Elicia Dennis Due November 19, 2013 Nanotoxicology and the Need for Further Research Nanotechnology has

a variety of applications that with further research could dramatically change the field of how the world approaches healthcare. Common problems may be totally eliminated allowing challenges we once faced will become a thing of the past. It is quite possible that nanotechnology holds the key to the cures for many ailments including cancer and infections. The small size of nanomaterials allows researchers to develop treatments that can be tailored to the individual patient, reducing treatment times while increasing the likelihood of success for such therapies. Nanotechnology has opened the door to innovations such as treatments that target specific cells while leaving the rest of the body unaffected. One such example is seen in the treatment of cancer. Previous cancer therapies could wreak havoc on the entire body, leaving the patient suffering from additional and often debilitating side effects. Nanotechnology reduces the effect on the body by attacking the cancer cells directly. Nanomaterials can be used to deliver the medicine used to combat the illness directly to the cancer cells, leaving the body otherwise unharmed. Additionally, nanotechnology creates the potential to totally reprogram cells with applications in everything from gene therapy to providing another option in cancer treatment. By using nanomaterials to send signals to specified cells, cell death can be triggered, eliminating the need for additional chemicals to be added to the body. Another problem that currently plagues researchers is drug delivery. It is often difficult to get a sufficiently high dose of medication to the site where it is needed. Nanotechnology presents scientists with a solution: synthesis of the medicine at the site where it is needed. By producing the drugs in the body, close to the cells where they will be used, there is less risk of the medication being broken down by the body before it is used. Unlike previous methods, the drugs

no longer need to travel through the digestive system before they are delivered to the location they are needed. On a larger scale, nanofibres are being used to improve medical procedures. Nanomaterials are currently being used to replace traditional surgical mesh. While the old style of mesh was often stiff and difficult to work with, nanotechnology has allowed for the creation of mesh that is flexible and of various thicknesses. Similarly, doctors have used nanotechnology to engineer artificial organ components that are more effective and have better longevity than their predecessors. While nanotechnology has the potential to drastically change medicine and improve lives in ways never imagined, evidence suggests that there can be severe consequences associated with their usage. The harmful side effects that have been observed call into question the chance that the materials have the ability to cause more harm than good in the long term. As a result, it can be argued that to truly harness the innovative potential of nanotechnology, more research must be conducted to understand the risks. Ultimately, guidelines surrounding the manufacturing, handling and disposal of nanomaterials must be put in place to protect the health of the general population. 1 To truly understand what makes nanomaterials dangerous, one must investigate how they interact with other chemicals. First, a definition of the term nanomaterial is in order. A nanomaterial is one that has at least one dimension that falls in the size range of 1nm to 100nm. This small size puts them on the nanoscale, hence the name nanomaterial. At that small size, the particles develop physical and chemical properties that are not seen at the larger scale.2 That small size leads to the second major aspect of the definition of a nanomaterial, a high surface area to volume ratio. This characteristic is what causes the materials to behave differently than

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2

Wade Robison. "Nano- Technology, Ethics, and Risks." NanoEthics 5.1: 1-13. Print. Robert L. Maynard. "Nano- technology and nano-toxicology." Emerging Health Threats Journal 5.0: 1. Print.

their larger counterparts.3 The ratio between surface area and volume is directly related to chemical reactivity. Generally speaking, a particle is more reactive is the ratio between its surface and volume is large as it creates a large area for chemical reaction to take place. The increased reactivity of nanomaterials makes them ideal for usage in medicine as fewer articles are required to achieve the desired effect. 4 Unfortunately, the same traits that make nanomaterials ideal for medical applications is also what makes them dangerous. Due to their small size, nanoparticles easily move around the body, rapidly traveling from the site of exposure and collecting in distant, critical organ structures in a matter of hours.5 The size of nanomaterials is also significant in the relationship with the bodys waste system. Unlike many other chemicals, nanomaterials are too large to fit through the small channels of the kidneys preventing them from leaving the body with the other unwanted filtrate. Ultimately, nanoparticles are able to stay in the body for long periods of time prolonging exposure and increasing their ability to wreak havoc on the body. It is currently unknown if frequent exposure to nanoparticles will result in large amounts collecting in the body. If this is in fact the case, it is possible that these particles will collect into larger groups or masses and eventually cause significant damage to organs. Similarly, it has been shown that nanoparticles behave differently depending on their size and while one class may be considered benign in low concentrations, unforeseen reactions may result in their presence in higher concentrations. Buildup of the nanomaterials in the body could give way to compounds being found in clumps that react with the body in ways that were not seen on the nanoscale. As a result,

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4 5

Robert L. Maynard. "Nano- technology and nano-toxicology." Emerging Health Threats Journal 5.0: 1. Print. Project on Emerging Nanotechnolgies Risk Research Inventory Update Analysis, David Masci. "Nanotechnology." CQ Researcher 14.22 Print. ., 2008. Web.

it is difficult to say that a substance is totally safe without ruling out the potential for reactions with other nanoparticles changing the physical properties of the chemicals being used.6 Many nanoparticles belong to a class of compounds known as Reactive Oxidative Species or ROS. Typically, the nanoparticles used in medicine occur naturally in our bodies but at higher concentrations than those produced by our cells, adverse reactions can be seen. These species are crucial components of homeostasis (the bodys means of responding to environmental changes in a way that preserves the organism) as well as cell signaling or communication with other parts of the body. ROS also play an important role in the life cycle of a cell as their concentrations are directly related to energy production and timed cell death. The small size of nanomaterials, even those used in medicine allows them to easily enter cells and interact with key structures. Unlike many other chemicals, nanoparticles can enter the nucleus of the cell where the genetic information is stored as well as the mitochondria, the structure responsible for energy production. The nanoparticles that move with such freedom are also typically ROS and thus are able to interfere the normal function of these parts. In high concentrations, the cell reads the presence of ROS chemicals as an indication that decomposition is due and the cell begins to undergo programmed cell death or apoptosis. This self-destruction is the result of damage to the mitochondrias membrane. ROS interact with the fatty acids present in the membranes of the mitochondria, often causing irreversible damage. When the cell detects this damage, it assumes that it is nearing the end of its life span and begins to attack itself. While inside the cell, chemicals in the ROS family also interact with other important compounds such as proteins. The reactive oxygen present in ROS are able to easily oxidize the amino acids found in proteins rendering them ineffective. Using a similar process, necessary enzymes are often

Bengt Fadeel, Harri Alenius, and Kai Savolainen. "Nanotoxicology." Toxicology 313.1 (2013): 1-2. Print.

deactivated by the oxidative properties of ROS. If able to enter the nucleus of the cell, the ROS is able to interact with the DNA and RNA of the organism causing severe damage that can manifest itself on a much larger scale and potentially damage the entire body as a whole. 7 Reactive oxygen species also play a major role in inflammation. Relative to other particles that interact with the body, they have a higher inflammatory potential for their mass than their larger counterparts. Long term swelling in sensitive areas of the body can cause permanent damage and can cause chronic problems such as cardiovascular disease and hearing impairment. It is increasingly difficult to combat this illnesses when the source is nanomaterials as they are often difficult to remove from the body. As a result, nanomaterials can potentially build up and continue to exacerbate a problem caused by their presence in excess. It is also possible for nanoparticles to enter the body through inhalation and injure the lungs. In many cases, the inflammation caused was mild but significant and the potential for acute lung injury is still possible. A study also tested the deposition of nanoparticles in the lungs if the subject was exposed to them in the air.8 The test found that those with pulmonary conditions such as asthma or chronic obstructive pulmonary disease (COPD) had higher levels of particle deposition than those who did not suffer from such conditions. The information found in the study shows the potential for nanoparticles to make preexisting problems worse. Pulmanary conditions are often the result of inflammation in the lungs and the presence of nanomaterials can cause further inflammation increasing the patients likelihood of experiencing symptoms. It has also been found that carbon nanotubles, a type of nanomaterial, behaves much like asbestos when allowed to enter the lungs. Both materials have long thin fibers that damage the lungs and
7

Barry Halliwell. "Reactive oxygen species in living systems: Source, biochemistry, and role in human disease." The American Journal of Medicine 91.3, Supplement 3 (1991): S14-22. Print.
8

Zheng Li, et al. "Cardiovascular Effects of Pulmonary Exposure to Single-Wall Carbon Nanotubes." Environmental health perspectives 115.3 (2007): 377-82. Print.

can potentially cause cancer. Small scale studies have shown that lungs exposed to nanotubles have developed cancers such as mesothelioma, the same type that is often seen in patients previously exposed to asbestos. 9 The use of nanoparticles has been linked to several different types of cancer, not just mesothelioma. There is a significant relationship between ROS and cancer cells. The presence of ROS and the DNA damage they cause can lead to cancers developing as a result of the mutations inflicted by the altered genetic information. The inflammation the ROS cause is also an important mediator in cancers as it allows for the rapid reproduction of cells, even those that are damaging to the body. On a larger scale, nanoparticles have the potential to not only cause cancer in different parts of the body but overload the immune system. They are difficult to destroy, requiring several different parts of our defense systems at once. Not only does this take a toll on our bodies, it also weakens us to other attacks such as those from pathogens. If our immune systems are fighting off nanoparticles that it deems dangerous, it leaves itself vulnerable to other attacks making us more prone to illnesses. Also, while many pathogens are unable to enter our cells on their own, nanoparticles can and as a result, act as a means of entry for dangerous chemicals. Pathogens are able to bond with nanoparticles present in our bodies as use this to cross cell membranes and access important cellular components that were once safe from their damage. Similarly, there are some cellular barriers that nanoparticles cannot cross. It was originally believed that these barriers protected some tissues from the undesired effects of nanoparticles. Recent studies have shown that this is not the case. Although the particles cannot cross the barriers, they are still able to interact with the cells on the other side, influencing their signaling
9

"Lung Penetration.(NANOTOXICOLOGY)(Nanotubes' Health Effects)(Brief Article)." Nature 461.7268: 1176. Print.

patterns and causing damage. Particles that contain Cobalt and Chromium can change the uptake of ions from the cells surroundings which thus changes the signals the cell receives and can trigger things such as programmed cell death. Such trends have been observed across membranes of different thicknesses. The blood-brain barrier is particularly vulnerable to such attacks as it is just one layer making the interaction between nanoparticles and brain cells even easier. 1011 While considering the dangers of nanoparticles, an important distinction must be made. Nanoparticles occur naturally, in amounts that are orders of magnitude larger than those engineered for medical use. That being said, it is also pertinent to note that current knowledge indicates that in the general case, most nanoparticles are actually significantly less dangerous than the mediation they will be used to deliver or produce. In reality, nanoparticles as well as the class of chemicals they belong to, Reactive Oxygen Species (ROS) are actually necessary for life to exist. They play a key role in biological processes and are indispensable to the human body. Nanoparticles should not be feared as a whole so their dangers are not fully understood and some are known to be safe. It is the job of research teams to investigate which particles could be associated with adverse effects and properly regulate those so that their potential can be harnessed without sacrificing peoples health in the process.

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A. Sood1, S. Salih1, D. Roh2, L. Lacharme-Lora1 , M. Parry1 , B. Hardiman1 , R. Keehan1 , R. Grummer3 , E. Winterhager3, P. J. Gokhale4, P. W. Andrews4, C. Abbott5, K. Forbes6, M. Westwood6, J. D. Aplin6, E. Ingham7, I. Papageorgiou7, M. Berry8, J. Liu8, A. D. Dick8, R. J. Garland9, N. Williams9, R. Singh10, A. K. Simon11, M. Lewis12, J. Ham12, L. Roger13, D. M. Baird13, L. A. Crompton14, M. A. Caldwell14, H. Swalwell15, M. Birch-Machin15, G. Lopez-Castejon16, A. Randall17, H. Lin18, M-S. Suleiman18, W. H. Evans19, R. Newson20 and C. P. Case1 *. "Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness." Nature 6.12 (2011): 824. Print.
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Gevdeep Bhabra1, Aman Sood1, Brenton Fisher1 , Laura Cartwright2, Margaret Saunders2, William Howard Evans3, Annmarie Surprenant4, Gloria Lopez-Castejon4, Stephen Mann5, Sean A. Davis5, Lauren A. Hails5, Eileen Ingham6, Paul Verkade7, Jon Lane7, Kate Heesom8, Roger Newson9 and Charles Patrick Case1 *. "Nanoparticles can cause DNA damage across a cellular barrier." Nature 4.12 (2009): 876. Print.

Currently, only 3% of spending in the area of nanotechnology is invested in better understanding the risks associated with the new innovations. Many researchers are calling for more consideration being given to the potential hazards of increased nanomaterial usage but recent spending trends show that little consideration has been given to the numerous warnings that have been received.12 Although nanotech has the means of changing how many diseases are treated, it has also been shown to cause the exact same conditions, potentially nullifying its benefits. That does not have to be the case if preventative measures are taken. Such mistakes have been made previously with the widespread use of asbestos and thalidomide and many suffered as a result. Nanotechnology is one of the greatest revolutions of the modern century but it is necessary to properly investigate the dangers associated with it and put proper protocols in place to ensure that it is able to do as much good as possible, not cause more harm.

Works Cited

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John M. Balbus, et al. "Meeting Report: Hazard Assessment for Nanoparticles--Report from an Interdisciplinary Workshop." Environmental health perspectives 115.11 (2007): 1654-9. Print.

Balbus, John M., et al. "Meeting Report: Hazard Assessment for Nanoparticles--Report from an Interdisciplinary Workshop." Environmental health perspectives 115.11 (2007): 1654-9. Print.

Fadeel, Bengt, Harri Alenius, and Kai Savolainen. "Nanotoxicology." Toxicology 313.1 (2013): 1-2. Print. Gevdeep Bhabra1, Aman Sood1, Brenton Fisher1 , Laura Cartwright2, Margaret Saunders2, William Howard Evans3, Annmarie Surprenant4, Gloria Lopez-Castejon4, Stephen Mann5, Sean A. Davis5, Lauren A. Hails5, Eileen Ingham6, Paul Verkade7, Jon Lane7, Kate Heesom8, Roger Newson9 and Charles Patrick Case1 *. "Nanoparticles can Cause DNA Damage Across a Cellular Barrier." Nature 4.12 (2009): 876. Print.

Halliwell, Barry. "Reactive Oxygen Species in Living Systems: Source, Biochemistry, and Role in Human Disease." The American Journal of Medicine 91.3, Supplement 3 (1991): S14-22. Print.

Helland, Aasgeir, et al. "Reviewing the Environmental and Human Health Knowledge Base of Carbon Nanotubes." Environmental health perspectives 115.8 (2007): 1125-31. Print.

Li, Zheng, et al. "Cardiovascular Effects of Pulmonary Exposure to Single-Wall Carbon Nanotubes." Environmental health perspectives 115.3 (2007): 377-82. Print.

"Lung Penetration.(NANOTOXICOLOGY)(Nanotubes' Health Effects)(Brief Article)." Nature 461.7268 : 1176. Print.

Masci, David. "Nanotechnology." CQ Researcher 14.22 Print.

Maynard, Robert L. "Nano- Technology and Nano-Toxicology." Emerging Health Threats Journal 5.0 : 1. Print.

Oberdorster, G., E. Oberdorster, and J. Oberdorster. "Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles." Environmental health perspectives 113.7 (2005): 823-39. Print. Project on Emerging Nanotechnolgies Risk Research Inventory Update Analysis, ., 2008. Web.

Robison, Wade. "Nano- Technology, Ethics, and Risks." NanoEthics 5.1 : 1-13. Print. A. Sood1, S. Salih1, D. Roh2, L. Lacharme-Lora1 , M. Parry1 , B. Hardiman1 , R. Keehan1 , R. Grummer3 , E. Winterhager3, P. J. Gokhale4, P. W. Andrews4, C. Abbott5, K. Forbes6, M. Westwood6, J. D. Aplin6, E. Ingham7, I. Papageorgiou7, M. Berry8, J. Liu8, A. D. Dick8, R. J. Garland9, N. Williams9, R. Singh10, A. K. Simon11, M. Lewis12, J. Ham12, L. Roger13, D. M. Baird13, L. A. Crompton14, M. A. Caldwell14, H. Swalwell15, M. Birch-Machin15, G. Lopez-Castejon16, A. Randall17, H. Lin18, M-S. Suleiman18, W. H. Evans19, R. Newson20 and C. P. Case1 *. "Signalling of DNA Damage and Cytokines Across Cell Barriers Exposed to Nanoparticles Depends on Barrier Thickness." Nature 6.12 (2011): 824. Print.