Recommendations:

• Additional laboratory studies are needed to establish the significance of increased bile acids in relation to the hepatotoxic potential of trichloroethylene, as well as in relation to other systemic effects. Such studies will help clarify whether elevation of serum bile acids is an early indicator of changes in liver function or is a marker of exposure to trichloroethylene (or other halogenated solvents which induce this effect).

• More research is also needed to assess whether increases in serum bile acids in humans exposed to trichloroethylene are independent of discrete pathologic changes in the liver. Because histopathologic assessment would be difficult to perform in human subjects, new, highly sensitive, and noninvasive toxicologic parameters are needed to clarify the toxicologic importance of these effects of trichloroethylene.

• Additional studies of the effects of trichloroethylene on glycogen accumulation, perhaps using cultured human hepatocytes, should shed some light on the significance of this effect and its relevance to humans.

• More research is needed to determine whether an autoimmune response might play a role in trichloroethylene-mediated liver disease. Adducts formed between metabolites of trichloroethylene and liver proteins can result in the formation of neoantigens. These neoantigens can lead to antibody-dependent hepatocellular injury. The same process has been reported with chemicals such as halothane, which is well known to produce immune-mediated hepatotoxicity. Studies similar to those carried out with halothane could be instrumental in elucidating whether autoimmunity is a causal factor in the hepatotoxicity of trichloroethylene.

• Studies are needed to determine the metabolic pathway and yield for forming dichloroacetic acid from trichloroethylene either via trichloroacetic acid or via other pathway(s). If dichloroacetic acid is found to be a metabolite of concern, additional studies may be needed to understand its role in the toxicities associated with trichloroethylene.