Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM) 

Asbestos Toxicity
How Does Asbestos Induce Pathogenic Changes?

Learning Objective

Upon completion of this section, you should be able to

• describe the three mechanisms by which scientists hypothesize asbestos induces pathogenic changes in the lungs.

Introduction

The three main determinants of asbestos toxicity are

• fiber size
• durability
• iron content

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 disease related to fibrosis, or malignancy.

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

• direct interaction with cellular macromolecules
• generation of reactive oxygen species
• 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 protein function.

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

Release of Reactive Oxygen Species

The presence of asbestos fibers in lung and pleural tissue is also believed to cause the formation and release of reactive oxygen species (ROS). That is, when alveolar macrophages attempt to engulf and digest an asbestos fiber, they release ROS: hydrogen peroxide (H₂0₂), and the super oxide radical anion (O^2-) (Kamp and Weitzman 1999, 1997). (H202), and the super oxide radical anion (O^2-) (Kamp and Weitzman 1999, 1997). Through the Haber-Weiss (or Fenton) reaction, these ROS react with each other to produce hydroxyl radicals, which are even more potent oxidizers. This reaction is believed to be catalyzed by iron present on the surface of the asbestos fibers (Broaddus 2001; ATSDR 2001).

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, TNF-α ) that lead to multiple cellular processes such as

• inflammation
• macrophage recruitment
• cell and DNA damage
• cell proliferation
• apoptosis

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

All types of asbestos fibers tend to lodge in the lung at the bronchiolar-alveolar duct bifurcations, and some proceed to the smaller airways and alveolar sacs. From the lung, some fibers can migrate into the pleural space by unknown mechanisms (National Academy of Sciences, 2006). The length of time needed for migration and the number of fibers that successfully migrate may explain why asbestos-induced fibrosis occurs earlier in the lung than the more slowly developing pleural mesothelioma (Broaddus 2001).

Carcinogenicity

Asbestos has been designated a known human carcinogen as shown in the following table. 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). However, both types can cause mesotheliomas and are believed to be equally potent in causing lung cancer (ATSDR 2001).

International Agency for Research on Cancer (IARC)

Known human carcinogen

U.S. Environmental Protection Agency (EPA)

Known human carcinogen

Key Points

• The three processes hypothesized to account for asbestos’s pathogenicity are
  • direct interaction with cellular macromolecules
  • generation of reactive oxygen species (ROS)
  • other cell-mediated mechanisms (especially inflammation)
• Asbestos induces pathological changes leading to such outcomes as fibrosis and malignancy.
• Asbestos is genotoxic and carcinogenic.

Progress Check