Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse*1

Daniel, F. Bernard; DeAngelo, Anthony B.; Stober, Judy A.; Olson, Greg R.; Page, Norbert P.

doi:10.1016/0272-0590(92)90147-a

Cited by 149 publications

(72 citation statements)

References 40 publications

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“…Given the carcinogenic potential of DCA in rodent liver Daniel et al 1992;DeAngelo et al 1991DeAngelo et al , 1996DeAngelo et al , 1999Herren-Freund et al 1987;Pereira 1996) and the known concentrations of this compound in drinking water (Fair 1996;Krasner et al 1989;Uden and Miller 1983), reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer.…”

Section: Discussionmentioning

confidence: 99%

“…The carcinogenicity of DCA in the liver of the male and female B6C3F 1 mouse and the F344 male rat has been well demonstrated Daniel et al 1992;DeAngelo et al 1991DeAngelo et al , 1996DeAngelo et al , 1999Herren-Freund et al 1987;Pereira 1996). The question arose whether DCA was promoting the outgrowth of initiated cells already present in the liver because the male B6C3F 1 mouse has a high rate of spontaneous liver tumor formation, and prior initiation with a genotoxic carcinogen was not required for DCA-induced liver tumor formation .…”

mentioning

confidence: 99%

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A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Carter

Deddens

et al. 2003

Environ Health Perspect

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Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Carter

Deddens

et al. 2003

Environ Health Perspect

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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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In vivo genotoxicity of dichloroacetic acid: Evaluation with the mouse peripheral blood micronucleus assay and the single cell gel assay

Fuscoe

Afshari

George

et al. 1996

Environ. Mol. Mutagen.

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Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse*1

Cited by 149 publications

References 40 publications

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

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

In vivo genotoxicity of dichloroacetic acid: Evaluation with the mouse peripheral blood micronucleus assay and the single cell gel assay

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