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Asbestos Toxicity
How Does Asbestos Induce Pathogenic Changes?

Course: WB 2344
CE Original Date: January 29, 2014
CE Expiration Date: January 29, 2016
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Learning Objectives

Upon completion of this section, you will be able to

  • Describe the hypothesis behind the mechanisms scientists currently believe leads asbestos to induce pathogenic changes in the lungs.

Introduction

The main determinants of asbestos toxicity are

  • Fiber size,
  • Biopersistence,
  • Chemical composition, and
  • Particle surface characteristics [NIOSH 2011a].

The presence of asbestos fibers in the lungs sets off a variety of responses leading to inflammation, cell, and tissue damage, which can lead to malignant and non-malignant diseases.

The mechanisms by which asbestos causes disease are not fully understood. Currently, there are three hypotheses to account for the pathogenicity of asbestos:

  1. Direct interaction with cellular chromosomes,
  2. Generation of reactive oxygen species, and
  3. Other cell-mediated mechanisms (especially inflammation).

Asbestos is genotoxic and carcinogenic.

Interaction with Cellular Macromolecules

Because of their surface charge, asbestos fibers can adsorb to cellular macromolecules (proteins, DNA, RNA) and cell surface proteins. Binding of asbestos fibers to these cellular components is believed to induce changes in macromolecular conformation, thereby affecting macromolecule function.

Long asbestos fibers have been shown to interfere physically with the mitotic spindle and cause chromosomal damage, especially deletions [Broaddus 2001; ATSDR 2001; National Academy of Sciences 2006].

Release of Reactive Oxygen Species

Asbestos fibers in lung and other tissue are also believed to cause the formation and release of reactive oxygen species (ROS). That is, when alveolar macrophages attempt to engulf and fail to digest an asbestos fiber, they release lysosomal contents into the alveolar space [NIOSH 2011a]. This "frustrated phagocytosis" can generate reactive oxygen species (ROS): hydrogen peroxide (H202), and the super oxide radical anion (O2-) [Kamp and Weitzman 1999, 1997]. All these ROS induce tumor necrosis factor-alpha (TNF-α). TNF-α is a potent inflammatory cytokine currently felt to play an important role in pulmonary fibrosis [NIOSH 2011a].

Other Cell-Mediated Mechanisms

The presence of asbestos fibers also causes alveolar macrophages, lung cells, and pleural cells to release cellular factors (such as leukotrienes, prostaglandins ) that lead to multiple cellular processes such as

  • Apoptosis,
  • Cell and DNA damage,
  • Cell proliferation,
  • Inflammation, and
  • Macrophage recruitment.

The exact role of all these cellular processes in the formation of fibrosis and malignancy is still being defined [Broaddus 2001; Kamp et al. 2002].

Primary Sites Affected

When inhaled, asbestos fibers tend to deposit in the lung at the bronchiolar-alveolar duct bifurcations; some are deposited in the smaller airways and alveolar sacs. From the lung, some fibers can migrate into the pleural space by different mechanisms [National Academy of Sciences, 2006].

Biopersistence in the lung and the subsequent tendency to cause inflammatory changes is based on fiber durability. In addition to the low ph (4.8) of phagocytosis, a fiber is exposed to extracellular fluids in the lungs (ph =7) which may gradually dissolve it [NIOSH 2011a].

Carcinogenicity

Asbestos has been designated as a known human carcinogen by the agencies shown in the table below. All types of asbestos are carcinogenic, but some scientists believe that the amphibole type is more potent in causing mesotheliomas than the serpentine type (chrysotile) [IARC 2012]. However, both types can cause mesotheliomas and lung cancer [ATSDR 2001].

Table 4. Carcinogenicity of Asbestos

Agency Carcinogenicity Description
International Agency for Research on Cancer (IARC) 1 Known human carcinogen
U.S. Environmental Protection Agency Group A Known human carcinogen

Key Points

  • The three processes hypothesized to account for asbestos's pathogenicity are
    1. Direct interaction with chromosomes,
    2. Generation of reactive oxygen species (ROS), and
    3. Other cell-mediated mechanisms (especially inflammation induced by TNF-α).
  • Asbestos induces pathological changes leading to such outcomes as fibrosis and malignancy.
  • Asbestos is genotoxic and carcinogenic.
   

Progress Check

10. Asbestos induces pathogenic changes in lung tissue via

A. Direct interaction with chromosomes.
B. Generation of active oxygen species.
C. Cell-mediated inflammatory mechanisms.
D. All of the above.

Answer:

To review relevant content, see "Introduction" in this section.

11. As a result of its pathogenic actions, asbestos

A. Induces fibrotic changes in lung tissue.
B. Is genotoxic.
C. Is carcinogenic.
D. All of the above.

Answer:

To review relevant content, see "Introduction" and "Carcinogenicity" and in this section.

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