Dose-response analyses of the carcinogenic effects of trichloroethylene in experimental animals.

Abstract

In lifetime bioassays, trichloroethylene (TCE, causes liver tumors in mice following gavage, liver and lung tumors in mice following inhalation, and kidney tumors in rats following gavage or inhalation. Recently developed pharmacokinetic models provide estimates of internal, target-organ doses of the TCE metabolites thought responsible for these tumor responses. Dose-response analyses following recently proposed methods for carcinogen risk assessment from the U.S. Environmental Protection Agency (U.S. EPA) are conducted on the animal tumor data using the pharmacokinetic dosimeters to derive a series of alternative projections of the potential carcinogenic potency of TCE in humans exposed to low environmental concentrations. Although mechanistic considerations suggest action of possibly nonlinear processes, dose-response shapes in the observable range of tumor incidence evince little sign of such patterns. Results depend on which of several alternative pharmacokinetic analyses are used to define target-organ doses. Human potency projections under the U.S. EPA linear method based on mouse liver tumors and internal dosimetry equal or somewhat exceed calculations based on administered dose, and projections based on mouse liver tumors exceed those from mouse lung or rat kidney tumors. Estimates of the carcinogenic potency of the two primary oxidative metabolites of TCEtrichloroacetic acid and dichloroacetic acid, which are mouse liver carcinogens in their own rightare also made, but it is not clear whether the carcinogenic potency of TCE can be quantitatively ascribed to metabolic generation of these metabolites. Key words: carcinogenic potency, crossspecies extrapolation, dichloroacetic acid, internal dose, low-dose extrapolation, trichloroacetic acid, trichloroethylene. - Although several alternatives for selecting the PoD are provided in the new guidelines proposal, the "standard point of departure, adopted as a matter of science policy" is the LEDIO (lower [95%] statistical bound on effective dose to 10% of the population), the lower 95% confidence limit on a dose associated with 10% extra risk (10). Unless otherwise stated, this method ofselecting the PoD is used herein. These lower limits have been calculated as provided for in GLOBAL86 (25) and MULTI-WEIB (23), i.e., they are risk-specific calculations based on reoptimizing model parameters at the 10% extra risk level. In addition, the central estimate of the dose associated with 10% extra risk, i.e., the ED1o (effective dose to 10% of the population), calculated based on the maximum likelihood curve, is provided. Typically, the EDIo is higher (and its associated low-dose slope is lower) by about a factor of2 compared to the LED10.

Comparative Metabolism and Disposition of Trichloroethylene in Cyp2e1–/–and Wild-Type Mice

“…TCA and DCA were also shown to cause liver tumors in rats and mice through induction of peroxisome proliferation in hepatocytes (Herren-Freund et al, 1987). Spermatoxicity studies in rats showed that DCA causes delayed spermiation and morphological abnormalities in residual bodies and testes (Linder et al, 1997 Metabolism of TCE is influenced by many factors, including gender, tissue, and dose (Lash et al, 2000;Rhomberg, 2000) and is closely related to the expression and distribution of enzymes involved in the oxidation and glutathione conjugation pathways. Therefore, understanding the enzymatic basis of TCE metabolism is critical for scrutinizing the mechanisms of action and the human risks of this chemical.…”

“…Exposure to TCE causes a variety of tumors depending on species and tissues (Green, 2000;Clewell and Andersen, 2004). In mice, TCE causes lung and liver tumors after inhalation or gavage exposure (Rhomberg, 2000). Furthermore, exposure to TCE induces kidney and lung toxicity, and inhibits male fertility (Green et al, 1997;DuTeaux et al, 2004;Forkert et al, 2006).…”

“…Metabolism of TCE is influenced by many factors, including gender, tissue, and dose (Lash et al, 2000;Rhomberg, 2000) and is closely related to the expression and distribution of enzymes involved in the oxidation and glutathione conjugation pathways. Therefore, understanding the enzymatic basis of TCE metabolism is critical for scrutinizing the mechanisms of action and the human risks of this chemical.…”

A meta-analysis of occupational trichloroethylene exposure and multiple myeloma or leukaemia

“…The carcinogenicity of TCE based on animal models and epidemiologic studies has been reviewed [1,3,5,8]. Increased risks of liver, lung and kidney tumours have been reported in laboratory mice and rats [7,[9][10][11][12]; however, species disparities in TCE metabolism preclude extrapolation to human carcinogenesis. Furthermore, some studies reported no indication of carcinogenic potential in animals [13,14].…”

Trichloroethylene health risks--state of the science.

“…Rhomberg (19) presents a comprehensive analysis of the liver, lung, and kidney tumor data and pharmacokinetic model-derived dose metrics using default dose-response approaches. Not only does the analysis provide a choice of dose metrics from the two pharmacokinetic models and their uncertainty analyses, which yields four estimates for a single dose metric, it also examines the influence of several metabolites of the cytochrome P450 and glutathione-S-transferase pathways.…”