|
|
|
Instructions,
| Gunter Oberdorster, Eva Oberdorster, and Jan Oberdorster The title of this review, "Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles" defines this rapidly growing new field of study. This is a comprehensive review of the field of nanotoxicology from its origins about 10 years ago to present fields of study and finally to speculations concerning the future of nanotoxicology. Ultrafine particle research is the basis of the field of nanotoxicology. UFP or ultrafine particles are both ambient and laboratory created NSPs (nanosized particles) less than 100 nm in size that are not produced in a controlled manner. NSPs are defined as both ambient and engineered spherical particles less than 100 nm in size. NPs are engineered spherical nanoparticles less than 100 nm. All three terms are based on size and not on chemical compositions as used in this review. NSP are unique compared to larger particles because of their large surface area per unit mass. For example a 5,000 um diameter particle has a surface area of 12 nm2/cm3 while a 5 um particle has a surface area of 12,000 um2/cm3. In addition there are 0.15 particles of 5,000 um diameter per cm3 and 153,000,000 particles of 5 um diameter per cc3. The above refers to particles of unit density. The characteristic of a large surface area given a small diameter particle leads to specific properties important to nanotoxicology as opposed to the toxicology of larger particles. The surface atoms and molecules on NSP lead to greater surface reactivity which consequently causes greater biologic activity compared to that of larger particles. Humans were likely not exposed to NSPs in large concentrations until the onset of the industrial revolution. Natural sources of NPs and UFPs are forest fires, volcanoes, ferritin, gas-to-particle conversions, viruses and other biologic entities. As power plants, internal combustion engines, jet engines, metal fumes from smelting and welding, polymer fumes, cooking fumes and other sources of thermodegradation grow in number, so do NSPs. The potential increase of NPs in medicine, industry, and technology is emphasized in this review. Metals, semiconductors, polymers are all man made NPs and may be created in other shapes such as tubules, fibers, wires and rings. NSPs or UFPs were been produced long before their potential toxicity was known. The authors emphasize that several disciplines including bioinformantics, molecular biology, medicine, materials science and toxicology must be included in an interdisciplinary approach to estimate the risks of these particles and ultimately perform accurate risk assessment on these small particles to which humans and the environment are exposed. This summary will concentrate on the effects of inhaled UFPs as presented in the review. Toxicology of Airborne UFPs: Inhaled UFPs can cause adverse health in both the respiratory tract and other organs. Studies use both ambient and model UFPs in humans, rodents and in vitro. Epidemiologic and clinical studies have been done using humans exposed to UFPs. Some epidemiologic studies showed no adverse effects of UFPs in humans. UFP deposition efficiencies are great in humans and can cause systemic inflammation. UFPs also affect pulmonary diffusion capacity, the cardiovascular system, and blood coagulation in humans. There is pulmonary inflammation in the lungs of rodents exposed to UFPs in addition to movement of particles to other tissues from the lungs and effects on blood coagulation. When a variety of cells in vitro are exposed to UFP, proinflammatory and oxidative stress related cellular responses are found in a variety of cells in vitro. The mechanisms of these effects are discussed. However the variables in these experiments such as the cell types, particle compositions, and the high concentrations of UFPs used make conclusions from in vitro studies difficult. Concepts of Nanotoxicology: An example is given showing that NSP have higher inflammatory potential per mass relative to larger particles of the same chemical composition. Studies using intratracheally instilled TiO2 of two different sizes show compelling evidence that particle surface area is a better dose measurement than particle mass or number. The degree of inflammation was measured by the influx of neutrophils into the lung. A second example shows that severe acute lung injury is also dependent on the surface chemistry of NSPs. Polymer fume fever has been observed in humans since the 1960s. It is caused by inhaled polytetrafluoroethylene (PTFE) fumes. These fumes are actually NSP with a count median diameter (CMD) of 18 nm. When rats are exposed to PTFE fumes for 15-min, high mortality results within 4 hours. This review also discusses the toxicology of engineered nanomaterials with a variety of shapes such as planes, rings, tubes, fibers and spheres. It is already known that exposure to natural fibers such as asbestos leads to increased risk of cancer and fibrosis. However it is not clear whether fiber toxicology principles will apply to engineered nanotubules. Experiments with nanotubules used high doses administered by intratracheal instillation in rodents. The authors emphasize that inhalation studies in rodents need to be done with a range of concentrations of nanomaterials. A relatively small number of ecotoxicologic studies have been performed to date. Another concept of nanotoxicology discussed is the role of reactive oxygen species (ROS). NSP can create ROS in UFPs, C60 fullerenes, and SWNTs (single walled carbon nanotubes). NSPs are also attracted to mitochondria where they may interfere with antioxidant defenses and may change ROS. The concept of exposure dose-response considerations is reviewed. Both in vitro studies and experiments using intratracheal instillations in rodents use very high doses of NSPs compared to real life scenarios. The authors emphasize that the mechanisms of action of NSPs at high doses is different than the mechanism at lower doses. The reasoning is that high doses of NSPs suppress defenses of the target cells or animals. Portals of Entry and Target Tissues Respiratory Tract: The respiratory tract is the organ where most NSP research has been done both because it is hypothesized that NSPs gaining access to the respiratory system cause much damage and because UFPs are studied here. The skin and GI tract are other routes of exposure that have been studied. Deposition mechanisms applying to larger particles do not apply to NSPs. Diffusion is the primary deposition mechanism and occurs when NSPs collide with air molecules. Particle size is critical in determining the area of deposition. For example, when considering 1-nm particles, 90% are deposited in the nasopharyngeal region, 10% in the tracheobronchial region and none in the alveolar region. 5-nm NSPs are deposited equally in all three regions of the lung. But 20-nm particles have highest deposition in the alveolar region. It has long been known that each part of the respiratory tract has different defensive mechanisms for larger particles. NSPs move to extrapulmonary sites more easily and using different mechanisms than larger particles. NSPs can enter the blood from the lungs by first crossing the pulmonary epithelium and interstitium. They are then distributed throughout the body via the circulatory system and the lymphatics. Sensory nerve endings in the pulmonary epithelium can also take up NSPs. The NSPs are then transported to both ganglions and CNS structures. The target site of the NSP is not the alveolar space but the epithelium and then interstitium. Thus NSPs are not efficiently cleared by alveolar macrophage phagocytosis. The larger dose or surface area and dose rate are important in causing the NSPs to cross the epithelium into the interstitial compartment. The interstitium is also where the inflammatory cell response occurs. The translocation of NSPs into the interstitium is greater in larger species leading to the assumption that it is also greater in humans. Surface chemistry of NSPs determines movement across epithelial and endothelial layers. When NP are coated with albumin or lecithin, they bind to caveolae in endothelial cells. They do not cross tight junctions unless the animal is compromised by an agent such as endotoxin. In humans data on the translocation of NSP in the circulatory system are not clear. It appears that several factors determine whether inhaled particles reach the blood. These factors are particle size, particle surface chemisty and other surface characteristics. The implications of translocation of NSPs from the lung to blood and consequent cardiovascular events are discussed here. Finally delivery of NSPs to the liver via Kupfer cells, the spleen and the CNS is discussed. The authors discuss uptake and translocation of NSPs by axonal neurons, emphasizing that this pathway has not been studied by toxicologists until recently although it was identified 60 years ago. Olfactory nerves and bulbs, trigeminal nerves and sensory nerves endings in the tracheobronchial region of the lung are all pathways for NSP to the CNS. The early studies of this means of NSP transport used polio virus ( 30-nm) and colloidal gold particles. Recently classic NSPs such as C and MnO2 of different MMADs have been used to study this pathway of NSP transport. The authors point out differences between humans and rodents that lead to questions regarding the relative significance of the olfactory pathway for NSP entry to the CNS when comparing species. Finally the use of NPs for drug delivery to the CNS is discussed. NPs seem to have potential for both diagnosis and treatment of problems in the CNS yet many potential risks must be considered. Risk assessment of NPs is lagging because there isnt enough toxicology
data on NPs yet. The authors list a number of basic questions regarding the
toxicology of NPs which have not been answered. It is emphasized that
nanomaterials are already used in substances to which the public is exposed
including cosmetics, clothing, fuel cells, electronics, and tires. At this point
in time governmental regulation is impossible. Although NPs are not the same as
the material from which they are derived as far as biologic, mechanical,
electrical, and optical properties, many regulatory agencies consider them to be
the same. Outlook:
By: Susan G. Shami, ScD Note: www.Inhalation.net has previously reviewed a number of articles on UFPs and near UFP sized particles. The links go to the original review in www.inhalation.net : Size effect of intratracheally instilled particles on pulmonary inflammation and vascular thrombosis - UFP are involved in the etiology of the cardiovascular effects. UFP have been shown to be even more inflammatory than PM10 when measured per unit mass.Pulmonary effects of inhaled ammonium salts - The geometric diameter of UF was 0.04 0.12 um and of F was 0.20 0.60 um as determined by SEM of ammonium particles. CB (carbon black) particles were observed by SEM to be about 0.03 to 0.07 um and spherical. Olfactory Transport of Inhaled Manganese to the Rat Brain - The olfactory route contributes the majority (>90%) of inhaled 54Mn found in the olfactory pathway but not in the striatum of the rat brain up to 8 days post exposure. Particle size was average (MMAD) of 2.51 um.The Significance of Ultrafine Particles - Ultrafine Particles in the Urban Air: To the Respiratory Tract - And Beyond? "Perspectives, Editorial" And earlier review by Oberdorster and Utell.Ultrafine Particles and Macrophage Cytoskeleton - The authors conclude that the UFP-induced cytoskeletal toxicity reported in the study is a relatively complicated process.Particle Size and Asthma Treatment - Other treatment modalities such as beta2 agonists and anticholinergic agents appear to have optimal effect with MMAD of <3 um. Thus new advances in the technologies of MDI development may aid in improved long-term treatment and outcome in asthmaDistribution of Particle Surface Area by Particle Size increasing surface area with decreasing particle size explained by Doug Cooper, PhD Particle Size Distributions Traditional particle size distributions in the lung. Assessing Risk in the New Millennium - The use of the precautionary principle for new technologies reviewed.
|