Absence of Mutagenic Effects of Sodium Dichloroacetate

Fox, Anthony W.

doi:10.1006/faat.1996.0110

Cited by 33 publications

(6 citation statements)

References 19 publications

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“…In mammalian systems, gene mutations were reported from in vivo experiments with DCA (Leavitt, et al, 1997), and limited evidence exists for increased mutations after treatment in vitro (Harrington-Brock, et al, 1998; Zhang, et al, 2010). DCA was positive for induction of chromosomal aberrations in mouse lymphoma cells (Harrington-Brock, et al, 1998), but not in CHO cells (Fox, et al, 1996). With regards to micronuclei, there are conflicting results (Fuscoe, et al, 1996; Harrington-Brock, et al, 1998).…”

Section: Metabolism and Genotoxicity Of Tcementioning

confidence: 96%

Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard

Rusyn

Chiu

Lash

et al. 2014

Pharmacology & Therapeutics

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The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. Strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin's lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.

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Section: Metabolism and Genotoxicity Of Tcementioning

confidence: 96%

Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard

Rusyn

Chiu

Lash

et al. 2014

Pharmacology & Therapeutics

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“…In bacterial assays, DCAA was weakly mutagenic [DeMarini et al, 1994;Giller et al, 1997;Kargalioglu et al, 2002]. However, DCAA was not clastogenic in newts, rat bone marrow, or mouse lymphoma cells [Fox et al, 1996;Giller et al, 1997;Harrington-Brock, 1998], but it was a weak inducer of chromosome breaks in mice [Fuscoe et al, 1996] and induced mutation and chromosome aberrations in mouse lymphoma cells [Harrington-Brock, 1998]. Although DCAA was weakly mutagenic in transgenic Big Blue mice [Leavitt et al, 1997], it did not induce DNA damage in CHO cells or in rodent liver cells [Chang et al, 1992].…”

Section: Introductionmentioning

confidence: 98%

Mammalian cell cytotoxicity and genotoxicity of the haloacetic acids, a major class of drinking water disinfection by‐products

Plewa

Simmons

Richardson

et al. 2010

Environ and Mol Mutagen

272

190

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The haloacetic acids (HAAs) are disinfection by-products (DBPs) that are formed during the disinfection of drinking water, wastewaters and recreational pool waters. Currently, five HAAs [bromoacetic acid (BAA), dibromoacetic acid (DBAA), chloroacetic acid (CAA), dichloroacetic acid (DCAA), and trichloroacetic acid (TCAA); designated as HAA5] are regulated by the U.S. EPA, at a maximum contaminant level of 60 μg/L for the sum of BAA, DBAA, CAA, DCAA, and TCAA. We present a comparative systematic analysis of chronic cytotoxicity and acute genomic DNA damaging capacity of 12 individual HAAs in mammalian cells. In addition to the HAA5, we analyzed iodoacetic acid (IAA), diiodoacetic acid (DiAA), bromoiodoacetic acid (BIAA), tribromoacetic acid (TBAA), chlorodibromoacetic acid (CDBAA), bromodichloroacetic acid (BDCAA), and bromochloroacetic acid (BCAA). Their rank order of chronic cytotoxicity in Chinese hamster ovary cells was IAA > BAA > TBAA > CDBAA > DIAA > DBAA > BDCAA > BCAA > CAA > BIAA > TCAA > DCAA. The rank order for genotoxicity was IAA > BAA > CAA > DBAA > DIAA > TBAA > BCAA > BIAA > CDBAA. DCAA, TCAA, and BDCAA were not genotoxic. The trend for both cytotoxicity and genotoxicity is iodinated HAAs > brominated HAAs > chlorinated HAAs. The use of alternative disinfectants other than chlorine generates new DBPs and alters their distribution. Systematic, comparative, in vitro toxicological data provides the water supply community with information to consider when employing alternatives to chlorine disinfection. In addition, these data aid in prioritizing DBPs and their related compounds for future in vivo toxicological studies and risk assessment.

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“…When administered to mice in their drinking water, DCA and TCA have been shown to induce and to promote hepatocellular adenomas and carcinomas [7][8][9][10][11]. There is little evidence to indicate genotoxic or mutagenic activity for DCA and TCA [12][13][14][15][16]. Because DCA and TCA are peroxisome proliferators [17][18][19][20], they could, similarly to other peroxisome proliferators, increase the yield of liver tumors in rodents by a nongenotoxic mechanism.…”

Section: Introductionmentioning

confidence: 99%

The effect of dichloroacetic acid and trichloroacetic acid on DNA methylation and cell proliferation in B6C3F1 mice

Yang

Kramer

et al. 2001

J Biochem & Molecular Tox

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The chlorine disinfection by-products, dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are carcinogenic in mouse liver. We have previously reported that DCA and TCA induced DNA hypomethylation in mouse liver. In the present study, we determined the temporal association for DNA hypomethylation and cell proliferation. Female B6C3F1 mice were administered daily doses of 500 mg/kg DCA or TCA by gavage and sacrificed at 24, 36, 48, 72, and 96 hours after the first dose. The proliferating cell nuclear antigen-labeling index in the liver was increased at 72 and 96 hours by both DCA and TCA, that is, at 72 hours the index was 1.00 +/- 0.21, 0.51 +/- 0.11, and 0.095 +/- 0.016 for DCA, TCA, and the vehicle control, respectively. The mitotic index was also significantly increased at 96 hours. The promoter region for the c-myc gene was hypomethylated only at 72 and 96 hours and not at the earlier sacrifices. Similarly, the methylation of the c-myc gene in the kidney and urinary bladder was decreased only at 72 and 96 hours. In summary, enhancement of cell proliferation and decreased methylation of the c-myc gene were first observed simultaneously at 72 hours after the start of exposure. Thus, the results support the hypothesis that DCA and TCA induce DNA hypomethylation by inducing DNA replication and preventing the methylation of the newly synthesized strands of DNA.

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Absence of Mutagenic Effects of Sodium Dichloroacetate

Cited by 33 publications

References 19 publications

Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard

Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard

Mammalian cell cytotoxicity and genotoxicity of the haloacetic acids, a major class of drinking water disinfection by‐products

The effect of dichloroacetic acid and trichloroacetic acid on DNA methylation and cell proliferation in B6C3F1 mice

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