The carcinogenicity of dichloroacetic acid in the male fischer 344 rat

DeAngelo, Anthony B.; Daniel, F. Bernard; Most, Bernard M.; Olson, Greg R.

doi:10.1016/s0300-483x(96)03510-x

Cited by 149 publications

(95 citation statements)

References 51 publications

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“…Dichloroacetaldehyde has been given a moderate concern because it is a potential cross-linking agent. It can also be readily oxidized to dichloroacetic acid, which has been shown to be a rodent carcinogen with multiple mechanisms of action (43)(44)(45). Dibromonitromethane has been given a moderate concern because the corresponding dichloronitromethane is believed to be the proximate mutagen of chloropicrin (46).…”

Section: Distribution Of Disinfection By-products Within Structure-acmentioning

confidence: 99%

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Woo

Lai

McLain

et al. 2002

Environ Health Perspect

225

100

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Disinfection by-products (DBPs) are formed when disinfectants such as chlorine, chloramine, and ozone react with organic and inorganic matter in water. The observations that some DBPs such as trihalomethanes (THMs), di-/trichloroacetic acids, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) are carcinogenic in animal studies have raised public concern over the possible adverse health effects of DBPs. To date, several hundred DBPs have been identified. To prioritize research efforts, an in-depth, mechanism-based structure-activity relationship analysis, supplemented by extensive literature search for genotoxicity and other data, was conducted for ranking the carcinogenic potential of DBPs that met the following criteria: a) detected in actual drinking water samples, b) have insufficient cancer bioassay data for risk assessment, and c) have structural features/alerts or short-term predictive assays indicative of carcinogenic potential. A semiquantitative concern rating scale of low, marginal, low-moderate, moderate, high-moderate, and high was used along with delineation of scientific rationale. Of the 209 DBPs analyzed, 20 were of priority concern with a moderate or high-moderate rating. Of these, four were structural analogs of MX and five were haloalkanes that presumably will be controlled by existing and future THM regulations. The other eleven DBPs, which included halonitriles (6), haloketones (2), haloaldehyde (1), halonitroalkane (1), and dialdehyde (1), are suitable priority candidates for future carcinogenicity testing and/or mechanistic studies.

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Section: Distribution Of Disinfection By-products Within Structure-acmentioning

confidence: 99%

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Woo

Lai

McLain

et al. 2002

Environ Health Perspect

225

100

View full text Add to dashboard Cite

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“…DCA has also been used as an investigational drug for metabolic and cardiovascular disorders Stacpoole and Green, 1992;Stacpoole et al, 1992;Shangraw et al, 1994). However, due to adverse effects in laboratory animals DeAngelo et al, 1991DeAngelo et al, , 1996, therapeutic use of DCA has been limited. The toxicity of DCA has been studied in animals, but its immunotoxicity is not known.…”

Section: Introductionmentioning

confidence: 99%

Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL^+/+and B₆C₃F₁Mice

Cai

Boor

Khan

et al. 2007

Journal of Immunotoxicology

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Dichloroacetic acid (DCA) is a by-product of chlorination that occurs in drinking water disinfected with chlorine. Metabolism of trichloroethene (TCE) also generates DCA. TCE exposure is associated with the development of autoimmune diseases, which may be induced by TCE metabolites, such as DCA. Thus, it is important to understand immunotoxic responses to DCA. We chose 2 murine models, autoimmune-prone MRL +/+ and normal B 6 C 3 F 1 mice. Both strains of mice were exposed to DCA for 12 weeks. Following DCA treatment, liver weights and liver-to-body weight ratios were significantly increased in both strains of mice when compared to their respective controls. The serum activity of alanine and aspartate aminotransferases was not significantly altered in either strain. In MRL +/+ mice, the serum concentrations of IgG and IgM were significantly increased, whereas in B 6 C 3 F 1 mice, only serum IgG 3 was increased. DCA treatment did not change the levels of inflammatory cytokines in the serum. However, independent of treatment, the concentrations of G-CSF in the serum were lower in MRL +/+ mice than in B 6 C 3 F 1 mice, whereas IL-12 serum levels were higher in MRL +/+ mice. DCA treatment decreased IL-10 and KC chemokine concentrations in the livers of MRL +/+ mice, whereas T-helper cell cytokines (IL-4, IL-5, IL-10, IFNγ, and GM-CSF), pro-inflammatory cytokines (IL-6, IL-12, and G-CSF), and KC chemokine were increased in the livers of DCA-treated B 6 C 3 F 1 mice. Stimulation of splenic T-lymphocytes with antibodies against CD3 and CD28 resulted in a marked difference in the secreted cytokines between the two strains of mice. T-lymphocytes from MRL +/+ mice secreted more IL-2, IL-4 and IL-10, but less IFNγ and GM-CSF, than did T-lymphocytes from B 6 C 3 F 1 mice. Thus, the cytokine levels in serum and liver, and the cytokine secretion patterns from stimulated splenic T-lymphocytes suggested

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“…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 . More recent data for the female B6C3F 1 mouse and for the C3H and C57BL parental strains revealed a biphasic dose-response curve for the number of carcinomas (CAs) per liver (DeAngelo 2000b;DeAngelo et al 1996DeAngelo et al , 1999. There was an increase in the number of CAs for the male B6C3F 1 and C3H mouse, strains with high spontaneous tumor rates, when animals were given 0.5 g/L DCA.…”

mentioning

confidence: 98%

“…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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The carcinogenicity of dichloroacetic acid in the male fischer 344 rat

Cited by 149 publications

References 51 publications

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL^+/+and B₆C₃F₁Mice

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.

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The carcinogenicity of dichloroacetic acid in the male fischer 344 rat

Cited by 149 publications

References 51 publications

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL+/+and B6C3F1Mice

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.

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Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL^+/+and B₆C₃F₁Mice