Handbook of Solvents - George Wypych - ChemTech - Ventech!

1396 David K. Bonauto, C. Andrew Brodkin, William O. Robertson
dimethylformamide, and nitroparaffins. 5,11 Other agents such as styrene have been associated
with hepatotoxicity in some studies. 17,18 Potential interactive effects of solvent mixtures
should always be considered in the assessment of hepatotoxicity, even if composed of
solvents not commonly associated with hepatotoxicity.
20.8.2.1 Haloalkanes and haloalkenes
Some of the most extensively studied and most concerning hepatoxins are the haloalkane
solvents. Major haloalkanes encountered industrially, with documented animal and human
hepatotoxicity, are carbon tetrachloride, chloroform, 1,1,2,2-tetrachlorethane, methyl chloroform
and 1,1,2-trichloroethane, tetrachloroethylene, and trichloroethylene. 5,6,19 The relative
hepatotoxicity of each is correlated inversely with the carbon chain length, and carbon
halogen bond energy and correlated directly with the number of halogens on the molecule
and the atomic number of the halogen. 5,20 Some of these solvents have been eliminated from
common industrial use due to their deleterious environmental and human effects, though
they may still be encountered in specific processes and regions (e.g., developing countries).
Carbon tetrachloride is the most extensively studied and serves as a model for
hepatotoxicity for other haloalkanes. 21,22
20.8.2.2 Carbon tetrachloride
Carbon tetrachloride hepatotoxicity has been reported since the early twentieth century. 23
The toxicological literature is extensive with regard to carbon tetrachloride hepatotoxicity
in animals. 21,23 Human toxicological information derives primarily from accidental or intentional
ingestion in humans or by inhalational exposure in groups of workers. 21 The industrial
use of carbon tetrachloride has declined precipitously, due to the recognized health
effects and regulatory policy. 21 Historically, it was used as a solvent in the manufacture of
industrial chemicals, in the dry cleaning industry and even as an antiparasitic medication. 5
Presently the main means of exposure is in research laboratory settings, or as low level environmental
contaminant. 21 Because it is so volatile, the main mode of carbon tetrachloride
exposure in occupational setting is via inhalation, although exposure by the dermal route
also occurs.
Animal and human susceptibility to carbon tetrachloride hepatotoxicity is dependent
on many different factors. There is substantial interspecies variation in carbon tetrachloride
induced hepatotoxicity in animals due to differences in metabolic pathways among species.
21 Based on animal models, hepatotoxicity in humans is most likely mediated from the
trichloromethyl radical formed from the metabolism of carbon tetrachloride by hepatic
cytochrome p 450 2E1. 24 Animal studies suggest differential hepatotoxicity based upon the
animal’s age and gender, with greater toxicity demonstrated in adult rats compared to newborns,
25,26 and males compared with females. 5 Cytochrome p-450 enzyme systems are present
in the human fetus suggesting a potential for in utero liver toxicity. 27 Human gender
differences in the metabolism of carbon tetrachloride have not been demonstrated despite
potential sex steroid influences on the cytochrome p-450 system. 28
The hepatotoxic effects of carbon tetrachloride are more severe in the setting of alcohol
consumption. 21,29,30 Animal studies demonstrate that the temporal relationship between
ethanol ingestion and carbon tetrachloride exposure determines the severity of toxicity. 31-33
Maximal hepatotoxicity is derived from ethanol ingested eighteen hours preceding exposure
to carbon tetrachloride, 32,33 whereas exposure to ethanol three hours prior to carbon tetrachloride
exposure leads to minimal hepatotoxicity. 33 The mechanism for this interaction is