Handbook of Solvents - George Wypych - ChemTech - Ventech!

1382 Nachman Brautbar
Table 20.7.2. Some occupational solvents that produce acute and chronic liver
disease
Carbon tetrachloride
Chloroform
Trichloroethylene
Tetrachloroethylene
Dinitrobenzene
Halothane
Trichlorodiphenyl
Trichloroethene
Trinitrotoluene
Ethyl alcohol
A mixture of solvents such as
toluene and xylene
Dichloromethane
Tables 20.7.3 and 20.7.4 describe two major phases in the liver metabolism and detoxification
of drugs, foreign agents and solvents.
Carbon tetrachloride was found to cause liver injury in man and in experimental animals.
14 Carbon tetrachloride is a known and potent liver toxicant, and therefore has been
studied extensively in experimental animals. Recknagel 6 and Reynolds 15 have shown that
single doses will lead to areas of necrosis in the liver within a few minutes. This has been
shown to be associated with changes in liver enzymes which are known to indicate liver
damages. 10,11 Prolonged exposure to carbon tetrachloride has been shown to lead to liver cirrhosis
and to liver cancers. In order to become toxic the carbon tetrachloride has to undergo
metabolic changes in the liver. 6,16 The lesions described initially in animals have been
shown in humans poisoned with carbon tetrachloride. 14,17 It has also been shown that alcohol
enhances the susceptibility to carbon chloride toxicity. 18 Several factors play a role in
the susceptibility to toxicity by carbon tetrachloride, among them are sex, age, diet, underlying
preexisting liver dysfunction and alcoholism. Over the years in both clinical and experimental
studies and observations, it has been shown that carbon tetrachloride induced liver
damage is divided to fatty metamorphosis, and independently liver necrosis. Fat starts to accumulate
in experimental animals as early as one hour after administration of a high dose of
carbon tetrachloride. Liver necrosis occurs as early as 6 to 12 hours, and a maximum of 24
to 36 hours.
The concept of steatosis (fat accumulation in the liver) is a common one for looking at
the effect of solvents (those which are known to be toxic to the liver). The fat accumulation
is the result of abnormal transport of lipids and as a result, accumulation of lipids in the
liver. Therefore clinically industrial exposure to hepatotoxic solvents is associated with
liver steatosis, among others.
Necrosis, which is the second most common effect of liver damage of solvents toxic to
the liver, is the result of destruction of the cell architecture as well as biochemical pathways.
It has been shown in many experimental studies that the toxicity of carbon tetrachloride
(and some of the other solvents which are toxic to the liver and other organs, such as benzene
and the hematopoietic system) requires several reactions, in order to produce the toxic
metabolites which are causing the damage to the liver. Most studies point to the responsibility
of cytochrome P450 system. 6 The metabolite responsible for the liver damaging effect of
carbon tetrachloride is a C Chloride III which is formed from carbon tetrachloride. 6,19 There
is however also information that non-metabolized carbon tetrachloride contributes to the injury,
especially that of the cell membrane, 20,21 something which is logical since solvents are
a mechanistic injury to various tissues is through the effects on the cell membrane which is
either dissolved or damaged by the solvent. A consolidation of the data available and views
on the pathogenesis of carbon tetrachloride liver damage has been eloquently described by
Zimmerman. 7