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Toxicology of nanoparticles

Nanotoxicology is a sub-specialty of particle toxicology. It addresses the toxicology of nanoparticle (particles <100 nm diameter) which appear to have toxicity effects that are unusual and not seen with larger particles. Nanoparticles can be divided into combustion-derived nanoparticles (like diesel soot), manufactured nanoparticles like carbon nanotubes and naturally occurring nanoparticles from volcanic eruptions, atmospheric chemistry etc. Typical nanoparticles that have been studied are titanium dioxide, alumina, zinc oxide, carbon black, and carbon nanotubes, and "nano-C60". Nanoparticles seem to have some different properties from larger particles that are known to have pathogenic effects, like asbestos or quartz. These differences seem to be a result of their size. Nanoparticles have much larger surface area to unit mass ratios which in some cases may lead to greater pro-inflammatory effects (in, for example, lung tissue). In addition, some nanoparticles seem to be able to translocate from their site of deposition to distant sites such as the blood and the brain. This has resulted in a sea-change in how particle toxicology is viewed- instead of being confined to the lungs, nanoparticle toxicologists study the brain, blood, liver, skin and gut. Nanotoxicology has revolutionised particle toxicology and rejuvenated it.
The smaller a particle is, the greater its surface area to volume ratio and the higher its chemical reactivity and biological activity. The greater chemical reactivity of nanomaterials results in increased production of reactive oxygen species (ROS), including free radicals. ROS production has been found in a diverse range of nanomaterials including carbon fullerenes, carbon nanotubes and nanoparticle metal oxides. ROS and free radical production 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 much more readily gain entry into the human body than larger sized particles. How these nanoparticles behave inside the body is still a major question that needs to be resolved. The behavior of nanoparticles is a function of their size, shape and surface reactivity with the surrounding tissue. In principle, a large number of particles could overload the body's phagocytes, cells that ingest and destroy foreign matter, thereby triggering stress reactions that lead to inflammation and weaken the body’s defense against other pathogens. In addition to questions about what happens if non-degradable or slowly degradable nanoparticles accumulate in bodily organs, another concern is their potential interaction or interference with biological processes inside the body. Because of their large surface area, nanoparticles will, on exposure to tissue and fluids, immediately adsorb onto their surface some of the macromolecules they encounter. This may, for instance, affect the regulatory mechanisms of enzymes and other proteins.
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 via inhalation or ingestion.At least some nanomaterials can penetrate the skin;even larger microparticles may penetrate skin when it is flexed. Broken skin is an ineffective particle barrier,suggesting that acne, eczema, shaving wounds or severe sunburn may accelerate skin uptake of nanomaterials. Then, once in the blood stream, nanomaterials can be transported around the body and be 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 mutationn and induce major structural damage to mitochondria, even resulting in cell death.Size is therefore 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 or absence of functional groups of other chemicals.The large number of variables influencing toxicity means that it is difficult to generalise about health risks associated with exposure to nanomaterials – each new nanomaterial must be assessed individually and all material properties must be taken into account.
Since there is no authority to regulate nanotech-based products, there are many products that could possibly be dangerous to humans. Scientific research has indicated the potential for some nanomaterials to be toxic to humans or the environment. In March 2004 tests conducted by environmental toxicologist Eva Oberdörster, Ph.D. working with Southern Methodist University in Texas, found extensive brain damage to fish exposed to fullerenes for a period of just 48 hours at a relatively moderate dose of 0.5 parts per million (commensurate with levels of other kinds of pollution found in bays). The fish also exhibited changed gene markers in their livers, indicating their entire physiology was affected. In a concurrent test, the fullerenes killed water fleas, an important link in the marine food chain.The extremely small size of fabricated nanomaterials also means that they are much more readily taken up by living tissue than presently known toxins. Nanoparticles can be inhaled, swallowed, absorbed through skin and deliberately or accidentally injected during medical procedures. They might be accidentally or inadvertently released from materials implanted into living tissue.
Researcher Shosaku Kashiwada of the National Institute for Environmental Studies in Tsukuba, Japan, in a more recent study, intended to further investigate the effects of nanoparticles on soft-bodied organisms. His study allowed him to explore the distribution of water-suspended fluorescent nanoparticles throughout the eggs and adult bodies of a species of fish, known as the see-through medaka (Oryzias latipes). See-through medaka were used because of their small size, wide temperature and salinity tolerances, and short generation time. Moreover, small fish like the see-through medaka have been popular test subjects for human diseases and organogenesis for other reasons as well, including their transparent embryos, rapid embryo development, and the functional equivalence of their organs and tissue material to that of mammals. Because the see-through medaka have transparent bodies, analyzing the deposition of fluorescent nanoparticles throughout the body is quite simple. For his study, Dr. Kashiwada evaluated four aspects of nanoparticle accumulation. These included the overall accumulation and the size-dependent accumulation of nanoparticles by medaka eggs, the effects of salinity on the aggregation of nanoparticles in solution and on their accumulation by medaka eggs, and the distribution of nanoparticles in the blood and organs of adult medaka. It was also noted that nanoparticles were in fact taken up into the bloodstream and deposited throughout the body. In the medaka eggs, there was a high accumulation of nanoparticles in the yolk; most often bioavailibility was dependent on specific sizes of the particles. Adult samples of medaka had accumulated nanoparticles in the gills, intestine, brain, testis, liver, and bloodstream. One major result from this study was the fact that salinity may have a large influence on the bioavailibility and toxicity of nanoparticles to penetrate membranes and eventually kill the specimen.
As the use of nanomaterials increases worldwide, concerns for worker and user safety are mounting. To address such concerns, the Swedish Karolinska Institute conducted a study in which various nanoparticles were introduced to human lung epithelial cells. The results, released in 2008, showed that iron oxide nanoparticles caused little DNA damage and were non-toxic. Zinc oxide nanoparticles were slightly worse. Titanium dioxide caused only DNA damage. Carbon nanotubes caused DNA damage at low levels. Copper oxide was found to be the worst offender, and was the only nanomaterial identified by the researchers as a clear health risk.
Immunogenicity to nanoparticles. Very few attention has been concentrated in the potential immunogenicity of nanostructures. Nanostructures can activate the immune system inducing inflammation, immune responses, allergy, or even affect to the immune cells in a deleterious or beneficial way(immunosuppression in autoinmmunity diseases, improving immune responses in vaccines). Many studies are needed in order to know the potential deleterous or beneficial effects of nanostructures in the immune system. Comparing to the conventional pharmeceutical agents, nanostructures has a huge size and immune cells, specially phagocytic cells, recognize and try to destroy them.
In addition, standarization of toxicology tests between laboratories are needed. Díaz, B. et al from the University of Vigo (Spain) has shown (Small, 2008) that many different cell lines should be studied in order to know if a nanostructure induces toxicity, and human cells can intenalize aggregated nanoparticles. Moreover, it is important to take into account that many nanostructures aggregate in biological fluids, but groups manufacturing nanostructures do not care much about this matter. Many efforts of interdisciplinary groups are strongly needed in order to progress in this field

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