Species differences in the metabolism of trichloroethylene to the carcinogenic metabolites trichloroacetate and dichloroacetate,☆☆

https://doi.org/10.1016/0041-008X(92)90333-NGet rights and content

Abstract

Differing rates and extent of trichloroethylene (TCE) metabolism have been implicated as being responsible for varying sensitivities of mice and rats to the hepatocarcinogenic effects of TCE. Recent data indicate that the induction of hepatic tumors in mice may be attributed to the metabolites trichloroacetate (TCA) and/or dichloroacetate (DCA). The present study was directed at determining whether mice and rats varied in (1) the peak blood concentrations, (2) the area under the blood concentration over time curves (AUC) for TCE and metabolites in blood, and (3) the net excretion of TCE to these metabolites in urine in the dose range used in the cancer bioassays of TCE, and to contrast the kinetic parameters observed for TCE-derived TCA and DCA with those obtained following direct administration of TCA and DCA. Blood and urine samples were collected over 72 hr from rats and mice after a single oral dose of TCE of 1.5 to 23 mmol/kg. The AUC values from the blood concentration with time profiles of TCE, TCA, and trichloroethanol (TCOH) were similar for Sprague-Dawley rats and B6C3F1 mice. Likewise, the percentages of initial TCE dose recovered as the urinary metabolites TCA and TCOH were comparable. Nevertheless, the peak blood concentrations of TCE, TCA, and TCOH observed in mice were much greater than those in rats, while the residence time of TCE and metabolites was prolonged in rats relative to that of mice. DCA was detected in the blood of mice but not in rats. The blood concentrations of DCA observed in mice given a carcinogenic dose of TCE (15 mmol/kg) were of the same magnitude as those observed with carcinogenic doses of DCA. In conclusion, the net metabolism of TCE to TCA and TCOH was similar in rats and mice. The initial rates of metabolism of TCE to TCA, however, were much higher in mice, especially as the TCE dose was increased, leading to greater concentrations of TCA in blood. The fact that the blood concentrations of TCA and DCA in mice approximated those produced by carcinogenic doses of the chlorinated acetates makes it highly likely that both compounds play a role in the induction of hepatic tumors in mice by TCE.

References (23)

Cited by (91)

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    Such an exercise demonstrates that the oral TCE doses required to achieve the internal TCA levels associated with the TCA-CHD effect levels would approximate or exceed the LD50 of TCE in rats (i.e., acutely lethal; data not shown). For DCA, the limited empirical data indicate that oral administration of TCE in rats leads to internal DCA levels ∼1000-fold lower than TCA (Delinsky et al., 2005; Larson and Bull, 1992b), which would result in substantially greater TCE equivalent doses for the DCA oral studies than those of the TCA oral studies in rats. Further, because multiple, high dose in utero studies are available for TCE in mammalian models, the potential impact of a TCE metabolite on cardiac development is already accounted for in the TCE studies.

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    In contrast, male mice gavaged daily for 6 weeks were reported to exhibit linear metabolism of TCE up to 1600 mg/kg (Buben and O'Flaherty, 1985). Male B6C3F1 mice have a substantially greater capacity to oxidize TCE than do male S-D rats (Larson and Bull, 1992). The higher rate of TCE metabolism is attributable to higher liver microsomal CYP2E1 levels in the mice (Nakajima et al., 1993).

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    A larger portion of the parent compound undergoes metabolism in TCE-treated mice (15.7%–38.3%) as compared to PCE-treated mice (6.6%–9.7%), a finding that provides empirical data in strong support of the estimates from PBPK models (Chiu et al., 2014; Chiu and Ginsberg, 2011). The more efficient oxidative metabolism of TCE as compared to PCE is also concordant with previous animal studies (Cichocki et al., 2017a; Green and Prout, 1985; Larson and Bull, 1992) and PBPK modeling estimates (Chiu et al., 2014; Chiu and Ginsberg, 2011; Chiu et al., 2009). Among the most notable findings of this study is the observation of high levels of conjugates of metabolites of PCE in the kidney.

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    In addition, kinetic analysis of blood levels of DCA and TCA following oral administration of TCE in the mouse also shows that TCA is not the only source of DCA in vivo [34,35]. DCA has an extremely rapid disposition [36,37] to glyoxylic, oxalic, and monochloroacetic acids. The major pathway for DCA biotransformation is complete dechlorination to glyoxylate in a reaction catalyzed by glutathione transferase ζ (GSTz) [38].

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This work was supported by U.S. Air Force Grant AFOSR-86-0284 and by EPA Cooperative Agreement CR-815216-01.

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Presented in part at the 29th Annual Meeting of the Society of Toxicology, February 1990, Miami, FL.

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