Trichloroethylene: Mechanisms of Renal Toxicity and Renal Cancer and Relevance to Risk Assessment

Abstract

1,1,2-Trichloroethylene (TCE) is an important solvent that is widespread in the environment. We have reviewed carcinogenicity data from seven bioassays with regard to renal injury and renal tumors. We report a consistent but low incidence of renal tubule carcinoma in male rats. Epidemiology studies on workers exposed to TCE (and other chlorinated solvents) indicate a weak association between high-level exposure and renal cancer. There appears to be a threshold below which no renal injury or carcinogenicity is expected to arise. TCE is not acutely nephrotoxic to rats or mice, but subchronic exposure to rats produces a small increase in urinary markers of renal injury. Following chronic exposure, pathological changes (toxic nephrosis and a high incidence of cytomegaly and karyomegaly) were observed. The basis for the chronic renal injury probably involves bioactivation of TCE. Based on the classification by E. A. Lock and G. C. Hard (2004, Crit. Rev. Toxicol. 34, 211-299) of chemicals that induce renal tubule tumors, we found no clear evidence to place TCE in category 1 or 2 (chemicals that directly or indirectly interact with renal DNA), category 4 (direct cytotoxicity and sustained tubule cell regeneration), category 5 (indirect cytotoxicity and sustained tubule cell regeneration associated with alpha2u-globulin accumulation), or category 6 (exacerbation of spontaneous chronic progressive nephropathy). TCE is best placed in category 3, chemicals that undergo conjugation with GSH and subsequent enzymatic activation to a reactive species. The implication for human risk assessment is that TCE should not automatically be judged by linear default methods; benchmark methodology could be used.

Nephrotoxic effect of subchronic exposure to <i>S</i>-(1,2-dichlorovinyl)-<i>L</i>-cysteine in mice

“…The kidneys are the primary target of TCE, and nephrotoxicity is linked to metabolism of TCE via the glutathione conjugation pathway (Caldwell and Keshava, 2006;Lock and Reed, 2006;Lash et al, 2000aLash et al, , 2000b. Once glutathione conjugate is formed, it is further metabolized to the cysteine conjugate DCVC, which is subsequently activated through α,β-elimination by the action of the cysteine conjugate β-lyase (Tateishi et al, 1987).…”

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

“…Evidence of the continued interest in the toxicity and human health risk of TRI is highlighted by a series of recent reviews that summarize current state of knowledge and uncertainties [3][4][5][6]. Evaluation of the risk for humans potentially exposed to TRI in either the workplace or due to environmental contamination is complicated by the existence of multiple metabolic pathways, multiple target organs, poor or incomplete exposure data for many epidemiology studies, and sex-and species-dependent differences in sensitivity to toxic effects [3,6,7].…”

“…The kidneys are one target organ for TRI, and toxicity and carcinogenicity are linked to metabolism of TRI by the glutathione (GSH) conjugation pathway [3,5,7,8]. Once the GSH conjugate is formed, it is further metabolized to the cysteine conjugate S-(1,2-dichlorovinyl)-L-cysteine (DCVC), which is the penultimate nephrotoxic species and has been the focus of most of the mechanistic studies of TRI-induced nephrotoxicity.…”

“…Despite these advances in our understanding of mechanisms of action of DCVC in renal injury, extrapolation of these findings to human kidney involves uncertainties because of species differences in metabolism, transport, and overall susceptibility to injury [3][4][5]7,8]. To solve the problems inherent in interspecies extrapolation, one approach has been to conduct studies in freshly isolated and primary cultures of human PT (hPT) cells.…”

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

“…It is well established that TCE undergoes metabolism by hepatic cytochrome P450 in experimental animals and man to produce chloral hydrate (CH) which is then further metabolised to TCE-OH and TCA (Davidson and Beliles, 1991;Elfarra et al, 1998;Lash et al, 2000;Bloemen et al, 2001;Lock and Reed, 2006). The target organs for toxicity and carcinogenicity following exposure of rats or mice to TCE are the liver, kidney and lung (Bull, 2000;Green, 2000;Lock and Reed, 2006).…”