The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver

Herren-Freund, Sydna L.; Pereira, Michael A.; Khoury, Marlene D.; Olson, Greg R.

doi:10.1016/0041-008x(87)90325-5

Cited by 255 publications

(129 citation statements)

References 22 publications

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“…These same DCA-promoted proliferative lesions were TGF-r3-negative, while the nontumor parenchymal hepatocytes were TGF-r3-positive (Fig. 3A) the hepatocyte and internalized (6,13,16 (20,24,26). Recently, there have been several reports that concomitant overexpression of c-myc and TGF-a in rodent liver resulted in acceleration of neoplastic development (26,32,35).…”

Section: Methodsmentioning

confidence: 98%

“…Additionally, after the trihalomethanes, DCA and TCA are the most common organic contaminants formed as reaction by-products during chlorine disinfection of water containing humic acids and other organic substances (8,25); they are found in finished chlorinated drinking water with concentrations ranging from 34 to 160 pLg/ml (22,36). Administering DCA or TCA in the drinking water to B6C3F1 mice has been shown to cause hepatocellular adenomas and carcinomas (3,10,20,(29)(30)(31). Differences in dose-response curves, histopathology, progression to tumor, and postexposure regression of tumors suggest that TCA and DCA work through different mechanisms (3,10,(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

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Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice

Latendresse

Pereira

1997

Toxicol Pathol

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Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-response curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. The purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCA and DCA using biomarkers of cell growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates. Fifteen-day-old female mice were initiated with 25 mg/kg N -methyl-N -nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmol/L) in drinking water from age 49 days until euthanasia at age 413 days. The pathologic assessment showed that the foci of altered hepatocytes and tumors occurring in the animals promoted with DCA were eosinophilic and positive immunohistochemically for TGF-α, c-jun , c-myc , CYP 2E1, CYP 4A1, and glutathione S -transferase-π (GST-π). The DCA lesions also were essentially negative for c-fos and TGF-β, but nontumor hepatocytes were consistently TGF-β-positive. In contrast, tumors promoted by TCA were predominantly basophilic, lacked GST-π, and stained variably; usually, more than 50% of the tumor hepatocytes were essentially negative for the other biomarkers. This study demonstrates some striking differences in certain molecular biomarkers of cell growth, differentiation, and metabolism between DCA and TCA. The results also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the premise that these two chloroacetates promote hepatocarcinogenesis in different ways, and provide a rational basis for a similar comparison with TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carcinogenesis of the parent compound, TCE.

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Section: Methodsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice

Latendresse

Pereira

1997

Toxicol Pathol

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“…It is noteworthy that three of the principal metabolites of TCE-TCA, DCA, and chloral (CH)-are stable compounds that have been shown to cause mouse liver tumors in their own right when administered in drinking water or (in the case of CH) by gastric intubation (11)(12)(13)(14)(15) [reviewed by Bull (16)]. These are three metabolites of the oxidative pathway of TCE metabolism (as opposed to the conjugative pathway hypothesized to be responsible for the rat kidney tumors).…”

Section: Pharmacokinetic Models and Internal Dosesmentioning

confidence: 99%

“…Table 5 gives incremental risk per jig/L of drinking water contamination, on the assumption of lifetime consumption of 2 L/day. (11)(12)(13)(14)(15)(16). For neither compound has a full lifetime bioassay of the usual design been conducted, but a number of studies have examined mice for various durations of exposure to a variety of drinking water concentrations (Table 7).…”

Section: Dose-response Analysismentioning

confidence: 99%

“…* TCE pharmacokinetics and metabolism are now much better elucidated, and a good deal ofwork has been done on physiologically based pharmacokinetic modeling of TCE and its major metabolites in experimental animals and humans (5-9). * Some of the principal metabolites of TCE are carcinogenic in their own right when directly administered to experimental animals-in particular, trichloroacetic acid (TCA) and dichloroacetic acid (DCA) cause liver tumors in mice when administered in drinking water (10)(11)(12)(13)(14)(15). * The understanding of the mechanisms of carcinogenic action of TCE has improved.…”

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confidence: 99%

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

Rhomberg¹

2000

Environ Health Perspect

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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.

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Quantitative structure-activity relationships for the developmental toxicity of haloacetic acids in mammalian whole embryo culture

Richard

Hunter

1996

Teratology

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Developmental toxicity in mouse whole embryo culture assay has been reported for acetic acid (AA) and a series of ten haloacetic acids, including mono‐, di‐, tri‐fluoro (MFA, DFA, TFA), chloro (MCA, DCA, TCA), bromo (MBA, DBA, TBA), and monoiodo (MIA) acetic acids. Benchmark concentrations (BCm), calculated as the lower 95% confidence limit of molar acid concentration producing a 5% increase in embryos with neural tube defects, provided potency estimates for development of quantitative structure‐activity relationships (QSARs). The best overall regression was obtained for the ten halo‐acids (excluding AA) and related log (1/BCm) to the energy of the lowest unoccupied molecular orbital (Elumo) and acid dissociation constant (pKa) with a correlation coefficient of r = 0.97, and a sample size‐adjusted r2 = 0.92. This QSAR suggested a common basis for the mechanism of HA activity, which would imply additivity for mixtures of these acids. Examination of QSARs for subsets of the total data set (e.g., monohaloacids) highlighted parameter relationships embedded in the total QSAR, helping to unravel the separate contributions of Elumo and pKa to the overall potency. The relevance of these parameters is discussed in terms of postulated mechanisms of developmental toxicity involving changes in intercellular pH and redox metabolism. The whole embryo assay results pertain to direct embryo exposure and toxicity without the confounding influence of maternal factors. The resulting QSAR model offers possible insight into the mechanism of embryo toxicity that will hopefully contribute to understanding of the more complex, in vivo teratogenicity problem. © 1996 Wiley‐Liss, Inc.

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The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver

Cited by 255 publications

References 22 publications

Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice

Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice

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

Quantitative structure-activity relationships for the developmental toxicity of haloacetic acids in mammalian whole embryo culture

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