The Extent of Dichloroacetate Formation from Trichloroethylene, Chloral Hydrate, Trichloroacetate, and Trichloroethanol in B6C3F1 Mice

Abstract

Conflicting data have been published related to the formation of dichloroacetate (DCA) from trichloroethylene (TRI), chloral hydrate (CH), or trichloroacetic acid (TCA) in B6C3F1 mice. TCA is usually indicated as the primary metabolic precursor to DCA. Model simulations based on the known pharmacokinetics of TCA and DCA predicted blood concentrations of DCA that were 10- to 100-fold lower than previously published reports. Because DCA has also been shown to form as an artifact during sample processing, we reevaluated the source of the reported DCA, i.e., whether it was metabolically derived or formed as an artifact. Male B6C3F1 mice were dosed with TRI, CH, trichloroethanol (TCE), or TCA and metabolic profiles of each were determined. DCA was not detected in any of these samples above the assay LOQ of 1.9 microM of whole blood. In order to slow the clearance of DCA, mice were pretreated for 2 weeks with 2 g/liter of DCA in their drinking water. Even under this pretreatment condition, no DCA was detected from a 100 mg/kg i.v. dose of TCA. Although there is significant uncertainty in the amount of DCA that could be generated from TRI or its metabolites, our experimental data and pharmacokinetic model simulations suggest that DCA is likely formed as a short-lived intermediate metabolite. However, its rapid elimination relative to its formation from TCA prevents the accumulation of measurable amounts of DCA in the blood.

A review of analytical methods for the determination of trichloroethylene and its major metabolites chloral hydrate, trichloroacetic acid and dichloroacetic acid

“…Merdink et al (1998) dosed male B6C3F1 mice with TCE, CH, TCEOH or TCA in order to determine levels of DCA formed as a metabolite from each of the above parent compounds. Rat blood samples were derivatized, so that DCA and TCA were converted to their methyl esters and liquid-liquid extraction (LLE) was performed.…”

“…In addition, the majority of the GC methods discussed in this paper employ ECD detection. These methods include the simultaneous analysis of TCE and its metabolites in several biological matrices, including lung, liver, kidney and blood (Merdink et al, 1998;Muralidhara and Bruckner, 1999). A GC-ECD method also exists for the analysis of TCE in seminal fluids of humans exposed to TCE occupationally (Forkert et al, 2003).…”

“…Although the HAAs are very water-soluble, many methods exist in which HAAs in drinking water are either derivatized or neutralized by acidification in order to make them more lipophilic and volatile prior to LLE extraction (Ko et al, 2000;Ahrer and Buchberger, 1999;Martínez et al, 1998b;Kim et al, 1999Kim et al, , 2001Domino et al, 2003;Xie, 2001;Dalvi et al, 2000;Williams et al, 1997;LeBel et al, 1997;Wong et al, 2003;Hashimoto and Otsuki, 1998;Magnuson and Kelty, 2000;Wu et al, 2002;Gabryelski et al, 2003). In addition, LLE can also be used to extract TCE (Brown et al, 2003b;Song and Ho, 2003), CH (Yan et al, 1999;Henderson et al, 1997), and DCA and TCA Jia et al, 2003;Merdink et al, 1998;Ketcha et al, 1996;Brashear et al, 1997) from biological matrices by extracting the organic layer after adding an organic solvent to tissue homogenate, plasma, or blood samples.…”

“…TCA, as a long-lived metabolite (Merdink et al, 1998), may be metabolized to DCA after samples have been collected. Another possibility is that DCA may be further metabolized after sample collection.…”

“…Another possibility is that DCA may be further metabolized after sample collection. There is difficulty in monitoring DCA in vivo in time-course studies of TCE metabolism, leading to the theory that DCA is a short-lived metabolite (Merdink et al, 1998). A method to stop metabolism at the time of collecting samples would be ideal for preserving the chemical species found in samples.…”