Handbook of Solvents - George Wypych - ChemTech - Ventech!

20.8 Solvents and the liver 1395
Current research focuses on the effect of low doses of solvents on the liver, with concern
that low grade prolonged solvent exposure could lead to chronic injury and eventual
impairment. 5,12
Tests used to evaluate and screen for liver injury can be divided into three general categories:
serum biomarkers of disease, tests of hepatic clearance, and anatomic evaluation. 11
The hepatic enzymes most commonly screened for related to hepatocellular necrosis and inflammatory
changes are aspartate aminotransferase (AST), and alanine aminotransferase
(ALT). Elevation of these enzymes in the setting of significant exposure is indicative of
hepatotoxic injury, though alternative causes such as alcohol and viral hepatitis should be
excluded. Importantly, serum hepatic transaminase levels indicate hepatocellular necrosis
or inflammation, but may not indicate more subtle metabolic alterations in hepatic function.
Measures of other hepatic enzymes, gamma glutamyl transpeptidase (GGT), alkaline
phosphatase (Alk Phos), total and direct bilirubins may also be suggestive of solvent induced
hepatotoxicity. Specifically if hepatic excretion of bile, is diminished, the resulting
intrahepatic cholestasis is associated with elevations in GGT, Alk Phos and serum bile acids.
Significant elevations of bilirubins leads to the clinical observation of jaundice or yellowing
of the skin. However, pathologic obstruction of the biliary tract is not a common
finding in solvent induced hepatotoxicity. 5
Clearance tests of liver function assess a number of physiologic activities including
hepatic uptake, hepatic metabolism, and hepatic excretion. Typical clearance tests of liver
function include indocyanine green (ICG), antipyrine clearance test and 14 C aminopyrine
breath test. These tests give an estimation of the ability of the liver to extract and detoxify
exogenous toxins (xenobiotics). Measuring the excretion of endogenously produced serum
bile acids is an additional measure of hepatic clearance and has been used as a sensitive
measure of early solvent hepatotoxicity. 13,14
Anatomic evaluation of solvent hepatotoxicity centers on physical examination of the
liver, radiologic study and liver biopsy. Physical exam is nonspecific as to the cause and
characterization of the disease. Radiologic studies such as ultrasound can identify
hepatobiliary disease and liver parenchymal disease, namely steatosis and fibrosis.
Steatosis and fibrosis are noted on ultrasound by a change in the echogenicity of the liver.
While liver biopsy is the ‘gold standard’ for anatomic evaluation of the liver, the
invasiveness of the test, the morbidity and discomfort of the procedure, and its cost make it
prohibitive for routine screening. It is usually reserved for definitive diagnostic and prognostic
purposes. Algorithmic strategies for screening for liver injury and evaluation of abnormal
results have been reported in several references. 11,12,15,16
20.8.2 HEPATOTOXICITY ASSOCIATED WITH SPECIFIC SOLVENTS
The following section presents specific classes of organic solvents strongly associated with
hepatotoxicity in human populations or animal studies. While there is more limited evidence
of hepatotoxicity related to inhalational and dermal exposure to aliphatic hydrocarbons,
ketones, alcohols, aldehydes, esters and ethers, potential hepatotoxicity related to
these agents must be assessed on an individual basis with regard to concentration, duration,
and bioavailability of exposure. 5,11 Variations in individual susceptibility must also be considered
with regard to concurrent use of alcohol, mixed solvent exposure, underlying liver
diseases (e.g., viral hepatitis, hemochromatosis, hypertriglyceridemia and diabetes) as well
as demographic differences in hepatic metabolism. 11 Given these limitations, the organic
solvents of primary concern with regard to hepatotoxicity are the haloalkanes, haloalkenes,