Route Extrapolation Of MTBE Pharmacokinetics In Rats
Leavens, T; Borghoff, S
| HERO ID | 1455494 |
|---|---|
| In Press | No |
| Year | 2006 |
| Title | Route Extrapolation Of MTBE Pharmacokinetics In Rats |
| Authors | Leavens, T; Borghoff, S |
| Journal | Toxicological Sciences |
| Volume | 90 |
| Issue | 1-S |
| Abstract | Methyl tertiary-butyl ether (MTBE), an oxygenating fuel additive, is a common groundwater contaminant and causes male rat renal tumors at high inhalation exposures. MTBE is primarily metabolized to tertiary-butyl alcohol (TBA), which also causes renal tumors in male rats following chronic exposure. The pharmacokinetics of MTBE and TBA in rats has been described previously with a physiologically based pharmacokinetic (PBPK) model for single exposures by oral gavage or inhalation (Borghoff et al., 1996, Fundam. Appl. Toxicol., 30, 264-75). The model has not been used to predict the pharmacokinetics of MTBE and TBA from chronic drinking water, oral gavage, or inhalation exposures, which will be important for extrapolating effects from chronic rodent exposures to humans. The purpose of this work was to compare PBPK model predictions of the pharmacokinetics of MTBE and TBA in rats from drinking water, oral gavage, and inhalation exposure. The scenarios included exposure via drinking water (10-2ml increments) and oral gavage at both 1 and 15000 ppm MTBE vs. 6 h/d inhalation exposure to 400 and 3000 ppm MTBE for 5 days. Water concentrations represented high environmental concentrations (1 ppm) or concentrations resulting in carcinogenic responses in rats following chronic oral exposure (15000 ppm). Inhalation concentrations were the current NOAEL and LOAEL for MTBE. Model predictions of Cmax, Tmax, AUC, and steady state concentrations of MTBE and TBA in blood were compared among the exposure scenarios. The model predicted significant differences in the pharmacokinetics following drinking water exposure versus oral gavage, with inhalation exposure resembling a drinking water exposure scenario. Differences in TBA pharmacokinetics among exposures were mainly due to slow clearance resulting in accumulation over time. The model predictions of the pharmacokinetics of TBA can be used to extrapolate relevant effects among exposure scenarios in rats. |
| Is Certified Translation | No |
| Dupe Override | 1455494 |
| Is Public | Yes |
| Language Text | eng |