In vivo genotoxicity of dichloroacetic acid: evaluation with the mouse peripheral blood micronucleus assay and the single cell gel assay.
Chlorination is a widely used method for disinfection of drinking water supplies. Reaction of chlorine with naturally present organic compounds can result in toxic by-products. One major disinfection by-product from the chlorination of drinking water is dichloroacetic acid (DCA). This chemical has been shown to be carcinogenic in rodents, yet little genotoxicity data are available to assess the possible role of DNA and/or chromosomal damage in this process. We have used the peripheral blood erythrocyte micronucleus (MN) assay and the alkaline single cell gel electrophoresis (SCG) technique to investigate the in vivo genotoxicity of DCA in bone marrow and blood leukocytes, respectively. The MN assay detects chromosome breakage and/or malsegregation, while the SCG assay detects DNA damage (e.g., single strand breaks, alkali-labile sites, crosslinking). Mice were exposed to this compound in drinking water, available ad libitum, for up to 31 weeks. Our results show a small but statistically significant dose-related increase in the frequency of micronucleated polychromatic erythrocytes (PCEs) after subchronic exposure to DCA for 9 days. In addition, at the highest dose of DCA tested (3.5 g/l), a small but significant increase in the frequency of micronucleated normochromatic erythrocytes (NCE) was detected following exposure for > or = 10 weeks. Coadministration of the antioxidant vitamin E did not affect the ability of DCA to induce this damage, indicating that the small induction of MN by DCA was probably not due to oxidative damage. Based on the lack of any difference observed in the proportion of kinetochore-positive micronuclei between the treated and control animals, we interpret MN as arising from clastogenic events. The SCG technique suggested the presence of DNA crosslinking in blood leukocytes in mice exposed to 3.5 g/l DCA for 28 days. These data provide evidence that DCA may be an extremely weak inducer of chromosome damage when provided to mice in drinking water under conditions which lead to increased levels of tumors.
Fuscoe
J C
JC
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Afshari
A J
AJ
George
M H
MH
DeAngelo
A B
AB
Tice
R R
RR
Salman
T
T
Allen
J W
JW
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D004249:DNA Damage; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004587:Electrophoresis, Agar Gel; D004912:Erythrocytes / Q000187:drug effects; D018386:Kinetochores / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D014810:Vitamin E / Q000494:pharmacology; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D014881:Water Supply
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D014874:Water Pollutants, Chemical; D014810:Vitamin E; D003999:Dichloroacetic Acid