Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene.

Abstract

This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE.

Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines

“…The 2005 bioassay was negative at a dose that should have produced a small, but significant increase in tumor incidence if a linear low dose extrapolation were applied to the results of the corn oil gavage study. While DCA have been found genotoxic in some studies, the concentrations necessary to produce 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 30 these effects are so high relative to the systemic concentrations that produce cancer in animals as to make them irrelevant to in vivo carcinogenesis (Moore and Harrington-Brock, 2000). This conclusion is bolstered by the fact that DCA has been shown to selectively stimulate the growth of already initiated cells (Stauber and Bull, 1997), which can completely account for the development of liver cancer (Miller et al, 2000) at much lower systemic concentrations.…”

Indicators of uncertainty in chemical risk assessments

“…In a recent review it is concluded that the data on the mutagenicity of TCE indicate that neither TCE nor any of its major metabolites (chloral hydrate, dichloroacetic acid, trichloroacetic acid, and trichloroethanol) are potent genotoxic agents. However, the minor metabolite, dichlorovinylcysteine, that is formed locally in the kidneys of humans, mice, and rats, has been shown to be potent in inducing point mutations (in vitro) (Moore and Harrington-Brock, 2000).…”

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

“…In an article in this monograph, DCA is characterized as genotoxic only at high dose levels well above those expected at environmental exposure levels (39). Several hypotheses regarding the mechanism of carcinogenic action of TCE suggest underlying processes that might be markedly nonlinear.…”

“…Neither TCE nor TCA appears to be genotoxic, and the evidence on CH is debated, as there is some evidence that it can act as a clastogen (16,39). In an article in this monograph, DCA is characterized as genotoxic only at high dose levels well above those expected at environmental exposure levels (39).…”

“…It has been proposed that this toxicity, and the regenerative cell replication that it induces may be responsible for the lung tumors in mice and that the particular susceptibility of mice is attributable to the fact that mouse Clara cells generate a good deal of the metabolite CH by oxidative metabolism of TCE, but they are relatively deficient in chloral metabolic clearance (44). Chloral has shown dastogenic activity in some tests (16,39). It Table 8 along with relevant dose measures.…”