggesting the release of nanosilver particles by dual sorption diffusion and embedding . In addition to the migration of inorganic silver metal, migration trends of modified cellulose nanocrystals have been studied and the migration level of cellulose nanocrystal in isooctane was higher in 10% ethanol but was still within the permissible European Union legislation limits .
A modeling behavior was used to quantify the migration of nanoclay from PET beer bottles showing that migration will occur only when 1 nm radius small-sized particle will combine with a polymer of low dynamic viscosity. Two different sized TiO2 in low-density polyethylene (LDPE) packaging films were tested for migration behavior. The result showed that 100 nm TiO2 in LDPE film migrated more into the food matrix with the migration trend depending on the compatibility of the TiO2 with the packaging film and food stimulant liquid. In another experimental model, nanosized titanium nitride was blended with LDPE at 0, 100, 500, and 1000 ppm concentration with food stimulants used as ethanol, 95% iso-octane, and 3% acetic acid. In the results, titanium migration from 1000 ppm was highest with ethanol and iso-octane samples showing no migration . Thus, from the series of exhaustive experiments, it was concluded that the migration of nanomaterials in contact with plastic packaging is negligible. The critical point in migration estimation is the drawback and limitations in detection and quantification techniques. Inductively coupled plasma (ICP)-atomic emission spectroscopy and ICP-mass spectrometry are both used for the efficient identification of nanoparticles, but there are certain limitations in these methods, which make it necessary to include a pre-separation step before digestion. Therefore, for the accurate quantification of nanoparticles, it is important to develop an efficient separation characterization and quantification step .
The primary concern is to analyze the extent to which these particles migrate into the food and what happens when the nanoparticles are ingested into the mouth and then absorbed by various organs and then metabolized until they are ejected from the body. Some studies have shown that silver, TiO2, tin, and CNT enter the gastrointestinal tract from the blood. The physical properties of nanoparticles such as size, surface charge, mass, crystal structure, surface porosity, chemical composition, and state of agglomeration determine the adverse effects of these particles on target organs such as the spleen, liver, kidney, and brain. When nanosized hydrophilic and positively charged particles enter the bloodstream, blood circulation increases drastically. These nanoparticles may pose a threat to all the organs; however, long-term exposure studies are limited to unknown consequences that still need investigation . Dermal exposure, ingestion, and inhalation are the possible ways for nanoparticles to enter the body. Pulmonary inflammatory problems and vascular disease from long-term exposure to carbon nanoparticles have already provoked health concerns among people. TiO2 nanoparticles could penetrate the skin dermis layers interacting with the immune system through lymph nodes and cause oxidative damage to skin by generating hydroxyl radicals. The acute and chronic toxicity of nanoparticles when inhaled is because smaller particulates of 4 μm travel deeper to the alveolar region with particles of greater size. The particles once into the body are able to cross the blood-brain barrier and can cause pulmonary granuloma, oxidative damage, and pneumonia. However, the general statement regarding the toxicity of all nanosized particles cannot be made until it is evaluated through extensive experimentation trials. From the standpoint of nanoparticles being used in food, it is important to consider the particle size and mass to determine the toxicity. In some experimental trial, it has been shown that 20%–30% of nanoparticles made of polystyrene size 50 and 100 nm were absorbed by intestinal mucosa with penetration being faster for small-sized particles .
It is pertinent that nanoengineered particles interact with other food constituents when ingested, but how these particulates are metabolized is still an area that needs research. The use of nanosized emulsion or stabilizer in ice creams is absorbed more in the gut due to small size. In the case where nanoparticles are used in packaging matrix, a model formulated by Simon et al. suggests that the migration of nanomaterial from packaging film increases with decreasing polymer dynamic viscosity and nanoparticle size .
Nanoparticles interact with biomolecules and organelles and result in the formation of bio corna, which ultimately have a negative effect on cells such as immunotoxicity, cell death, and genotoxicity . Nanoparticles can cause an alteration in epigenetics by DNA methylation, histone modification, and post-transcriptional changes of gene expression and later can be transferred to generations. Fifty-five types of nanoparticles and 35 patents are identified worldwide in food applications , . Nanosized TiO2, SiO2, and MgO2 are used in food processing for various functions without the particle size being mentioned on the label and their properties can differ from conventional additives, thus creating consumer concerns. The detection of nanoparticles in food material is still a complex process and needs validation as various physicochemical processes may alter the properties of nanoparticles and pose a challenge for their acute quantification. Ingested nanoparticles are taken up by secondary organs and absorption varies from organ to organ. When nanoparticles are in contact with biological fluid, they can change the properties due to change in pH and ionic strength and can interact with proteins, lipids, blood cells, and genetic material. Lung inflammation, granuloma, and focal emphysema were demonstrated by in vivo studies of SiO2 nanoparticles. Gold nanoparticles are widely used in various food packaging applications and have been found to cause chromatin changes in the nucleus of human lung fibroblasts as well as significant changes in gene expression and epigenetic changes in mouse fetus leading to the risk of lung cancers . Toxicological studies of silver nanoparticles have shown that these particles enter the intestinal mucus barrier and are associated with increased ROS generation damaging cell membranes, DNA, and chromosomes as well. Even at low concentrations, the toxicological effects of silver nanoparticles have been evident, whereas abnormal cell damage, shrinkage, apoptosis, and skin cancers have been observed at higher concentrations .
7 Environmental impacts of nanoparticles
The growing use of nanoparticles in different products results in the release of a substantial quantity of the nanoparticles into the environment, which probably ends up in terrestrial and aquatic ecosystems. The release of the nanoparticles into the environment may be by any of the three ways viz., naturally, unintentionally, or intentionally. Natural nanoparticles are produced from a forest fire, volcanic eruption, ocean spray, clouds, dust storm, and soil erosion. Unintentional nanoparticles are generated through welding, metal smelting, smoking, mining, fossil fuel-burning industrial waste, and vehicle exhaust. The effect of natural and unintentional nanoparticles on the environment is well documented. The ecotoxicity of these nanoparticles depends on the physicochemical properties (chemical composition, surface chemistry, surface charge, particle size, size distribution, shape, crystal structure, agglomeration state, and porosity) of the nanoparticles . Some common problems such as atmospheric visibility and building soiling are due to the optical properties of the nanoparticles. Because of the black carbon content in the diesel particles, it strongly absorbs light, which can contribute to the global warming.
Nanoparticles that are produced to be used in different processes and materials are engineered nanoparticles. These nanoparticles may be released into the environment through various ways depending on their use. The ecotoxicity of the engineered nanoparticles has been extensively researched, especially the effect on aquatic ecosystem (Table 2).
8 Prospects in nanotoxicology research
The toxicity of different nanoparticles that have a potential to be incorporated in food has already been studied by different researchers. There are many studies that depict the nature of nanoparticles as toxic or nontoxic. During the preparation of this manuscript, it was observed that most of the studies on the toxicity of nanoparticles have been conducted with the homogenous nanomaterial only. As one of the main characteristics of a nanoparticle is the enhancement of its reactivity, it is quite possible that, when a nontoxic nanoparticle is incorporated in food, it may get converted to a harmful form or vice versa.
Food has different roles in the body and the composition of the food is important with respect to that role. A food may contain a functional ingredient that is specific to that food; for instance, beef contains vitamin B12. During the processing of such food, the main aim is to reduce the loss of such functional ingredients. Food, by its nature, is a pool that presents enormous possibilities for biochemical interactions and the incorporation of a highly reactive species of nanoparticles into food may trigger different reactions. The interaction of nanoparticles with such functional ingredients and other constituents is another area of research that needs to be explored.
Every development has its own shortcomings, but if it deals with food it turns out to be a serious issue. Despite the miracle properties of the nanoparticle, it may have some harmful effects on the human health. Due to the increasing health consciousness, knowledge, and vast Internet availability, there is a huge pressure on the scientific fraternity to come clear about the safety of nanomaterials used for food purposes. Different studies have been carried out on the safety of nanoparticles, where some nanoparticles have been confirmed to have toxicity and harmful effects on the humans. This type of research is continuously ongoing to support the full evidence of the toxicity or nontoxicity. In this review, we tried to compile as much data that are currently reported on the nontoxicity. However, we could not make a significant contribution in confirming the toxicity of nanoparticles associated with the food by one way or another. It seems that a lot of work is needed to confirm the toxicity of the nanoparticles used in food apart from their individual toxicity. The interactions of nanoparticles with the food systems need to be estimated, which might also have an effect on the digestibility of the food constituents.
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About the article
Published Online: 2018-10-25
Published in Print: 2018-12-19