Toxicokinetics and oral bioavailability of halogenated acetic acids mixtures in naïve and GSTzeta-depleted rats.

Disinfection of drinking water typically produces a mixture of mono-, di-, and tri-halogenated acetic acids (HAAs). In this study, we investigated the toxicokinetics of HAA mixtures in naive and glutathione transferase zeta 1 (GSTzeta)-depleted male F344 rats administered orally or iv to Mixture-1 (monobromo [MBAA]- dichloro- [DCAA], chlorodibromo- [CDBAA], tribromo- [TBAA] acetic acids) or Mixture-2 (bromochloro- [BCAA], dibromo- [DBAA], trichloro- [TCAA] bromodichloro- [BDCAA] acetic acids) at a dose of 25 micromol/kg HAA. Serial blood samples were collected at various times up to 36 h, and the plasma concentrations of each HAA quantified by GC-ECD. Rats were pretreated for 7 d with drinking water containing 0.2 g/l DCAA to deplete the GSTzeta (GSTZ1-1) activity in the liver. An additional group of GSTzeta-depleted rats were orally dosed with each mixture and euthanized at 0.25, 0.5, 1, 2, and 4 h to determine tissue distribution of mixture components. In both mixtures, GSTzeta depletion primarily affected the toxicokinetics of di-HAAs (DCAA, BCAA, and DBAA), with the total body clearance (Cl b) decreasing 3- to 10-fold. Interestingly, DCAA pretreatment appeared to increase the elimination of Mixture-2 tri-HAAs (TCAA and BDCAA). After oral administration, DCAA exhibited a complex time-course plasma profile with secondary peaks appearing long after completion of the initial absorption phase. This phenomenon coincided with elevated DCA levels in the lower portion of the GI tract compared to CDBAA and TBAA. Comparison of the results with previous studies employing similar or higher doses of individual HAAs indicated the primary difference in HAA toxicokinetics when administered as mixture was a reduction in Cl b. These results suggest competitive interactions between tri- and di-HAAs beyond what would be predicted from individual HAA studies. For di-HAAs, the total dose is important, as clearance is dose dependent due to competition for GSTzeta. When considering HAA dosimetry, importance should be placed on both the components of the mixture and prior exposure history to di-HAAs.