Renal carcinogenicity of trichloroethylene: update, mode of action, and fundamentals for occupational standard setting

Mechanistic data must be incorporated into the assessment of the human risks of chemical carcinogens, for trichloroethylene in particular. The total weight of evidence compiled from data on the genotoxicity of trichloroethylene indicates that systemic mutagenic activity is not expressed in vivo. New epidemiologic data on trichloroethylene generated in Denmark showed a steady decline of occupational exposure to trichloroethylene since 1947, but with occasions of high exposures before 1980. Earlier exposures were related to a slight increase in risk of non-Hodgkin's lymphoma, renal carcinoma, and esophageal carcinoma. Such confounders as coexposure to other industrial solvents (non-Hodgkin's lymphoma) and alcohol drinking (esophageal cancer) must be discussed. In Germany, a new consecutive case-control study on kidney cancer confirmed that the risk of renal cell cancer is significantly elevated in persons reporting long-term (several years) exposure to trichloroethylene. The results of all these studies indicate that low exposure (not higher than the current Occupational Exposure Limits) is not associated with increased risk of malignancy. In the kidney, trichloroethylene can act as a complete carcinogen at the stages of both tumor induction and tumor promotion/progresssion in a in a dose-dependent manner. Different types of kidney cancer can be triggered by different genes. Clear-cell renal carcinoma, preferentially induced by trichloroethylene, is linked with the homozygous inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. In highly exposed subjects, the local genotoxic effect of trichloroethylene results from bioactivation pathways leading to renal VHL gene damage and renal cell carcinomas. The view that renal cell cancer development after long-term (several years) and high (with prenarcotic episodes) occupational exposure to trichloroethylene is due to chronic damage of the proximal tubule of the kidney as a key step argues for the existence of a practical threshold. Prolonged and unusually high-dose exposure to trichloroethylene is deemed a strong risk factor for the development of renal cell cancer. The findings of experimental, mechanistic, and epidemiologic studies lead to the conclusion that trichloroethylene can be considered a human carcinogen for which a practical threshold appears likely and below which no relevant carcinogenic effect is to be expected.