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Nanotechnology: benefits vs toxic risks

This emerging technology promises advances in delivery systems as well as packaging, but the use of nano-sized particles may lead to more harm than good. George Burdock, PhD, and Sabine Teske, PhD, examine the pros and cons

Applications for the use of nanotechnology in food products, dietary supplements and their packaging offer tremendous potential for future gains in these industries. Nanotechnology, and all of its applications, is projected to be a trillion dollar global business by 2014.

Often, the most difficult concept to grasp about nanotechnology is the size and scale. A favourite scale of comparison is: 'a nanometer is to a meter, as the diameter of a dime is to the diameter of the earth.' But at this size, some of the rules get changed. At the nano-scale (particles less than 100 nanometers in their greatest dimension), the physical, chemical and biological properties of materials may differ in fundamental ways from the properties of individual atoms, molecules and the well-characterized bulk matter from which the nano-sized particles (NSPs) are derived.

As a consequence of these new physical and chemical properties, substances that could not have been used in a particular media previously because of instability or incompatibility (such as pH sensitivities or incompatibilities of solvents), may now have new applications. Some of these new nanotechnological advantages include enhanced solubilization, controlled delivery and absorption of ingredients.

For example, because NSPs defy conventional physics and are governed by quantum physics, particles may remain in suspension in a medium that does not normally support their solubility. Likewise, nano-sized liposomes (hollow balls made of lipids such as phosphatidylcholine) allow substances to remain suspended in nano-emulsions, keeping substances in suspension in an incompatible environment, but remaining clear to the naked eye. Also, nano-sized liposomes can affect a controlled delivery by protecting labile chemicals (such as enzymes or delicate chemical esters) against harsh environments (including stomach acid), but release the fragile cargo when ambient conditions are favourable.

Further, once consumed, these particles have enhanced absorptive properties because of their small size, and can gain entrance to cells via tiny surface pores (caveolae), or even travel between cells via 'tight junctions,' which block even micron-sized particles (a red blood cell is comparatively large with a diameter of 7 microns). Liposomes may also have the ability to simply merge with a cellular membrane and release their contents into the cell.

The advantages of nanotechnology for food-packaging ingredients include the use of new fibres or polymers to provide new packaging matrices. Also, there is research into functional-food packaging attributes such as conferring more efficient barriers (eg, ultraviolet resistance) and the incorporation of nano-silver particles into food wrappers to kill bacteria and lengthen the shelf life of products. Further, developers are working on 'smart packaging' that could allow the detection of outdated or contaminated product when the package changes colour or a message becomes visible.

At what cost?
However, these new properties may come with a price, as the same new rules that govern the advantageous behaviours may also give rise to new biological properties that alter the safety of these same materials. The study of these possible new safety paradigms is termed 'nano-toxicology,' and it promises to further our understanding of the biological properties of nano-materials, to ensure the safe application of this technology.

NSPs were found to traverse through lung tissue in unexpected ways, gaining access to blood and lymphatic systems
Nano-toxicology first discovered problems in the area of industrial and occupational worker safety regarding the use of nano-particles in the aerospace industry, as well as their production from welding fumes and forest fires. NSPs were found to traverse through lung tissue in previously unexpected ways, gaining access to the blood and lymphatic systems with relative ease. It was also found that some particles could be transported along nerves, similar to viruses such as polio and herpes.

Given these properties of ready anatomical access, some of these NSPs are thought to be able to gain access to the heart, causing heart attacks by literally short-circuiting the heart's delicate electrical system. Also, NSPs may cross into previously protected sites, passing with ease through the blood-brain-, blood-retinal-, and blood-placental-barriers.

Once in the body, some particles have changed the shape or conformation of proteins, creating a protein similar to that produced in Alzheimer's disease. Changing protein conformation can potentially create new allergenic proteins in organs to which the body could mount an immune response.

While easy entry into the cells of the intestine and target organs can be beneficial, the other side of the coin is that because these particles are so 'slippery,' how can they ever be excreted by the body? Because much of our excretory system at the cellular level is based on a cell successfully excreting a substance (as in the kidney) to be flushed away, how can the particle be made to remain in the waste stream if it can so easily gain re-entry into other cells downstream?

Kidneys could be trapped into a process of continually excreting and reabsorbing the same substances until the cells become exhausted or so full of recycled particles that conventional waste can no longer be excreted. The cell then becomes a warehouse of garbage and finally dies and disintegrates, spilling its contents, which are absorbed by other cells.

A similar situation could exist for phagocytic cells of the body, such as macrophages in the blood, liver and spleen, as many of these particles, once 'eaten' by these cells, cannot be digested and are held within the cell until it finally disintegrates, freeing the particle to be phagocytized by another macrophage — and the cycle would continue. The end result is that humans could eventually become bio-accumulators, and the only time the particle excretion and resorption cycle is broken is when the human 'landfill' is buried.

Some of these NSPs, once coated with various substances, have been found to be very stealthy, gliding past normal defence systems in the intestine, liver, spleen and lymph nodes. Unabated, they are free to enter cells, and those specific for mitochondria pierce delicate mitochondrial membranes, shutting down energy-producing pathways and releasing 'suicide' messages and materials, signaling the cell nucleus and scavenging cells that this particular cell needs to be removed.

The damage most often seen is the generation of reactive oxygen species
Other potential damage
While some of the more dramatic examples of actual physical damage are described above, the damage most often seen in response to nano-materials is the generation of reactive oxygen species, resulting in oxidative stress to the biological system.

In oxidative stress, the universal antioxidant chemical in the body, glutathione or GSH, is converted to the oxidized inactive form, GSSH. As reserves of GSH are depleted and the GSH:GSSH ratio lowers, the body mounts a progressively more assertive reaction. The first stage of oxidative stress is to produce special enzymes to detoxify the new invading chemical; if, however, there is no enzyme for this purpose or the human does not have the capability to produce the enzyme, the body progresses into the next stage, inflammation.

In inflammation, signaling pathways such as p38 mitogen-activated protein kinase and nuclear factor kappaB are activated. These pathways turn on genes within the cell to produce inflammation via signaling cytokines and chemokines, both of which alert neighboring cells and processes within the same cell that a critical point in maintaining cell viability has been reached. If the amount of cellular GSH continues to drop, the cell enters into a terminal stage where the cellular environment has now become toxic and the mitochondria become porous, leaking substances that signal the cell that it must close down in order to protect the rest of the body from its own toxic state.

This last stage is called apoptosis. The cell goes through a process of destroying its own infrastructure and prepares to have its remains engulfed by a macrophage, which has already been signaled to come to this specific site and be ready for a disposal assignment.

Oxidative stress is the final chemical insult to the body, and the reason for the valid belief in the use of antioxidants as a method for keeping healthy. However, while nanotechnology might be used to efficiently deliver those life-benefiting antioxidants, the use of nano-sized particle delivery systems could lead to more harm than good.

The upside
This does not mean losing the valuable contributions of nanotechnology. The science of food-ingredient toxicology has seen this sort of problem before. For example, carrageenan (a thickening agent in foods) was thought to be thoroughly safe, until a process was discovered to make the molecules of carrageenan smaller for easier addition during processing. However, this finely divided carrageenan turned out to be carcinogenic in rats, so today there is an average minimal molecular weight limit to carrageenan. Similarly, very small particles of microcrystalline cellulose were found to have toxic properties. In response, the FDA prohibited the use of microcrystalline cellulose particles of less than 5 microns in size.

Scientists at Burdock Group and other organisations are investigating the possible toxic potential of NSPs and working on regulatory solutions before nanotechnology becomes an issue with the public, as happened with genetically modified foods and the irradiation of food to kill bacteria such as E coli.

The potential advantages of nanotechnology are great and the loss of the advantages this technology could confer to various aspects of human health would be a great loss to the manufacturer and, ultimately, the consumer.

Dr George A Burdock is president, and Dr Sabine Teske is staff toxicologist at the Burdock Group, a leading scientific and regulatory consulting firm specializing in the food, dietary supplements and cosmetics and personal-care industries. Burdock Group offers diverse scientific experience with GRAS dossier preparation and notification and Dietary Ingredient Notifications.

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