Handbook of Solvents - George Wypych - ChemTech - Ventech!

1394 David K. Bonauto, C. Andrew Brodkin, William O. Robertson
supply or the portal triad, zone one, are more resistant to oxidative stress, while hepatocytes
near the central vein, zone three or centrizonal region, are most susceptible to solvent induced
injury.
20.8.1.1 Factors Influencing Solvent Hepatotoxicity
Bioavailability: The physical and chemical properties of a solvent and its toxicokinetics determine
its availability to hepatic tissues. The primary route of absorption of most solvents
which cause hepatotoxicity into human biological systems is via the lung. Therefore, the
greater the volatility of the solvent, the greater its concentration in the air, and subsequently
the larger the potential dose. 4 While accidental or intentional ingestion of solvents is reported
in the medical literature, it is an uncommon route of exposure in the occupational setting.
Dermal absorption should be considered a significant route of exposure for most
solvent compounds based on their lipid solubility. The degree of exposure can often be
modified by the use of personal protective equipment such as gloves or a respirator and engineered
exposure controls such as building ventilation.
The lipid solubility of solvents also favors their deposition of into lipid rich organ systems
such as the liver. The toxicity of a particular solvent may be enhanced by its long residence
time in the liver. 6
Genetic and environmental factors: While some solvents are directly hepatotoxic, frequently
biotransformation of solvents by hepatic mixed function oxygenases, such as the
cytochrome p-450 system, result in toxic intermediates. 7 A variety of genetic and environmental
factors inhibit or induce the activity of these hepatic enzyme systems, effecting the
biotransformation and resulting toxicity. Genetic factors thought to determine the activity
or even the presence of an enzyme within an organism center around human polymorphisms
or variations in the genetic code. 7 As the activities of the liver enzymes are changed so will
the rate of formation of the metabolite thus increasing or decreasing the toxicity of the foreign
substance. 3 Environmental factors which determine the activity of liver enzyme systems
include co-exposure to other drugs and toxins or characteristics of the individual
particularly disease states which induce or inhibit the activity of liver biotransformation enzymes.
1,3,7-9 Individual characteristics such as age, nutritional status, pregnancy or disease
states such as diabetes or obesity may also change the activity of cytochrome p-450 enzymes.
7,9 The assessment of an individual’s susceptibility to exposure should attempt to account
for these variables in determining risk.
20.8.1.2 Microscopic, Biochemical and Clinical Findings Associated with
Liver Injury due to Solvents
Hepatotoxic manifestations associated with acute solvent exposure are dose dependent.
Acute cytotoxic injury of a solvent directly or by its metabolites causes an alteration in the
normal physiologic function leading to ballooning fatty change and ultimately cellular necrosis.
If the dose is minimal and doesn’t exceed the ‘regenerative capacity’ of the liver, inflammatory
changes generally resolve within two weeks to several months. Metabolic
derangement results in the accumulation of fats in the liver, termed steatosis. 10 A less common
form of acute cytotoxic injury is related to cholestatic injury with disruption of normal
biliary flow. 11 Severe long term exposures can lead to fibrosis or scarring and cirrhosis
which distort the hepatic architecture and lead to altered liver function.