Amoah 1
Cornelia Amoah
Biochem Mechanisms of Toxicology
Dr. Cooper
Final Paper
December 11th, 2012.
ASBESTOS
Introduction:The name Asbestos isspecified to a group of minerals that possess long and thin fibers. It is also a collective name for the family of hydrated silicates with a greater than three to one aspect ratio where the 3:1 is the ratio of length: diameter. Chrysolite accounts for most of the world’s production of asbestos and it is mainly a twisting fiber which is flexible. It is mined widely in the northern hemisphere but crocidolite is a more rod-like and less recyclable fiber in the lungs and of less industrial importance. In comparison, crocidolite is generally more pathogenic to humans than chrysolite. Asbestos usage became gradually popular among constructors and industrialistsaround the 19th century due to its ability to absorb sound, average ductile strength, resistance it has to heat, fire, electrical and chemical damage, and most importantly it is economical. Asbestos is used in some appliances such as wiring in terms of electrical insulation and in the protection of buildings. The fibers of asbestos are often mixed with cement creating fiber cement when it is used mainly for its resistance to fire and heat. They are sometimes also knitted into fabric and mats. The mining of asbestos began more than 40 centuries ago, but it did not start as big business until the end of the nineteenth century. And for the longest time, the largest asbestos mine in the world was named the Jeffrey mine – this is in the town of Asbestos, Quebec. Of course now it is very evident that asbestos exposure is doing more harm than good. Dating from the 1970 onwards there was growingapprehension about the dangers of asbestos and the use of it began to phase out around 1989 and then it was totally banned in December 2003 (
Exposure increases risk of developing lung diseases. That risk is somewhat increased significantly by smoking. Generally, the greater the exposure to asbestos, the greater the probability of developing the harmful health effects associated with it. The symptoms of the disease, however, may take many years to surface following the time of exposure. However, one thing that is essential to note is that asbestos-related conditions are very difficult to identify sometimes. The prospect of asbestos exposure and health related illnesses like lung diseases can be identified by health care workers by taking an in-depth medical check-up. This includes a historical look at the individual’s medical, work, cultural and environmental history. A suspected asbestos-related health condition can be further clarified by physical examination, chest x-ray and pulmonary function tests. The three major health effects allied with exposure to asbestos are lung cancer, mesothelioma, a rare form of cancer which is located in the thin lining of the lung, chest, heart and the abdomen and also asbestosis; this is a serious and rather advanced, long-term but a non-cancerous disease of the lungs ( With these serious illnesses accompanying the exposure of asbestos known, even today America is not completely free from asbestos exposure. Asbestos is still found in many constructed buildings in the US. A sizeable percentage of schools still have asbestos engaged in their buildings that was placed between 1946 and 1972. There have been arguments which are still on going about the health hazards and on the other hand the cost versus benefit statistics which is required to completely replace all these structures. Studies have proven that even minor exposures may be risky to one’s health.
The epidemiology of asbestos-related mesothelioma is as follows; the precise number of Americans who have been exposed to asbestos is unknown, but there are reasonable estimates made that show that between the years 1940 to 1979, about 27.5 million people have been exposed to asbestos in the United States occupationally alone. The calculated annual death rate from mesothelioma in the US would be statistically around 2200 new cases. And then the age-adjusted occurrence of pleural mesothelioma, which is mostly around the surface of the lung and chest wall, and peritoneal mesothelioma is nearly 14.2 million annually.Statistics also show that there is a somewhat three times increase in occurrence of pleural mesothelioma in white males between 1973 and 1984. Also, it is four times more common in males compared to females reflecting an increased occurrence of occupational exposure in men compared to women who do not often find themselves working certain types of jobs especially mining etc. The incidence of mesothelioma also increases steadily with age such that there is a drastic increase in the disease infection in men as they move from the 30s to the 60s. There is also a wide geographical variation in the incidence of mesothelioma within the states. This then reflects the past existence of asbestos relating industries and the extent of asbestos exposures in such facilities (
Physical and Chemical Properties (ADME): On the physical and chemical properties of asbestos, there is growing evidence that the size of the fiber and its shape play a vital role in the production of health effects that relate to asbestos. The dimensions measured from airborne fibers which were collected at various stages of the processing of fiber in some mines and mills which produce three types of asbestos were measured by use of technique called the phase contrast light microscopy and also transmission electron microscopy. It was found that most of the airborne fibers to which miner and millers were being exposed to were found to be short and thin and therefore very inhalable. The physical properties that separate crocidolite fibers from the other types of asbestos were median aspect ratio and the fraction of long thin fibers, such that fibers less than or equal to 0.2 μm in diameter and greater than 5 μm I length representing the percentage of total fibers. This observation concerning differences in size and shape of the airborne fibers have relevant implications for the work-setting and also important in explaining the differences in the health risks associated with different types of fibers (Hwang, 1983). Another research that was performed on dust samples produced by machining three asbestos-cement products were also studied in terms of their measurements, surface, and physiochemical characteristics. The respirability factor of asbestos can be figured by the measured aerodynamic diameter. The fibers have no odor or taste with which to detect and are all solids which do not move through soil and also does not dissolve in water; though, the color of the fiber may differ based on metallic composition and the type of asbestos. Crocidolite is the most colorful of all and has iron and sodium components as its only metallic components (Baeten, Hensen, and Deruyttere, 1980). The fibers are known to be insoluble and cannot be absorbed after inhalation, through the mouth or even dermal exposure. However, they may be absorbed after inhalation or exposure to the oral cavity whereby the main path of ingestion is through the lungs. When it gets into the lungs, its shape and size will determine the deposition and distribution of the fiber. Clearance by mucociliary action or by phagocytosis by the macrophages will get rid of some of the fibers from the lung. The absorbed fibers of asbestos are not passed across the GI tract, although the short fibers rather seem to pass through the epithelium of the GI tract fairly easily than the longer fibers. When the fibers manage to penetrate into the skin, they produce what is termed as asbestos warts.
The longer fibers that remain in the lungs then undergo certain processes such as translocation, fragmentation and not forgetting splicing or protein encapsulation. Although sometimes the asbestos fibers do not stay in the lungs alone, some get distributed to other tissues including the blood, lymph, and other various and vital organs such as kidney and liver; however, the fibers do not readily break through the skin barrier and move into the blood. The fibers of asbestos are coated with a thick layer of hyaline material. According to some authors, this same coating is suspected to contain silicates or silicic acid. Other studies have made mention that these bodies are formed by the diffusion of substances that have been dissolved from the ends of chrysolite fiber tube. But recently, it has been accepted that the coating consists of proteins, iron, and some other materials. This is true to some large extent, but the exact chemical nature of asbestos body capsule is still under study. Other findings indicate that acid mucopolysaccharides are involved in the initial production stages of asbestos bodies and colloidal iron is known to have a strong affinity for these polysaccharides. It is then reasonable to say that the asbestos bodies are first coated with acid mucopolysaccharides and then colloidal iron attaches later. As mentioned earlier, most of the asbestos fibers that are headed into the lungs are disposed of by mucociliary action where the long ones are cleared more slowly than the short ones. Those that are less than 1 μm in length are removed from the lungs within 10 days or lesser but those longer fibers that are averagely 16 mm in length take a longer span of time like 100 days. Also, the fibers that are coated with mucus are moved up to the throat, then swallowed to be excreted out of the body through the fecal matter. Those that are absorbed into the inner parts of the body are taken up by the blood into the kidneys then excreted in urine. The problem arises when it is not excreted but then stays in the body for a long time and therefore gets accumulated slowly. Averagely the chrysolite asbestos fibers do get excreted quickly as compared to the amphiboles since the former is in fragments. This is done to the fact that the fragments result in short fiber development which then gets easily engulfed by the macrophages. Quite remarkably also, is that almost all the asbestos fibers that are inhaled or taken into the body get phagocytized by the macrophages and also the kidneys within 48 hours (Governa and Rosanda, 1972).
Mechanism of Action: In a research study conducted in a lab by Rahman and other scientists, they tested the biochemical mechanisms that are responsible for the different effects of asbestos which include pleural plaques, respiratory difficulty, fibrosis, cancer, and cytotoxicity to name a few. For example, in asbestosis, lots of biochemical mechanisms are involved with deposits of collagen, damaging the plasma membrane of the macrophages and RBCs as well. Calcification, the absorption of the proteins on the asbestos fibers, changes in the enzymes, gas exchange deficiency and changes in molecular biology. The series of investigations were done to check at least the biochemical aspect of the biological effects that the compound has on the respiratory system. After development of asbestosis just after intratracheal injection, there is an observed increase in compounds such as hexosamine and hydroxyproline in the lungs. This correlates to changes in mucopolysaccharides and collagen in that area. An observed increase was found in asbestotic rats and pigs than in normal ones when comparing free activity of acid phosphatase in the cytosol from lung tissues. In the mitochondria found in the lungs, cytochrome c oxidase activity was observed to be greater in the asbestos-induced as opposed to the cytosol. In vitro, asbestos produced inhibition of cytochrome c oxidase but the activities of Ca2+ and Mg2+ which trigger ATPase were ominously decreased. These results, increase in cytochrome c oxidase with decrease in ATPase activity, were accountable for a defensive mechanism which preserves ATP that is needed for fibrosis. The changes that occurred in the mitochondria due to asbestos exposure were not only limited to terminal oxidase; but a decrease in aconitase and a substantial increase in fumarase indicated that the stimulation and initiation of Krebs cycle could also be affected. Bioenergic mechanisms in the lungs on a large scale were affected in response to the metabolic stress by exposure to asbestos (Rahman, Das, and Viswanathan, 1983).
In another experiment for testing the biochemical mechanism of asbestos, scientists Ian Adamson shares what he discovered in one scientific journal about the evidence of cell proliferation in pleural mesothelial cells. This occurs soon after asbestos fibers have been deposited. In studying this effect, the scientist inserted a single dosage of 0.1 mg crocidolite directly into the lungs of test mice on a time duration ranging between 1 to 6 weeks and after which labeled nuclei were counted after 3H-thymidine (3HT) was injected. The short fibers which are less than 1 μm were found to cause little changes in the lungs due to phagocytosis leading to marginal effects on the mesothelial cells labeling. However, long fibers of 20 μm caused damages to the bronchiolar epithelium and were later integrated into the connective tissue. There was also an observed increase in 3HT uptake by the fibroblast, epithelial cells and also in the mesothelial cells. But there was no indication of fibers in or near any labeled mesothelial cells, suggesting that a cytokine-reaction initiated in the lung at the early stage of response may have prompted the proliferation of mesothelial cells. To observe the cytokine effect in vitro, the scientists injected asbestos into the lungs of rats and they managed to collect bronchoalveolar and pleural lavage fluids as well as macrophages. They found alveolar macrophages to contain asbestos fibers, but the pleural macrophages did not have them. Another important thing Adamson discovered was that the increase of early mesothelial cells growth was not obstructed by cytokine made antibodies which includes platelet-derived growth factor, growth factors of fibroblasts, or TNF which is tumor necrosis factor but instead it was inhibited by anti-keratinocyte growth factor which is abbreviated anti-KGF. This observation concluded their hypothesis to be true based on the fact that an early growth of mesothelial cells after exposure to asbestos seems to have no correlation to translocation of particles to the pleura but rather it is connected with the release of cytokine apparently by KGF, by the lung cells (Adamson, 1997).
Mossman also studied the mechanism of asbestos in the body. He created possible pathways of mechanisms that the asbestos fibers could take starting from its interaction with the epithelial cells of the GI tract and also the respiratory tracts. He did this using cell, tissue, and organ cultures. Through his studies he found that after the asbestos fibers have been ingested it is taken by the mucosal cells which damages the cells and leads to death subsequently. This process, he believed, had a correlation with carcinogenicity, also the type of asbestos taken into the body, and the crystallization as well as the size of the fiber all matters in the mechanism. All these factors mentioned in one way or the other have an effect on the absorption of the body’s natural secretions to the asbestos fibers. This speeds up the process of cell damage and leads to cytotoxicity. After cytotoxicity and cell injury of mainly and most of the surrounding epithelial cells of the GI tract and respiratory tract, basal cells replace the luminal cells and these are suspected to be the precursors of carcinoma. This causes cell transformation in a malignant form and cell proliferation is abundant due to the asbestos exposure initiating the mechanism of carcinogenicity by attachment to the target cells. In terms of smoking, the asbestos fibers act simultaneously with the smoke to cause tumors occurring in the respiratory tract (Mossman, 1983). In conjunction with Joanne P. Marsh, Mossman conducted another study on asbestos induced mechanism in the body. The following were their observations. They found that at high concentrations, asbestos can cause damage to the erythrocytes – cytolysis and also cultured mammalian cells; but the low concentrations were observed to increase cell growth. One possible pathway that the asbestos uses to damage the cells is by lipid peroxidation by reactive oxygen species. Using chrysolite asbestos, this caused a large production of lipid peroxidation; the next was anthophyllite, amosite, and crocidolite. By the use of phospholipid emulsions they showed the necessity of iron as a catalyst for lipid peroxidation.
Another factor that causes lung diseases related to asbestos exposure is the formation of reactive oxygen species; this is termed as ROS. A single mechanism of ROS is popularly by redox reaction which metals catalyze on the asbestos fiber surfaces. To illustrate, asbestos is likely to direct a modified Haber-Weiss reaction, this reaction causes superoxide anion and hydrogen peroxide to be converted into a toxic hydroxyl occurring in a radical form. Conservatively, the higher the fiber content, the more ROS produced by this reaction. Mediation by ROS generation can also take place during phagocytosis of the fibers that have been inhaled by the macrophages in the alveolar. When the fiber is too long, a problem arises such that the cell is not able to fully engulf it – usually termed as “frustrated phagocytosis”. These results in a respiratory burst that produces ROS which force their way outside the area affected into the external compartments of the lung, this causes damage in all the surrounding cells (Quinlan et al, 1994).