Assessment of the mutagenicity of dichloroacetic acid in lacI transgenic B6C3F1 mouse liver

Dichloroacetic acid (DCA) is a chlorination byproduct found in finisheddrinking water. When administered in drinking water this chemical has beenshown to produce hepatocellular adenomas and carcinomas in B6C3F1 mice overthe animal's lifetime. In this study, we investigated whether mutantfrequencies were increased in mouse liver using treatment protocols thatyielded significant tumor induction. DCA was administered continuously ateither 1.0 or 3.5 g/l in drinking water to male transgenic B6C3F1 miceharboring the bacterial lacI gene. Groups of five or six animals werekilled at 4, 10 or 60 weeks and livers removed. At both 4 and 10 weeks oftreatment, there was no significant difference in mutant frequency betweenthe treated and control animals at either dose level. At 60 weeks, micetreated with 1.0 g/l DCA showed a 1.3-fold increase in mutant frequencyover concurrent controls (P = 0.05). Mice treated with 3.5 g/l DCA for 60weeks had a 2.3-fold increase in mutant frequency over the concurrentcontrols (P = 0.002). The mutation spectrum recovered from mice treatedwith 3.5 g/l DCA for 60 weeks contained G:C-->A:T transitions (32.79%)and G:C-->T:A transversions (21.31%). In contrast, G:C-->A:Ttransitions comprised 53.19% of the recovered mutants among controlanimals. Although only 19.15% of mutations among the controls were at T:Asites, 32.79% of the mutations from DCA-treated animals were at T:A sites.This is consistent with the previous observation that the proportion ofmutations at T:A sites in codon 61 of the H-ras gene was increased inDCA-induced liver tumors in B6C3F1 mice. The present study demonstratesDCA-associated mutagenicity in the mouse liver under conditions in whichDCA produces hepatic tumors.