title: Kinetics and effects of dichloroacetic acid in rainbow trout.
abstract: Halogenated acetic acids (HAAs) produced by chlorine disinfection of municipal drinking water represent a potentially important class of environmental contaminants. Little is known, however, about their potential to adversely impact fish and other aquatic life. In this study we examined the kinetics and effects of dichloroacetic acid (DCA) in rainbow trout. Branchial uptake was measured in fish confined to respirometer-metabolism chambers. Branchial uptake efficiency was <5%, suggesting passive diffusion through aqueous channels in the gill epithelium. DCA concentrations in tissues following prolonged (72, 168, or 336 h) waterborne exposures were expressed as tissue:plasma concentration ratios. Concentration ratios for the kidney and muscle at 168 and 336 h were consistent with the suggestion that DCA distributes primarily to tissue water. Reduced concentration ratios for the liver, particularly at 72 h, indicated that DCA was highly metabolized by this tissue. Routes and rates of elimination were characterized by injecting chambered animals with a high (5.0mg/kg) or low (50 microg/kg) bolus dose. DCA was rapidly cleared by naïve animals resulting in elimination half-lives (t(1/2)) of less than 4h. Waterborne pre-treatment of fish with DCA increased the persistence of a subsequently injected dose. In high dose animals, pre-treatment caused a 4-fold decrease in whole-body clearance (CL(B)) and corresponding increases in the area under the plasma concentration-time curve (extrapolated to infinity; AUC(0-->infinity)) and t(1/2). Qualitatively similar results were obtained in low dose fish, although the magnitude of the pre-treatment effect ( approximately 2.5-fold) was reduced. Renal and branchial clearance contributed little (combined, <3% of CL(B)) to the elimination of DCA. Biliary elimination of DCA was also negligible. The steady-state volume of distribution (V(SS)) did not vary among treatment groups and was consistent with results of the tissue distribution study. DCA had no apparent effects on respiratory physiology or acid-base balance; however, the concentration of blood lactate declined progressively during continuous waterborne exposures. A transient effect on blood lactate was also observed in bolus injection experiments. The results of this study suggest that clearance of DCA is due almost entirely to metabolism. The pathway responsible for this activity exhibits characteristics in common with those of mammalian glutathione S-transferase zeta (GSTzeta), including non-linear kinetics and apparent suicide inactivation by DCA. Observed effects on blood lactate are probably due to the inhibition of pyruvate dehydrogenase kinase in aerobic tissues and may require the participation of a monocarboxylase transport protein to move DCA across cell membranes.
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, MN 55804, USA. fitzsimmons.patrick@epa.gov
authors: Patrick N
authors: PN
authors: Fitzsimmons
authors: Alex D
authors: AD
authors: Hoffman
authors: Gregory J
authors: GJ
authors: Lien
authors: Dean E
authors: DE
authors: Hammermeister
authors: John W
authors: JW
authors: Nichols
mesh_terms: D000818:Animals; D001711:Biotransformation; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D005880:Gills / Q000378:metabolism; D007267:Injections; D008657:Metabolic Clearance Rate; D017686:Oncorhynchus mykiss / Q000378:metabolism*; D014018:Tissue Distribution; D018675:Toxicity Tests; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D014874:Water Pollutants, Chemical; D003999:Dichloroacetic Acid