Page 331 - Industrial Ventilation Design Guidebook

5.3 TOXICITY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS 287

and reduced functional capacity of the organ. It is noteworthy that effects of
various oxidants, such as quinones, can vary as a function of dose: at low
doses they may induce cellular proliferation, at moderate doses apoptosis, and
at high doses they induce necrosis. Thus again dose is the ultimate determi-
nant of the effect, even when very basic cellular responses such as death or
survival are involved. 124

Binding to Cellular Macromolecules
Many chemical compounds induce their toxic effect by binding to the ac-
tive site of an enzyme or to other proteins that are vital for cellular functions.
3+
As described above, hydrogen sulfide and cyanide bind to the Fe of cyto-
2+
chrome oxidase whereas carbon monoxide binds to the Fe of hemoglobin. 89
Consequently, cyanide prevents a cell from utilizing oxygen even if it would be
available and carboxyhemoglobin formation during CO exposure inhibits the
access of cells to oxygen and thereby terminates oxidative metabolism inside
the cells. Lead, mercury, and cadmium bind to SH-groups of proteins and
89 125
thereby inhibit their functions. ' A classic example of fatal enzyme inhibi-
tion is the covalent binding of organophosphate insecticides, such as the acti-
vated form of parathion, paraoxon, to the acetycholinesterase enzyme. This
leads to accumulation of acetylcholine in the central nervous system, endo-
crine glands, smooth muscle, and other organs. This, in turn, leads to clinical
signs such as breathing difficulties, excessive salivation, tremors, convulsions,
12< 127
and even death. V The mechanism of this enzyme inhibition is illustrated
in Fig. 5.46.
Covalent binding of chemicals to biological macromolecules can also
cause toxicity. During biotransformation and metabolic activation, chemi-
cal compounds can be changed to free radicals, which have an unpaired

+ AUH
FIGURE 5.46 Interaction of the serine hydroxyl residue in the catalytically active site of acetylcho-
linesterase enzyme with esters of organophosphates or carbamates. The interaction leads to binding of
the chemical with the enzyme, inhibition of the enzyme, inhibition of acetylcholine hydrolysis, and thus
accumulation of acetylcholine in the synapses.