nanotechnology and food

Nanomaterials in food. Which functions and applications? What are the risks?

Various nanomaterials, including organic nanocapsules, nano-silver, titanium dioxide and amorphous silica, are used by the food industry as food and packaging components. Consumption of certain products, such as confectionery, can lead to significant digestive exposures to nanotitanium. Does this result in oral toxicity? Is particle migration from certain functional packaging possible? How are these risks measured? Within the framework of the precautionary principle, can "bio-based" molecules, such as cellulose, represent an alternative to chemical materials? 
Ahe NanoRESP Forum has been running for three years and provides a cross-cutting forum to discuss issues related to the use of nanomaterials. We proceed with an inventory of the subject content in the Benchmark sheet, available on our website before the session. In today's session, we will be attentive to keep in mind the common thread of What can be the situations in which we find ourselves? Criticism of nanoparticle exposure through food?
We will first investigate, with Eric Houdeau, the possible toxicities of nanomaterials included in food, in particular titanium dioxide. We will then see, with Marie-Hélène Ropers, where they are found and their functions in food products, as well as their fate in the body. Régis Lebossé and Caroline Locre will illustrate the role of nanoparticles in different types of food packaging and the problems they raise.
These presentations will provide a better understanding of human exposure to food nanomaterials, their benefits and drawbacks in order to prioritize the issues and not to globalize things. Each of you is invited to make your own contribution in the discussions that will follow.
In order to support the joint survey, a summary will be made in the last part of the session by Jean Jacques Perrier. This will make it possible to characterise the points that are still unclear and to prioritise the questions.
With :
Eric HOUDEAUINRA, UMR 1331 ToxAlim, "Intestinal Development, Xenobiotics & Immunotoxicology" team, Labex SERENADE, Toulouse
Marie-Hélène ROPERSINRA, UR1268 "Biopolymers Interactions Assemblies" (BIA), Labex SERENADE, Nantes, France
Régis LEBOSSÉ, Head of the Chemistry and Physicochemistry of Materials Unit, Testing Department, National Metrology and Testing Laboratory (LNE), Trappes
- Caroline LOCRE, Surfaces & Functional Products" and "Hygiene - Food Contact" teams, Paper Technical Center, Grenoble, France

The report modifies the order thus announced in order to gather first the main information on nanoparticles used in food.

1. Which nanoparticles are used in food?

This is a summary of the beginning of the complementary presentations by Eric Houdeau and Marie-Hélène Ropers.
Nanomaterials are used in food either as additives or in packaging and coatings for refrigerators and freezers.
- Amorphous silica SiO2 (E551) is an anti-caking agent (anti-caking agent) for powdered preparations (salt, sugar, soups, etc.), and a viscosity modifier for tomato sauce, dressings, etc.
- Titanium TiO2 (E171) is a whitening agent for confectionery and cakes. It is also used in toothpastes (CI77891 of the INCI nomenclature (1)), an oral exposure in addition to that from food. There are other dyes (see table) that the INRS has suspected of containing nanoparticles (2).
- Money is rarely found in food, but rather in trays and freshness bags. It is used as an antimicrobial agent on the surface of refrigerator/freezer walls and in kitchen utensils.
- Phospholipid nanocapsules and micelles, marketed notably under the name NovaSOL, are used to transport food supplements, biocompatible dyes (E171, E172...), coenzyme Q10, omega-3 fatty acids, preservatives...
- New applications are barrier, antimicrobial and resistance properties of packaging: UV barrier (Oxonica, Air Products, etc.), moisture and gas barrier (Honeywell, nanoPack, etc.), antibacterial coating (Nanux, BioGate, etc.), increased packaging resistance (PET = polyethylene terephthalate + carbon nanotubes), etc.
- Nanosensors (e.g. NanoMas)
- RFID labelling and quality sensors (e.g. Nanoident) 
Types of nanomaterials used in food products and food contact (3)
The risk of organic particles is not assessed because the body knows how to metabolize them. For inorganic or mixed organic/inorganic particulate matter, the risk must be assessed since it is exogenous to the human body and not metabolizable, such as titanium dioxide. Knowledge of the nanoparticle state of these materials used in food is still lacking. The R-nano registry will make it possible to speed up their characterization.

2. Nanoparticles and food: evidence of oral toxicity? by Eric Houdeau, Toxalim

We develop here the case of titanium dioxide (TiO2, E171). The subject is topical, following the televised intervention last March by José Bové (4) or to the petition launched in the United States in June 2014. (5)which called for the removal of titanium dioxide from confectionery products and dairy desserts respectively.
TiO2 has no interesting properties for food other than whiteness. But the estimated levels of dietary exposure in humans are in milligrams per day. When you are concerned about endocrine disruptors such as bisphenol A, these are doses of no more than 0.5 to 1 microgram per kg per day. For titanium dioxide, the doses are 1,000 times higher: in adults from 0.2 to 1 mg/kg body weight/day, and in children/adolescents in the United States from 1 to 3 mg/kg/day (up to an estimated maximum of 6 mg in the UK for the most highly exposed), probably because children are greater consumers of confectionery. (6), (7).
E171 has been authorized since 1969 (8) based on its very low intestinal absorption (less than 5%). Based on this finding, no human toxic reference value (TRV) of the "Acceptable Daily Intake" type has been established. Today, measurements show that commercial titanium dioxide used for food contains up to 40 % of nanoparticles (size less than 100 nm). In the late 1960s, there were probably fewer nanoparticles in food titanium. It was the processing that led to a high proportion of nanoparticles in the titanium powders manufactured today. Similarly, in food matrices such as chewing gum, the proportion of nanoparticles is high (as can be seen by the
extracting in water) (9).
Fate of TiO2 after oral exposure
According to in vitro studies involving nanotitanium in contact with cells, these particles have a wide variety of effects: genotoxicity, oxidative stress, apoptosis, inflammation ... It is however difficult to draw conclusions of chronic oral toxicity by transposing in vitro studies. These reveal only the toxicity likely to appear under conditions of in vivo exposure.
There are few in vivo studies, mainly in animals. Based on their results, after analysis by electron microscopy, X-ray and mass spectrometry, nanoparticles of TiO2 at high doses (100 mg/kg/day and above) can be found within a few days in the liver, spleen, heart, kidney, brain, and endocrines (10), (11). However, the accumulation observed in animals in organs often corresponds to doses that do not reflect actual human exposure.
In addition, nanotitanium is known to be eliminated in the stool at 95 %. Only 5 % are likely to be absorbed from the intestine. This seems low. For example, the team of Roberta Tassinari and Francesco Cubbada (Health Institute of Rome) (12) observed a titanium concentration in the spleen of 0.046 micrograms per gram fresh weight in rats at an exposure similar to that in humans (1-2 mg/kg/day), compared to 0.036 micrograms per gram after treatment with distilled water. The difference appears small, but it shows that there may be accumulation of titanium dioxide over time, thus intestinal absorption, and potential long-term impact.
Note that if the control indicates the presence of titanium it is because this metal is found in the environment, for example in the roots of cereals and vegetables.
The forgotten bowel
In addition, several studies point to an accumulation of nanotitanium (but also silica dioxide and aluminium silicate) in Peyer's patches of the small intestine in humans. (13), (14), (15). These plates are filled with immune cells involved in tolerance to food antigens and the fight against pathogenic bacteria. Studies show that food pigments accumulate there with age and therefore with consumption.
Method for investigating immunotoxic effects in rats
To study the effects of nanotitanium on Peyer's patches in the small intestine, water-suspended TiO2 nanoparticles are dispersed by sonication and administered orally to rats at doses of 10 mg/kg/day for 1 week (acute exposure) and 100 days (chronic exposure). After one week of treatment, their distribution in tissues and on isolated cells (lymphocytes of different types, dendritic cells...) is examined.
It is essential to choose beforehand :
- A nano-dimensional reference standard: in our case, this is P25 (NM-105), well characterized at the European level (in safety tests on titanium sponsored by the OECD), very homogeneous for its size, spherical, strictly less than 100 nm and comprising anatase titanium at 85 %, i.e. the crystalline form mainly found in food additives. 
- An additive representative of the market. The E171s available on the market have a very heterogeneous size distribution (17 % to 40 % of nanoparticles).(16). The European definition stipulates that the nanomaterial must contain at least 50 % of nanostructured substances. But there is a paragraph that specifies that this rate can be reduced to 1 % when it comes to health safety issues in particular. In our case, we buy a white dye on a commercial site in France, we look at the nature of the elements of this powder (purity) with X-rays, we compare its composition in anatase with the referent. The sample used consisted of 45 % of nanoparticles.
Bowel results
The fate of particles in the gut in rats was studied by SynchrotronDiffaBs imaging after one week of treatment with E171 (sonicated at 10 mg/kg/day), a dose just above the maximum observed in children.
As a result, particles are observed in the Peyer's plates of the jejunum (hail), in the epithelial cells of the colon and also in the liver (the particles reach there through the portal vein). The particles pass from the lumen of the intestine into the wall and the bloodstream through the enterocytes (i.e. the epithelial cells of the intestine) and between themselves. (17). In addition, Peyer's patches are a gateway to the immune system: an experiment by Marie Carrière's group at the CEA in Grenoble shows that intestinal epitheliums can be reproduced in vitro; it can be seen that the closer the epithelium is to the epithelium bordering Peyer's patches, the greater the accumulation. (18).
An inflammatory hazard?
Researchers have looked at the amount of mineral pigments in Peyer's patches in patients with inflammatory bowel disease, Crohn's disease or ulcerative colitis. The result: there is as much in the controls as in the patients. There is therefore no causal relationship between the presence of these mineral pigments and the disease.
However, in vitro, in the presence of bacterial antigens (LPS-type) that pre-stimulate immune cells, particulate mineral additives (E171 but also E559 and aluminium silicate) may act as adjuvants to induce the release of pro-inflammatory immune mediators (cytokines such as TNF alpha and interleukin 8), particularly in patients with Crohn's disease12.
This means that under conditions where inflammatory bowel disease sets in or is established, the presence of titanium dioxide, silica or aluminum silicate is likely, because of their adjuvant properties, to exacerbate the inflammatory response.
Maybe that's the danger after all, increasing the severity of the diseases.
Immune consequences in rats
According to the Secondary Ion Mass Spectrometry (SIMS) study - a tissue section is bombarded with primary ions that detach the secondary ions, which can be analyzed by spectrometry - the resulting map shows the presence of titanium dioxide in immune cells, including their DNA (Sarah Bettini's thesis in progress).
The duration of oral treatment results in a decrease in Treg regulatory T lymphocytes (involved in oral tolerance) and dendritic (antigen-presenting) cells. This results in an imbalance of immune homeostasis with an immunosuppressive effect in the intestine. But at the level of the spleen a pro-inflammatory effect is promoted, especially for certain mediators known as susceptibility factors for autoimmune diseases. 

3. The use of nanomaterials in food products (excluding packaging) by Marie-Hélène Roper

What consumption?
According to the R-nano register of the Anses, food represents only 2.6% of the applications declared in 2013, which does not mean that in tonnage it is the same thing. As Eric Houdeau indicated, the consumption of certain nanomaterials, such as titanium dioxide, which is completely exogenous to food, is significant. It varies according to eating habits, and therefore geographical location, and the availability of ready-made meals, confectionery, etc., which are not always available. On average, titanium dioxide consumption is around 2.5 mg/person/day. (19). To this should be added, as already noted, non-food oral intakes: oral medications (15 mg/d/person), toothpaste, and dietary supplements (silica, iron oxides, titanium dioxide, 37.5 mg/d/person).
However, there is no precise estimate of the number of ingested nanoscale particles! Moreover, the form in which the additives are found in the food (isolated or agglomerated particles).
Why the uncertainty?
Uncertainty in the calculation of TiO2 exposure comes firstly from the variability in the proportion of particles smaller than 100 nm between batches and between manufacturers: data provided by research teams vary from 17 % to 44 %. It should be added that the physical form of titanium also varies, with some samples having more anatase, others more rutile.
The characterization of nanomaterials is too recent for us to be clear. In the 1930s and 1960s, the authorization of incorporation in food of substances called food additives providing a technological function (colorants, anti-caking agents ...) was based on 5 physico-chemical criteria: purity, synthesis, quantity, structure and toxicity.
Size was not one of those criteria. The democratisation of electron microscopes outside the laboratory in the 1970s, followed by the multiplication of criteria for identifying the nanometric character of particles in the 2000s (definition adopted by the European Commission), has made it possible to considerably improve this characterisation.
Today, there are 15 physico-chemical criteria (Recommendations of the European Food Safety Authority, EFSA, 2011), 8 of which are essential: composition, particle size, aggregation/agglomeration, shape, specific surface, surface chemistry; surface charge, solubility/dispersibility, to which are added toxicological criteria classified according to a decision tree. 
Agglomeration and dispersion of nanoparticles
The toxicity of nanomaterials remains difficult to assess, in particular because their behaviour changes according to the environment. For example, nanoparticles tend to agglomerate in aqueous or acidic environments and to regain individuality in basic environments.
For example, silica is particulate in salivary medium, agglomerated after acidification in the stomach and again particulate in the intestine at neutral pH, according to a study carried out without protein. Another difficulty factor is that there is not one form of nanomaterial but several. Thus silica can be "pyrogenic", made of aggregated (30 to 50) and agglomerated (100nm to 100 µm) nanometric beads (5 to 10 nm), or it can be precipitated made of non-aggregated but agglomerated nanometric beads (5 to 10 nm).
Proteins in body fluids also change the behaviour of nanoparticles. In cell culture, TiO2 surrounds itself with a crown of proteins: as the medium becomes complex and rich in proteins, the particles disperse again.
Fate of TiO2 in the body
If silica dioxide is eliminated in the feces at 95 %, the remaining 5 % are far from negligible as transfer through the intestinal wall is observed in rats and humans. The organization of the intestinal wall is disrupted by E17120 particles. In rats, the storage of titanium nanoparticles in the liver and spleen and their slow elimination from these tissues was observed. (21). Their persistence in the intestinal walls and their hypothetical link with inflammatory bowel disease are questionable. These findings led Boris Jovanović, from the Ludwig Maximilian University of Munich, to state that TiO2 no longer meets the criteria that led to the authorisation of its use in food in 1969: "A re-evaluation of the safety of TiO2 as a food additive in human food must be carried out immediately by the competent government agencies. » (22)
Despite their rather varied functions, applications and advantages, food nanomaterials raise unresolved questions: in particular the forms present in food, and the fate of the part absorbed by the intestine, even if it is a minority compared to the part eliminated. The marketing of new nanometric additives seems unlikely in view of these uncertainties and insofar as industrialists lack enthusiasm for them. The time has come for naturalism! 

4. Nanomaterials and packaging for food contact by Régis LEBOSSÉ, LNE

Numerous innovations
The food packaging sector is marked by numerous innovations that take into account several issues:
- the fight against waste: multiplication of small containers for nomadic consumption, single-serve portions and the "silver" economy;
- Ecological constraints: ecodesign, bio-sourced packaging;
- reduction of environmental impact: recyclability, circular economy, ecommerce ;
- reducing costs without sacrificing service and design;
- the development of functional properties: resistance, practicality, barrier effects, information, intelligent packaging. 
Nanomaterials are implemented for the last 4 issues, namely cost reduction and functionality.
A few examples :
- Titanium nitride in PET - polyethylene terephthalate - bottles for water storage. According to industrialists, this nanomaterial provides PET's heating properties, thermal properties and productivity gains.
- Titanium nitride in LDPE (low density polyethylene) films provides mechanical properties, gas barrier properties and optical properties. Manufacturers are also advancing the reduction of material thickness.
- Zeolite (alumina silicate) nanoparticles in EVOH (ethylene vinyl alcohol) films, a material widely used in rigid food packaging for its gas barrier properties. As the film is relatively fragile and unstable, placed between two layers of polymer, the zeolite gives it stability and oxidation resistance properties.
- Silver nanoparticles in coatings of food contact materials have antibacterial and antifungal properties.
- Polysaccharide nanocrystals in PLA (polylactic acid) films are a bio-based, biodegradable material with good mechanical and barrier properties.
- Many other examples of nanomaterials, such as inks and chips, offer opportunities for innovation in food packaging.
Undeniably, consumer health safety is a key concern for the packaging and food contact materials industry (EC Framework Regulation n°1935/2004). However, the guarantee of consumer health safety in the field of nanoparticles for packaging is based on regulations that are not very precise (such as the specific Regulation 10/2011 on plastic materials). It recommends a case-by-case analysis, does not require a threshold for nanoparticles, nor specific labelling for packaging.
The submission of a dossier to the European Food Safety Authority (EFSA) for the placing on the market of a package containing a nanomaterial therefore follows a case-by-case approach including an assessment of the risk of transfer of nanoparticles into food.
Risk assessment
Risk = Danger (toxicity of substances) x Occurrence (migration or transfer phenomena from the material to the food)
The migration phenomena of nanoparticles are related to several parameters: temperature, thermodynamics and kinetics (shape and size) of the particles, concentration (very low often), material structure (amorphous areas are more conducive to the movement of particles), thickness and geometry of the material (the food contact surface).
There are two approaches to measuring this migration:
- In the laboratory with a simulant (acetic acid, ethanol, oil, etc.) under standard temperature and contact conditions. The quantity of nanoparticles that has migrated to the simulant is then measured. The technical difficulties concern the characterization of nanoparticles. 
- By modelling the transfer phenomena of nanoparticles in packaging materials: the aim is to predict the concentration of nanoparticles over time. This is an approach that is increasingly used. It would eventually make it possible to predict the migration as a function of time for 30 % of packaging.
Evaluation results
According to the few available studies carried out, particularly on polyethylene under standard conditions, there is no measured migration of nanoparticles. This does not allow a definitive conclusion to be drawn. Research on methods for measuring and characterising migration is still needed.
Outstanding Issues :
- Case of active/smart packaging (Specific Regulation EC n°450/2009)
- Recycling potential of nanostructured packaging
- Environmental impact at end of life (burial/incineration)
- Chronic toxicity and bioaccumulation: what are the long-term impacts?
- The case of unintentionally added substances (NIAS, non Intentionally Added Substances), impurities or substances not initially present in the packaging and which may be formed over time by reaction or degradation. 

5. The performance of bio-based nanomaterials for food packaging by Caroline Locre

The Paper Technical Centre (CTP) is an industrial technical centre dedicated to the paper industry. Among other things, it focuses on the transformation and functionalization of paper and cardboard packaging to obtain gas and moisture barrier effects while taking into account consumer safety and the end of life of the materials, in order to recycle them and avoid their incineration or landfill.
The PTC roadmap
The CTP aims to develop packaging materials based on lignocelluloses, biopolymers that can partially replace the current majority of petro-sourced materials. Paper (cellulose) has assets to constitute the packaging materials of the future: it is a recyclable and biodegradable biomaterial, printable and suitable for transformation.
But a paper, as is, is not enough: it must be given barrier properties, functionalities, performance in a humid environment or atmosphere, 3-dimensional shapes. It is also necessary to be able to carry out specific developments according to the product to be packaged, to multiply the functions required of the packaging, to follow the evolution of regulations while being part of the packaging value chain (raw materials, manufacturing, transformation, recycling). Nanoparticles can address some of these issues.
Nanoparticles used in paper diapers
So-called coated papers are surface-treated papers (i.e. approximately 50% of today's paper and cardboard). The coating sauce, deposited on the surface of the paper by various processes, is typically a dispersion of pigments, binders, additives (printing-writing papers) or an emulsion of polymer, wax, etc.. (barrier layers), the paper itself providing the mechanical strength and processability of the coating. (16).
Nanoparticles can be added to the coating sauce depending on the end use of the paper :
- Printing or writing: precipitated calcium carbonate, colloidal silica, precipitated (silica gel), or pyrogenic for improved printability, especially in the case of printing technologies such as inkjet.
- Gas and moisture barrier: improvement of barrier properties through inclusion of nano clays, nanotalcs, starch nanoparticles, cellulose microfibrils, styrene maleimide
- Specialty papers: non-stick, antimicrobial (nano-silver) or photocatalytic (nanotitanium) effect. The antimicrobial effect is exerted either by release and diffusion or by direct contact:
o By release, diffusion decreases over time.
Examples: Triclosan (textiles, Microban®), enzymes (e.g. Lysozyme), organic acids (e.g. Sorbic acid), bacteriocins (e.g. Nisin)
o By contact, the effect is direct and lasts longer.
Examples: Chitosan (textiles), Silver (AgIONTM), Quaternary ammonium compounds
- The use of nanoparticles should be moderate as they cost 10 to 40 times more than conventional pigments. They must provide sufficient functionality.
Cellulose microfibrils (MFC)
CFCs have been studied in paper mills for several decades. They are nanometric in size and are obtained by chemical and mechanical treatment of cellulose fibres from wood and plants. (24). They are going to be used more and more because their properties are very interesting:
- Their diameter is 20 - 50 nm, with a length in the micron range.
- They are made from cellulose, a bio-based material that is very abundant and therefore an interesting alternative to fossil fuels.
- They are made in suspension in water.
- They have good physical characteristics: low density, high specific surface area, high mechanical strength, thermal stability at 200°C.
- Their oxygen and water vapour properties are comparable to those of some polymers.
- They can be chemically modified to functionalize them with, for example, antimicrobial products or nanowires.
- The results of some toxicological studies suggest that CFCs are not cytotoxic and do not cause inflammatory effects.
- It would therefore be possible to use CFMs for food packaging papers, replacing plastic materials and giving them specific properties (e.g. antibacterial). 
The problem is that their suitability for food contact cannot be guaranteed at the moment. At the European level, the regulatory framework for paper and cardboard packaging does not exist, so we have to proceed on a case-by-case basis, country by country, unlike plastic packaging. In addition, as with other packaging, if active substances are incorporated into CFM paper, it will be necessary to control their release into food, identify and evaluate the reaction products and possible migration of substances to food. 

6. Synthesis: the key points of the previous presentations by Jean-Jacques Perrier

- The agri-food sector is marked by many innovations, but mainly in the field of packaging. These use nanomaterials for a variety of applications.
- The impact studies, particularly on the migration of nanoparticles to food, need to be more in-depth, whereas the regulatory framework favours a case-by-case analysis.
- The level of exposure to titanium dioxide used as a food additive is significant, especially in children.
- Up to 40 % of the titanium dioxide additive is nanometric (less than 100 nm in size).
- The titanium dioxide particles are agglomerated in the stomach but are likely to disperse again in the intestine.
- Although 95 % of the ingested titanium dioxide is eliminated with the stool, intestinal absorption of the remaining 5 % and by the Peyer's patches of intestinal mucosa suggests that this material may have pro-inflammatory effects at play in inflammatory bowel disease and even autoimmune diseases.
- The accumulation of titanium dioxide particles in certain organs, especially the liver and spleen, probably increases with age and therefore with food consumption. The danger of this is not known.
- Titanium dioxide has no proven genotoxic effect in vivo, but this effect exists in vitro.
- The observed effects are related either to the nanoparticles or to the chemical substance independently of an effect of size, or to both.
- For silica and other nanomaterials, similar effects cannot be excluded, but there are not enough studies to show this.
- It is generally not known in what physical forms (nanoparticulate, microparticulate, aggregates, agglomerates) additives are found in food.
- The question of substitutes or alternatives must be asked.
- Reassurance" is a term that calls for a redefinition of the use of certain additives and a basis for stakeholder dialogue based on scientific evidence.

Final discussion

Dorothée Browaeys :
Concerning the effects of TiO2 and whether they are related to the "nano" form or not, the important point is the exposure of children for a use that seems incidental: having nice white candy. Isn't this a situation where we should say: is it worth it? Can you react to this question, today or on the website?
Nicolas Feltin, LNE :
We've had a paradigm shift. For the common industrialist, toxicity was only linked to chemistry. Today they realize that physics, i.e. size and specific surface area in particular, can also be dangerous. We therefore need to educate people. As part of the NANOMET project led by the LNE and financed by the DGE, we asked industrialists what parameters they were measuring. The answer was: no parameters. Their problem is the final product, they only check the properties of the product. 18 optics of their product if it is paint, for example, and do not care about nanometric properties. However, in the field of food, it is by no means certain that the TiO2 that was authorised in 1969 is the same as that currently used. Some studies show that food TiO2 today has, on average, 30 % of the particle size distribution in numbers less than 100 nanometres. From
plus, according to a literature search, one can have a very white TiO2 even if one decreases the size down to 30 nm. The information that TiO2 must be micrometric to be white is therefore false.
Mr. Donat :
The essential question is indeed, as has just been said, whether it is worth using titanium dioxide to put white on a sweet. The other question is the reality of the criteria for discriminating against toxicity. It seems to me that the benefit-risk assessment needs to be redone using the alder of the nano criteria. Otherwise, we create a climate of non-confidence. We have to learn together to put the debate on a scientific basis and a risk assessment before opening the discussion to the general public, which does not have the capacity to differentiate between scientific relevance and sensationalism. Industrialists like us have no place in the assessment, which must be carried out by scientists and independent bodies (in particular European health agencies in collaboration with national agencies to avoid divergent discourse). Industrialists in the sector have to make choices in collaboration with researchers on the basis of scientific assessments, without disadvantaging the opportunities for real innovation prospects.
D. Browaeys Are you able internally to think about alternatives and implement them?
Mr. Donat : We have already started to demand certain things from our suppliers, but we have to take into account the criteria of technological feasibility and confidentiality. We're going to do it because it's our interest, since it is the interest of the consumer. The food industry has long maintained that there are no nanoparticles in food. It has recognised this for some years now, but it is a low user in terms of quantity and for substances whose use has been authorised a priori. Nevertheless, this remains a subject that is difficult to commit to, because who commits exposes himself.
C. Pétigny Everyone in society plays its role and these exchanges between all the players are very important and very interesting. But it also seems to me fundamental to take decisions that are based on relevant and scientific criteria. The issue of substitution of a substance is a real issue and it is not always easy to find more suitable substances. Finally, as we were talking about "putting things into perspective" earlier, and even though I fully understand the questions that are being asked today, I cannot help but remind you that the health issue for the consumption of sweets may not only be nanotitanium?
(1) International Nomenclature of Cosmetic Ingredients
(2) 4
(3 ) R. Peters et al, Inventory of Nanotechnology applications in the agricultural, feed and food sector, EFSA supporting publication 2014:EN-621. 
(4 ) See for example
(6 )A. Weir et al, Titanium dioxide nanoparticles in food and personal care products. Approximately Sci Technol. 2012 Feb 21;46(4):2242-50.
(7) M.C. Lomer et al, Dietary sources of inorganic microparticles and their intake in healthy subjects and patients with Crohn's disease. Br J Nutr. 2004 Dec;92(6):947-55.
(8) Joint FAO/WHO Expert Committee on Food Additives (JECFA). See :
(9) X.X. Chen et al, Characterization and preliminary toxicity assay of nano-titanium dioxide additive in sugarcoated chewing gum. Small. 2013 May 27;9(9-10):1765-74. 
(10) W.S. Cho et al, Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration. Part Fibre Toxicol. 2013 Mar 26;10:9.
(11 ) G. Janer et al, Cell uptake and oral absorption of titanium dioxide nanoparticles. Toxicol Lett. 2014 Jul 15;228(2):103-10.
(12) R. Tassinari et al, Oral, short-term exposure to titanium dioxide nanoparticles in Sprague-Dawley rat: focus on reproductive and endocrine systems and spleen. Nanotoxicology. 2014 Sep;8(6):654-62.
(13) J.J. Powell et al, Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract. Br J Nutr. 2007 Oct;98 Suppl 1:S59-63.
(14) M. Butler et al, Dietary microparticles implicated in Crohn's disease can impair macrophage phagocytic activity and act as adjuvants in the presence of bacterial stimuli. Inflamm Res. 2007 Sep;56(9):353-61.
(15) T.Z. Hummel et al, Exogenous pigment in Peyer patches of children suspected of having IBD. J Pediatr Gastroenterol Nutr. 2014 Apr;58(4):477-80. 
(16) Y. Characterization of food-grade titanium dioxide: the presence of nanosized particles. Approximately Sci Technol. 2014 Jun 3;48(11):6391-400.
(17) S. Bettini & E. Houdeau, Oral Exposure to Titanium Dioxide Nanoparticles (TiO2): From Crossing the Oral and Intestinal Epithelium to Fate and Effects in the Body. Biol Today. 2014;208(2):167-75.
(18) E. Brun et al, Titanium dioxide nanoparticle impact and translocation through ex vivo, in vivo and in vitro gut epithelia. Part Fibre Toxicol. 2014 Mar 25;11:13. 
(19) E. Fröhlich & E. Roblegg, Models for oral uptake of nanoparticles in consumer products. Toxicology. 2012 Jan 27;291(1-3):10-7. 
(20) J.J. Faust et al, Food grade titanium dioxide disrupts intestinal brush border microvilli in vitro independent of sedimentation. Cell Biol Toxicol. 2014 Jun;30(3):169-88.
(21) L. Geraets et al, Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats. Part Fibre Toxicol. 2014 Jul 3;11:30.
(22) B. Jovanović, Critical review of public health regulations of titanium dioxide, a human food additive. Integr Environ Assess Manag. 2015 Jan;11(1):10-20.
(23) Editor's note: Some parabens are still under evaluation. See
For a discussion of their toxicity, see F. Castelain & M. Castelain,
Parabens: a real hazard or a scare story? Eur J Dermatol. 2012 Nov-Dec; 22(6):723-7.
One of the main synthetic preservatives used to replace parabens in cosmetics is methylisothiazolinone. It has recognized allergenic properties. See O. Aerts et al. Contact allergy caused by methylisothiazolinone: the Belgian-French experience. Eur J Dermatol. 2015 May-Jun; 25(3):228-33.
(24) A. Dufresne, Nanocellulose: a new ageless bionanomaterial, Materials Today, Vol. 16, No. 6, pp. 220-227, June 2013. Online:  



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