Asbestos Health Effects : Biologic Fate

by CDC

(Page 3 of 9)

The primary route of asbestos entry into the body is through inhalation. Ingestion of asbestos fibers can occur from drinking contaminated water (or ingestion from other sources) or after mucociliary clearance from the lungs and swallowing of the fibers. The fate of ingested asbestos is still being debated. However, it appears that a few ingested fibers pass through the gastrointestinal (GI) wall and reach blood, lymph, urine, and other tissues. (Fibers can also enter the lymphatic system via the lungs and migrate to other tissues.) Most ingested fibers will not be absorbed, but will be cleared in the feces. Asbestos fibers can also lodge in the skin and create hyperkeratoses or corns.

Asbestos fibers act differently from most types of inhaled particles in terms of the aerodynamics of reaching the depths of the lung. For most inhaled nonasbestos particles, generally only particles between 0.5 and 5 microns in diameter with a length-to-width ratio of 3:1 will be deposited in the respiratory regions (alveoli and terminal bronchioles) of the lungs. Larger particles of any kind tend to be filtered out in the upper airway and nasopharynx. Smaller particles tend to remain suspended in the inspired air, and the majority are exhaled. However, asbestos is an exception: Fibers ranging from 5 to 10 microns or more in length can also penetrate to the lower respiratory regions of the lungs, where they can have destructive effects.

In addition, asbestos fibers can fracture or split and break down into smaller diameter fibrils. Electron microscopy reveals that fibrils result from longitudinal and cross-sectional fragmentation of asbestos fibers. A single asbestos fiber can fracture into hundreds of submicroscopic fibrils. Research indicates that these uncoated fibrils might be the form that migrates into the peritoneal and pleural spaces.

A significant proportion of inhaled asbestos fibers can be retained in the lungs.

The fibrous nature of asbestos renders the lungs' defense mechanisms ineffective. Smaller, nonfibrous particles to which the lungs are exposed are normally engulfed by macrophages and removed by lymphatic or mucociliary mechanisms. However, attempts by the macrophages to engulf fibers might not always be successful. One result is an eventual deposition in various tissues of ferrous material in a drumstick configuration called a ferruginous or asbestos body. The release of various chemicals and messengers by macrophages, as a result of the inability to engulf the fibers, is discussed below.

The size and shape of asbestos fibers affect the lung's ability to effectively remove them.

The size of the fiber appears to play a role in its toxicity. According to Lippman (1990), asbestosis is most closely related to the number of fibers longer than about 2 micrometers (µm) and thicker than about 0.15 µm; mesothelioma to the number of fibers longer than about 5 mm and thinner than about 0.1 µm; and lung cancer to the number of fibers longer than about 10 µm and thicker than about 0.15 µm. Durability also plays a role in toxicity. Once inside the lungs, fibers can translocate along epithelium and ciliated epithelium, lymphatic drainage, or after ingestion by alveolar macrophages, if the fiber is short enough to be fully ingested.

Asbestos fibers can penetrate to the terminal bronchiolar level and enter the peribronchiolar space, resulting in a fibrogenic response. Because the fibers concentrate in the lower lung fields, there is a tendency for fibrosis to occur first in the lungs' bases, and for pleural effects to be confined to the lower two-thirds of the thorax. However, location is not diagnostic, because lesions can occur in all lung fields.

The mechanisms of fibrosis and carcinogenesis due to asbestos have been the target of much investigation. Fibrosis results from persistent release of inflammatory mediators such as lysozymes, interleukins, and fibroblast growth factors at the site of asbestos fiber penetration and deposition. It appears that fibers, because of a combination of physical/mechanical and chemical properties, stimulate cellular responses and enzyme secretions at critical target sites, leading to alterations in cell functions, differentiation patterns, quantities, and distributions. When the fibers are sufficiently durable in the lung, or at the pleura after translocation, the stimulation can continue for a sufficient length of time to produce chronic structural alteration and disease.

According to Mossman and Churg (1998), both inflammation and fibrosis, as well as expression of genes linked to cell proliferation and antioxidant defense, occur in a dose-related fashion after inhalation exposures to asbestos. Reactive oxygen species (ROS) and free radicals could also play a role. It appears that longer, more fibrogenic asbestos fibers cause a frustrated, ineffective phagocytosis and more protracted elevations in the release of ROS; activated inflammatory cells such as alveolar macrophages (AMs) might release increased amounts of oxidants. Oxidants generated by fibrogenic dusts such as asbestos might induce uptake of a variety of particle types, lipid peroxidation, stimulation of cell-signaling cascades and transcription factors, and release of cytokines such as tumor necrosis factor-alpha. These interrelated events are important in inflammation and fibrogenesis. A variety of cell types conventionally have been regarded as key participants in the inflammatory process: the AM, mast cell, T lymphocytes, and neutrophils. Communication via elaboration of chemokines or cytokines by these cell types and their interactions with epithelial cells and fibroblasts may govern the eventual outcomes of cell injury and proliferation in response to pathogenic minerals.

Kamp and Weitzman (1999, 1997) hypothesize that free radicals activate signaling cascades and cause DNA damage that results in altered gene expression and cellular toxicity, which is important in the pathogenesis of asbestos-associated pulmonary diseases. The authors discuss the roles of ROS and reactive nitrogen species, apoptosis, and tumor promotion. The evidence shows that asbestos-induced free radical production is closely associated with the onset of DNA damage, signaling mechanisms, gene expression, mutagenicity, and apoptosis. The pathogenesis of asbestos-induced diseases probably derives from the long-term interplay between persistent free-radical production and the expression of cytokines, growth factors, and other inflammatory cell products.

It is likely that few asbestos fibers cross from the GI lumen into the blood, although several animal studies have revealed that asbestos fibers are capable of penetrating the GI tract. The risk of noncarcinogenic injury to tissues such as lung, heart, muscle, liver, kidney, skin, or eyes from GI absorption of asbestos should therefore be negligible (Agency for Toxic Substances and Disease Registry 2001). Another possible route of distribution of asbestos fibers in the body is inhalation exposure: Fibers that enter the lymphatics are presumably able to reach other tissues of the body. This is supported by the finding that people with high levels of asbestos fibers in the lung (measured as asbestos bodies) also had asbestos bodies in kidney, heart, liver, spleen, adrenals, pancreas, brain, prostate, and thyroid tissues. (This could also have been due to GI absorption following mucociliary clearance.) Data do not clearly relate GI tumors or peritoneal mesotheliomas to direct ingestion of asbestos fibers, although in occupational studies, workers exposed to asbestos by inhalation have been reported to have a twofold greater risk of colorectal cancer than unexposed workers. Some investigators believe this malignancy is caused by fibers removed from the lungs' upper respiratory regions by ciliary mechanisms and then swallowed. Asbestos bodies have been identified within some human specimens of colorectal adenocarcinomas.

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