HEPATOTOXICITY OF THE DRINKING-WATER DISINFECTION BY-PRODUCT, DICHLOROACETIC ACID, IN THE MEDAKA SMALL FISH MODEL

Recent studies have shown that dichloroacetic acid (DCA), a by-product of chlorination of public water supplies, is carcinogenic to both rat s and mice. However, conflicting data have left the mechanism of DCA c arcinogenicity, vital to assessment of human health risk, unclear. Elu cidation of this mechanism in another animal model at a different phyl etic level than rodents would advance the risk assessment process for government agencies concerned with regulation and provision of safe dr inking water. The Japanese medaka (Oryzias latipes), a well characteri zed small fish model, is being used increasingly for carcinogenicity t esting because of its low cost, ease of maintenance and carcinogen sen sitivity. In this study, 6-week-old medaka were exposed to diethylnitr osamine (DEN, a known initiator), followed by continuous exposure to 0 .5 or 2.0 g/l DCA in the ambient water, over a 4 week period. At both exposure concentrations, changes in the liver included marked hepatoce llular cytoplasmic vacuolation, cytomegaly, karyomegaly, nuclear atypi a and multifocal areas of hepatocellular necrosis and loss as early as week two of DCA exposure. The majority of the hepatocellular cytoplas mic vacuoles were shown by periodic acid Schiff (PAS) staining to cont ain large amounts of glycogen. These elevated glycogen levels may refl ect a disruption in the enzyme pathways for glycolysis. The total cell ular changes seen in this short-term exposure regimen are compatible w ith preneoplastic changes seen in rats and mice exposed to DCA. The re sults of this study strengthen the role of the Japanese medaka as a su itable species in carcinogenicity testing as well as its implementatio n in the risk assessment process for DCA across several phyletic level s. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.