RISK ANALYSIS OF NANOTECHNOLOGY IN HEALTH

INTRODUCTION:

The health impact of nanotechnology are the possible effects that the use of nanotechnological materials and devices will have on human health. As nanotechnology is an emerging field, there is great debate regarding to what extent nanotechnology will benefit or pose risks for human health. Nanotechnology's health impact can be split into two aspects: the potential for nanotechnological innovations to have medical applications to cure disease, and the potential health hazards posed by exposure to nanomaterials. Nanoparticleswhich are the width of 210 atoms, that is, less than 100 nanometerscould potentially invade body systems with possible health consequences. For example, nanomaterials, such as metal oxides and carbon nanotubes, could theoretically behave like quartz dust or asbestos particles and result in similar damaging effects on the respiratory system. Studies to date show that the human body's normal defense mechanisms treat nanoparticles like micro-organisms but nanoparticles could link together to form fibers that are too large to be engulfed by macrophages. Nanoparticles with a high proportion of transition metals might have reactive surfaces that could alter the particles' toxicity and consequently harm human cells.

THE RISKS OF NANOTOXICITY TO HUMAN HEALTH:

In the past, incidentally produced nano-sized particles have been a by-product of forest fires and volcanoes, and high-temperature industrial processes including combustion, welding, grinding and vehicle combustion. The widespread use of manufactured nanomaterials in consumer, industrial and agricultural products will dramatically increase our exposure to particles in this size range. Study of the negative health impacts of exposure to very small particles in air pollution, coal and silica dust, welding fumes and asbestos is informing the emerging field of nanotoxicology, but much more research is needed to understand the health risks of nanomaterials already used in hundreds of products world-wide.

Why do nanomaterials present greater toxicity risks than larger particles and materials?

The toxicity of nanomaterials is often linked to their extremely small size. Smaller particles have a greater reactive surface area than larger particles, are more chemically reactive and produce greater numbers of reactive oxygen species that include free radicals. Reactive oxygen species production has been found in a diverse range of nanomaterials including carbon fullerenes, carbon nanotubes and metal oxides. This is one of the primary mechanisms of nanoparticle toxicity; it may result in oxidative stress, inflammation, and consequent damage to proteins, membranes and DNA. The extremely small size of nanomaterials also means that they are much more readily taken up by the human body than larger sized particles. Nanomaterials are able to cross biological membranes and access cells, tissues and organs that larger sized particles normally cannot. Nanomaterials can gain access to the blood stream following inhalation or ingestion. At least some nanomaterials can penetrate the skin, especially if skin is flexed. Broken skin is an ineffective particle barrier, suggesting that acne, eczema, shaving wounds or severe sunburn may enable skin uptake of nanomaterials more readily. Once in the blood stream, nanomaterials can be transported around the body and are taken up by organs and tissues including the brain, heart, liver, kidneys, spleen, bone marrow and nervous system. Nanomaterials have proved toxic to human tissue and cell cultures, resulting in increased oxidative stress, inflammatory cytokine production and cell death. Unlike larger particles, nanomaterials may be taken up by cell mitochondria and the cell nucleus. Studies demonstrate the potential for nanomaterials to cause DNA mutation and induce major structural damage to mitochondria, even resulting in cell death. Size is clearly a key factor in determining the potential toxicity of a particle. However it is not the only important factor. Other properties of nanomaterials that influence toxicity include: chemical composition, shape, surface structure, surface charge, aggregation and solubility, and the presence of functional groups of other chemicals. The large number of variables influencing toxicity means that it is difficult to generalize about health risks associated with exposure to nanomaterials each new nanomaterial must be assessed individually and all material properties must be taken into account in safety assessment.

What evidence is there that commonly used nanomaterials pose serious toxicity risks? Preliminary scientific studies indicate that nanomaterials now used in consumer products could present serious risks to human health and the environment. The Scientific Committee on Emerging & Newly Identified Health Risks (SCENIHR) issued a preliminary opinion on "The appropriateness of the risk assessment methodology in accordance with the Technical Guidance Documents for new and existing substances for assessing the risks of nanomaterials" in March 2007 [http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_004c.p df ] In general, the report concluded that it is unclear whether existing EU risk assessment methods could capture the potential environmental impacts of

nanomaterials, though it was generally likely to identify risks to human health. The following conclusions (Page 51, 4.3.1. Conclusions of human health chapter) are specifically relevant to human health, and also single out certain vulnerable groups: there is evidence that nanoparticles may cross the blood brain barrier under some circumstances, that they may be associated with long term inflammation in several different types of tissue and organ and may be associated with cardiovascular effects. Although this data is still limited, these possibilities have to be taken into account. Similarly, the available evidence suggests that certain subpopulations, particularly those with pre-existing disease such as asthma and cardiovascular disease may be more susceptible to the adverse effects of nanoparticles, which again should be considered in the assessment of human health hazards. Nanoparticles behave unlike lumps of the same materialsstronger, more toxic, and with radically different properties. What makes them so useful also makes their safety so uncertain. Immediate, further research into nanoparticle toxicities and its dissemination is needed. Effects on human health and the environment result from nanoparticles reaching waterways through wastewater treatment and disposal sites, affecting the organisms that live in the water and the people who drink and cook with water. Three types of nanoparticles are of particular concern: nanosilver particles; carbon nanofibers; and buckyballs, or microscopic, football-shaped cages of carbon. NANOPARTICLES OF SILVER Nanoparticles of silver are now used in toothpastes, soaps and face creams, food packaging, clothing, household appliances, disinfectants and wound dressings. Silver nanoparticles have a potent ability to kill bacteria. In fact, the manufacturers of a washing machine which uses silver nanoparticles claim that their product will kill over 650 different bacteria. However there are concerns that silver nanoparticles may also kill beneficial bacteria in environmental systems. The United States Environmental Protection Agency has announced plans to regulate as pesticides products that contain silver nanoparticles and which make antimicrobial claims. At the same time, silver nanoparticles may also compromise our ability to control harmful bacteria. Harmful bacteria may become resistant to silver nanoparticles, but because of the type of resistance mechanism developed, they may also potentially develop resistance to 50% of commonly used antibiotics (beta-lactams). Silver nanoparticles may also be toxic to humans: test tube studies show that silver nanoparticles are highly toxic to rat brain cells, mouse stem cells and rat liver cells. Nanosilver is known to be highly toxic to aquatic life. While silver is safer for people than other toxics such as lead and chromium, for aquatic organisms, the story is quite different. Silver is more toxic to many fresh- and salt-water organisms, ranging from phytoplankton (at the bottom of the food chain) to marine invertebratessuch as oysters and snailsto different types of fish, especially in their immature stages. Many species of fish and shellfish, as well as their food, are susceptible; widespread exposure to silver impacts and disrupts ecosystem health. Nanosilver is significantly more toxic than lumps of silver because the tiny particles huge surface area increases their ability to interact with the environment. Nanosilver has been shown to break

down and leach into water systems when, for example, sports garments incorporating silver nanoparticles for odor control are agitated in washing machines. In one study of silver nanoparticles used as antimicrobials in fabrics, of seven nanoparticle fabrics tested, four of them lost 20 percent to 35 percent of their silver in the first wash, and one brand lost half of its silver content in just two washings all of which drained directly into the environment. Many waterways are just recovering from high levels of silver introduced by the photography industry during the twentieth century. New silver nanoparticle products may result in highly toxic levels of silver being reintroduced into rivers and lakes through water treatment facilities. CARBON NANOFIBERS Carbon nanofibers, which are added to tires and woven into clothing to produce different colors without using dyes, are also likely to be shed where they can be inhaled and cause lung damage. In a study published in the Journal of Molecular Cell Biology, Chinese researchers discovered that a class of nanoparticles being widely developed in medicineployamidoamine dendrimers (PAMAMs)cause lung damage by triggering a type of programmed cell death known as autophagic cell death. In the study, the researchers first showed, through several independent experiments, that several types of PAMAMs killed human lung cells in the lab. They did not observe any evidence that the cells were dying by apoptosis, a common type of programmed cell death. However, they found that the particles triggered autophagic cell death through the Akt-TSC2-mTOR signaling pathway. Autophagy is a process that degrades damaged materials in a cell and plays a normal part in cell growth and renewal, but scientists have found that sometimes an over activity of this destruction process leads to cell death. The researchers also found that treating the cells with an autophagy inhibitor known as 3MA significantly inhibited the process, increasing the number of cells that survived exposure to the nanoparticles. "Those results, taken together, showed that autophagy plays a critical role in the nanoparticle-induced cell death," said Dr. Jiang. The scientists then tested their findings in mice. They found that introducing the toxic nanoparticles significantly increased lung inflammation and death rates in the mice, but injecting the mice with the autophagy inhibitor 3MA before introducing the nanoparticles significantly ameliorated the lung damage and improved survival rates. "These experiments indicate that autophagy is indeed involved in lung damage caused by these nanoparticles and that inhibition of this process might have therapeutic effects," Dr. Jiang said. "We will likely need to look for additional new inhibitors to block lung damage as this particular compound is not stable in humans, but this gives us a promising lead for the first time." "Our study has identified the principle for developing such compounds. The idea is that, to increase the safety of nanomedicine, compounds could be developed that could either be incorporated into the nano product to protect against lung

damage, or patients could be given pills to counteract the effects," Dr. Jiang said, adding that the findings could also provide important insight into how nanopaticles cause other toxic effects. It is not clear whether other types of nanoparticles would cause lung damage via the same mechanism, but some may, Dr. Jiang said. The group's research also suggests that blocking autophagic cell death could perhaps be useful in combating other causes of lung damage. BUCKYBALLS Carbon-based buckyballs have shown to be absorbed by simple organisms, raising concerns that toxicities contaminate the food chain at the most damaging lower levels. Carbon fullerenes (buckyballs), currently used in some face creams and moisturisers, have been found to cause brain damage in fish, kill water fleas and have bactericidal properties. Test tube studies have found that even low levels of exposure to water soluble fullerenes are toxic to human liver cells, carcinoma cells and skin connective tissue. This is cause for serious concerns given the capacity of fullerenes to enter human cells and to localise within cell nuclei Fullerene-based amino acid damaged human skin cells. In test tube studies in the presence of biological reducing agents (eg NADH) similar to the concentrations found in biological systems, photoactivated fullerenes destroyed supercoiled DNA. Other scientific issues include:

Nanomaterials may enter the body by routes not typically found with other chemicals because of their small size. If nanomaterials of certain sizes are able to enter the body, they may pass through cell membranes or cross the blood-brain barrier because of their small size. In some cases this is a beneficial characteristic when used for drug delivery and disease treatments. This characteristic could also result in unintended impacts for manufactured nanomaterials not designed for disease therapies. Nanomaterials may interact with environmental media and pollutants to produce by-products that may have the potential to cause health effects.

What are the potential sources of nanoexposure? Members of the general public face exposure to nanomaterials through use of products that contain nanomaterials, for example cosmetics, sunscreens, clothing or cling wrap, or through ingestion of products that contain nano-ingredients, for example foods, beverages, nutritional supplements or lipstick. Occupational exposure to nanomaterials is of particular concern as workers may be exposed at much higher levels than the general public and on a more consistent basis49 Workers may

experience nanoexposure in the production, manufacture, packaging or transport of products that contain nanomaterials, or in cleaning or maintenance work. Environmental exposure to nanomaterials is likely to increase as the industry expands. Waste containing nanomaterials will be released into the environment from households and industry, and products containing nanomaterials will disposed of in landfill. Even nanomaterials that are fixed in products, for example lights, car parts or building equipment, may enter waste streams as free nanomaterials following product disposal or recycling. Large quantities of nanomaterials may also be released into the environment intentionally, for example for agriculture, military or remediation. There is a complete lack of data for current human and environmental exposure to manufactured nanomaterials.

BENEFITS: Reducing the global disease burden - Improvements in health care through enhanced diagnosis and treatment will increase personal well-being worldwide. Example: Research on nanoelectronics-based cancer diagnostics could lead to tests that can be done in pharmacies. The results promise to be highly accurate and the product promises to be inexpensive. They could take a very small amount of blood and detect cancer anywhere in the body in about five minutes, with a sensitivity that is a thousand times better than in a conventional laboratory test. These devices that are built with nanowires to detect cancer proteins; each nanowire detector is primed to be sensitive to a different cancer marker. The biggest advantage of the nanowire detectors is that they could test for anywhere from ten to one hundred similar medical conditions without adding cost to the testing device. Nanotechnology has also helped to personalize oncology for the detection, diagnosis, and treatment of cancer. It is now able to be tailored to each individuals tumor for better performance. They have found ways that they will be able to target a specific part of the body that is being affected by cancer. Nanotechnology is helping to advance the use of arthroscopes, which are pencilsized devices that are used in surgeries with lights and cameras so surgeons can do the surgeries with smaller incisions. The smaller the incisions the faster the healing time which is better for the patients. Arthroscopic surgery is hoping to make the scope smaller than a strand of hair in the future.

CHALLENGES:

The assessment of nanomaterials as new chemicals

Mandatory safety testing of nanomaterials prior to their inclusion in commercial products Requirements for product labels to indicate the presence of manufactured nano materials/particles The consideration of nanotechnologys broader societal implications alongside questions of basic safety Public participation in decision-making regarding nanotechnologys introduction and in determining priorities for public spending on nanotechnology research and development