Page 326 - Industrial Ventilation Design Guidebook

CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGICAL CONSIDERATIONS

Production of ROS is not only a detrimental process; several cells carry
out their functions in the body by generating ROS. For example, neutro-
phils and macrophages produce ROS upon activation. This is one of their
ways of destroying invading microorganisms. However, other exposures,
such as mineral fibers, and inorganic and biological particles are also able
to activate phagocytes to produce ROS. Excessive ROS production may be
93 10
harmful to the host cell and surrounding cells. ' '*
Cells have defense systems to protect themselves against these radical spe-
cies. The defense systems constitute intracellular thiols, such as glutathione
(GSH), a molecule rich in SH groups, and thus capable of scavenging the reac-
tive species through oxidation of the SH groups. This oxidation leads to the
formation of disulfide bridges; oxidized GSH (GSSG) is unable to scavenge
oxygen radicals. GSH has to be regenerated and this reduction is performed
l05
by a specific enzyme, glutathione reductase. Cells also contain water- and
lipid soluble molecules that remove ROS. The most important of these mole-
cules are a water-soluble vitamin, vitamin C, that acts in the cytoplasm, and a.
lipid-soluble vitamin, vitamin E, that functions in the cell membrane. Cellular
defense mechanisms against excessive production of ROS also include en-
zymes that metabolize these reactive species; superoxide dismutase (SOD) me-
tabolizes superoxide anion to hydrogen peroxide, and catalase breaks down
hydrogen peroxide to molecular oxygen and water. Oxidative stress results
when activation of cells leads to such a high production of ROS that it over-
whelms the capacity of the defense mechanisms. The initial phases of stress
are associated with depletion of cellular GSH. Then the depletion of defense
vitamins C and E occurs. This means that vital biological macromolecules, no-
tably DNA, proteins, carbohydrates, and lipids, can be attacked by the reac-
tive species. This cascade of events may lead to cell death through necrosis or
apoptosis. 104 106
"
Effects on Excitable Membranes
Maintenance of electrical potential between the cell membrane exterior and
interior is a necessity for the proper functioning of excitable neuronal and muscle
cells. Chemical compounds can disturb ion fluxes that are essential for the main-
tenance of the membrane potentials. Fluxes of ions into the cells or out of the
cells can be blocked by ion channel blockers (for example, some marine tox-
ins). 107
Insecticides, such as DDT and lindane, cause their neurotoxic effects by
affecting the functions of ion channels in the neuronal cell membrane, thereby
altering depolarization of the cell membrane. Organic solvents also modify the
normal functioning of excitable neuronal membranes. It was originally as-
sumed that organic solvents non-specifically altered the fluidity of the cell
membrane. Current knowledge is that the effects of organic solvents are more
specifically directed toward cell membrane proteins such as ion channels,
other receptors, and specific enzymes. 107
Effects on Cellular Energy Metabolism
Several toxic compounds act by inhibiting the oxidation of carbohydrates
or by inhibiting the formation of adenosine triphosphate (ATP), a molecule that