title: Trichloroacetic acid: updated estimates of its bioavailability and its contribution to trichloroethylene-induced mouse hepatomegaly.
abstract: Trichloroacetic acid (TCA) is a common drinking water disinfection byproduct that produces a spectrum of liver effects, including hepatomegaly and liver tumors, in mice. It is also an oxidative metabolite of trichloroethylene (TCE), a solvent used in degreasing with widespread environmental exposure, which also produces hepatomegaly and liver tumors in mice. Physiologically based pharmacokinetic (PBPK) modeling of TCE and TCA can be used to quantitatively compare the dose-responses for hepatomegaly for these two chemicals on the basis of internal TCA dose, and thereby test the hypothesis that TCA could fully explain TCE-induced hepatomegaly. Previously, using a PBPK model calibrated using kinetic data from i.v. and gavage dosing of TCA and from TCA produced from TCE, it was concluded that TCA accounted for only about one-fifth of the degree of hepatomegaly produced by TCE. However, recently available data suggest a non-linear change in internal TCA dose attributed to a dose-dependent fractional absorption of TCA administered in drinking water, the primary route of exposure of TCA both environmentally and in experimental toxicity studies. Therefore, in the present reanalysis, the PBPK modeling of TCA was updated using these data and the comparison between TCA- and TCE-induced hepatomegaly was revisited using updated internal dose predictions. With respect to updated PBPK modeling results, incorporating less than complete absorption of TCA administered in drinking water substantially improves the PBPK model fit to the newly available data, based on goodness-of-fit comparison. However, inter-experimental variability is high, with nearly complete absorption estimated for some studies. With respect to the comparison of TCA and TCA-induced hepatomegaly, this reanalysis predicts that TCA can account for roughly one-third to one-half of the effect observed with TCE - greater than previously reported, but still inconsistent with TCA being the sole active moiety for this effect. However, given uncertainty as to the precise degree of contribution of TCA and due to high inter-experimental variability in estimated fractional absorption, a more precise quantitative estimate of the relative contribution of TCA may obtained through an appropriate experiment in mice simultaneously measuring TCA kinetics and TCE- and TCA-induced hepatomegaly.
authors.affiliation: National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC 20460, USA.
authors.forename: Weihsueh A
authors.initials: WA
authors.lastname: Chiu
mesh_terms: D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D006529:Hepatomegaly / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D014238:Trichloroacetic Acid / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014241:Trichloroethylene / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D014241:Trichloroethylene; D014238:Trichloroacetic Acid