Toxicological Sciences, Vol 49, 172-185, Copyright © 1999 by Society of Toxicology
DA Keys, DG Wallace, TB Kepler and RB Conolly
Di(2-ethylhexyl) phthalate (DEHP), a commercially important plasticizer,
induces testicular toxicity in laboratory animals at high doses. After oral
exposure, most of the DEHP is rapidly metabolized in the gut to
mono(2-ethylhexyl) phthalate (MEHP), which is the active metabolite for
induction of testicular toxicity. To quantify the testes dose of MEHP with
various routes of exposure and dose levels, we developed a physiologically
based pharmacokinetic (PBPK) model for DEHP and MEHP in rats. Tissue:blood
partition coefficients for DEHP were estimated from the n-octanol: water
partition coefficient, while partition coefficients for MEHP were
determined experimentally using a vial equilibration technique. All other
parameters were either found in the literature or estimated from blood or
tissue levels following oral or intravenous exposure to DEHP or MEHP. A
flow-limited model failed to adequately simulate the available data.
Alternative plausible mechanisms were explored, including diffusion-limited
membrane transport, enterohepatic circulation, and MEHP ionization
(pH-trapping model). In the pH-trapping model, only nonionized MEHP is free
to become partitioned into the tissues, where it is equilibrated and
trapped as ionized MEHP until it is deionized and released. All three
alternative models significantly improved predictions of DEHP and MEHP
blood concentrations over the flow-limited model predictions. The pH-
trapping model gave the best predictions with the largest value of the log
likelihood function. Predicted MEHP blood and testes concentrations were
compared to measured concentrations in juvenile rats to validate the
pH-trapping model. Thus, MEHP ionization may be an important mechanism of
MEHP blood and testes disposition in rats.
ARTICLES
Quantitative evaluation of alternative mechanisms of blood and testes disposition of di(2-ethylhexyl) phthalate and mono(2-ethylhexyl) phthalate in rats [published erratum appears in Toxicol Sci 1999 Nov;52(1):140]
Department of Statistics, North Carolina State University, Raleigh 27695, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. A. Keys, I. R. Schultz, D. A. Mahle, and J. W. Fisher A Quantitative Description of Suicide Inhibition of Dichloroacetic Acid in Rats and Mice Toxicol. Sci., December 1, 2004; 82(2): 381 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Keys, J. V. Bruckner, S. Muralidhara, and J. W. Fisher Tissue Dosimetry Expansion and Cross-Validation of Rat and Mouse Physiologically Based Pharmacokinetic Models for Trichloroethylene Toxicol. Sci., November 1, 2003; 76(1): 35 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Andersen, R. Sarangapani, R. H. Reitz, R. H. Gallavan, I. D. Dobrev, and K. P. Plotzke Physiological Modeling Reveals Novel Pharmacokinetic Behavior for Inhaled Octamethylcyclotetrasiloxane in Rats Toxicol. Sci., April 1, 2001; 60(2): 214 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Mylchreest, D. G. Wallace, R. C. Cattley, and P. M. D. Foster Dose-Dependent Alterations in Androgen-Regulated Male Reproductive Development in Rats Exposed to Di(n-butyl) Phthalate during Late Gestation Toxicol. Sci., May 1, 2000; 55(1): 143 - 151. [Abstract] [Full Text] [PDF]
|
|