For definition of Groups, see Preamble Evaluation.
VOL.: 84 (2004) (p. 359)
5.1 Exposure data
Dichloroacetic acid is used as an intermediate in the production of glyoxylic acid, dialkoxy and diaroxy acids, sulfonamides and iron chelates. It is used to a lesser extent as a cauterizing agent in dermatology. Wider exposure to dichloroacetic acid occurs at microgram-per-litre levels in drinking-water and swimming pools as a result of chlorination and chloramination.
5.2 Human carcinogenicity data
Several studies were identified that analysed risk with respect to one or more measures of exposure to complex mixtures of disinfection by-products that are found in most chlorinated and chloraminated drinking-water. No data specifically on dichloroacetic acid were available to the Working Group.
5.3 Animal carcinogenicity data
In eight studies, neutralized dichloroacetic acid administered in the drinking-water to male and/or female mice increased the incidences of hepatocellular adenomas and/or carcinomas. Following oral administration of dichloroacetic acid in the drinking-water to male rats, an increased incidence of hepatocellular carcinomas was found at a dose that decreased body weight and an increase in the combined incidence of adenomas and carcinomas was found at a lower dose. When administered in the drinking-water, dichloroacetic acid promoted hepatocellular carcinomas in carcinogen-initiated male and female mice in three studies.
5.4 Other relevant data
Dichloroacetic acid is metabolized to glyoxylic acid, which may be oxidized to oxalic acid, reduced to glycolic acid and transaminated to glycine. The metabolism of dichloroacetic acid to glyoxylic acid is catalysed by glutathione S-transferase zeta-1. Dichloroacetic acid is a mechanism-based inactivator of this enzyme, which decreases its own metabolism in humans or rats treated with the compound.
Clinically, administration of dichloroacetic acid for the treatment of congenital lactic acidosis has been associated with nervous system toxicity, which has also been observed in experimental animals. Animal studies have demonstrated toxic effects in the liver and testis. Treatment of rats with dichloroacetic acid has also given rise to developmental effects, primarily in the cardiovascular system. However, these have not been observed consistently.
Dichloroacetic acid produces a variety of effects on intermediary metabolism, including increases in hepatic glycogen at low concentrations (less than or equal to 1 micromol/L) in the blood and inhibition of pyruvate dehydrogenase kinase at higher concentrations (more than or equal to 100 micromol/L). Dichloroacetic acid also affects gene expression, including various proto-oncogenes and enzymes involved in lipid metabolism. In some cases, changes in gene expression have been associated with decreased methylation of DNA in the promoter region of the gene.
Studies on proto-oncogenes in mice have compared mutation induction in codon 61 of H-ras proto-oncogenes in hepatic tumours from dichloroacetic acid-treated mice and untreated mice. The spectrum of mutations showed a decrease in the frequency of CAA®AAA mutations and an increase in the frequency of mutations from CAA®CGA and from CAA®CTA in treated mice compared with controls. No loss of heterozygosity on chromosome 6 was observed in liver tumours promoted by dichloroacetic acid in female mice.
The evidence for induction of DNA strand breaks in liver cells of rodents exposed to dichloroacetic acid in vivo was inconclusive, as were the results of measurements of dichloroacetic acid-induced 8-hydroxydeoxyguanosine DNA adducts in mouse liver. Dichloroacetic acid caused a decrease in the level of 5-methylcytosine in DNA of liver cells and liver tumours of female mice. In peripheral blood cells of mice in vivo, dichloroacetic acid induced DNA damage in the single-cell gel electrophoresis assay. It caused mutations (decrease in G:C®A:T and increase in mutations at T:A sites) in male transgenic mice harbouring the bacterial lacI gene. Dichloroacetic acid induced the formation of micronuclei in vivo in mouse polychromatic erythrocytes but not in rat bone-marrow cells.
DNA strand breaks were not induced in human or rodent cells in vitro. The results of assays for mutagenesis in bacteria and in mouse lymphoma cells were inconsistent. Dichloroacetic acid did not induce micronuclei in a mouse lymphoma cell line in vitro or in erythrocytes of newt larvae in vivo. It caused chromosomal aberrations in one of two studies in vitro. Dichloroacetic acid induced no aneuploidy in mouse lymphoma cells in vitro.
Dichloroacetic acid affects cell proliferation and cell death both in normal livers and tumours throughout the dose range that induces liver tumours in mice. These changes are associated with differential effects on intermediary metabolism in preneoplastic lesions versus normal liver and by changes in gene expression and DNA hypomethylation.
Dichloroacetic acid is genotoxic in vivo and in vitro. It also causes DNA hypomethylation in vivo. Thus, a genotoxic effect, possibly involving an indirect, epigenetic mechanism, may contribute to the carcinogenic mode of action of dichloroacetic acid.
There is inadequate evidence in humans for the carcinogenicity of dichloroacetic acid.
There is sufficient evidence in experimental animals for the carcinogenicity of dichloroacetic acid.
Dichloroacetic acid is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Vol. 63 (1995)
· DCA (acid)
· Dichloracetic acid
· Dichlorethanoic acid
· Dichloroethanoic acid
Last updated: 29 September 2004
See Also: Toxicological Abbreviations Dichloroacetic acid (ICSC) Dichloroacetic Acid (IARC Summary & Evaluation, Volume 63, 1995)