Physiologically Based Pharmacokinetic Model for Developmental Exposures to TCDD in the Rat

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent developmental toxicant in rodents, and these effects occur at exposures similar to background human body burdens. A physiologically based pharmacokinetic (PBPK) model can aid in quantitatively describing the relationship between exposure, dose, and response. The aim of this work was the development a PBPK model to describe the relationship between maternal TCDD exposure and fetal TCDD concentrations during critical windows of susceptibility in the rat. This PBPK model is a modification of an eight-compartment model that describes the adult female rat. The modified model reduces the compartments from eight to four maternal compartments (liver, fat, placenta and rest of the body). Activation of the placental compartment and a separate fetal compartment occurs during gestation. The systemic circulation connects the maternal compartments. The physiological and biochemical parameters were obtained from the literature. The model validation used experimental data from acute and subchronic exposures prior to and during gestation. The simulations predict the TCDD tissue concentrations of the maternal compartments within the standard deviation of the experimental data. The model overestimates the fetal concentrations by approximately a factor of two at low subchronic exposures, but does predict the fetal tissue concentrations within the range of the experimental data at the higher exposures. This model may provide a framework for the development of a human PBPK model to estimate fetal TCDD concentrations in human health risk assessments.

Metabolism of 2,6-Dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl Ether (Pyridalyl) in Rats after Repeated Oral Administration and a Simple Physiologically Based Pharmacokinetic Modeling in Brown and White Adipose Tissues

“…The elimination rate from white fat calculated with the equation {P w / [K w ϫ V w ϫ (1 ϩ P w /Q w )]} (from eq. 1) was very low (0.0028/h) and was comparable with that published for TCDD (0.0016/h) (Emond et al, 2004).…”

“…The values of equilibrium coefficient (K), absorption rate (k), permeability (P), and unbound fraction times the hepatic intrinsic clearance (f ϫ CL int ) were optimized by model fitting to the datasets as follows. The values of equilibrium coefficient (K) and absorption rate (k) were initially obtained from Table 6 and data of TCDD (Emond et al, 2004), respectively, and permeability (P) was presumed from distribution and elimination rate of 14 C concentration in adipose tissues (Tables 2 and 3 of the present study). The 14 C concentration in adipose tissues was considered as the pyridalyl concentration because the majority of 14 C in adipose tissue was the result of pyridalyl itself.…”

“…The 14 C concentrations in white adipose tissues increased until day 14. Adipose tissues (brown and white) showed the (Roth et al, 1993) and the volume fraction for the rest of the body were estimated from the total volume fraction of 91% (Emond et al, 2004). b Values are from the previous literature (Roth et al, 1993), including the percentage of cardiac output of the rest of the body (Emond et al, 2004).…”

“…Therefore, we also used such a model for fitting the observed data, and model parameters were determined to quantitatively assess the pharmacokinetics of pyridalyl in rats. Relevant data for lipophilic compounds, such as TCDD, chlordecone, p,pЈ-DDE, and hexachlorobenzene, have been generated previously (Roth et al, 1993;Li et al, 1995;You et al, 1999;Evans and Andersen, 2000;Wang et al, 2000;Emond et al, 2004;Lu et al, 2006;Belfiore et al, 2007), allowing direct comparison. Thus, the present report deals with metabolism ( 14 C excretion into feces, urine, expired air; 14 C concentrations in tissues including brown and white fat; and amounts of metabolites in excreta and tissue) of [dichlorophenyl-14 C]pyridalyl in male and female rats during and after repeated oral administration for 14 consecutive days at 5 mg/kg/day to determine the extent of accumulation and elimination of accumulated radioactivity.…”

Risks and Management of Dioxins and Dioxin-like Compounds in Baltic Sea Fish: An Integrated Assessment

“…Petroff et al (2001) even maintained that the most critical difference between rats and humans regarding risks from dioxins is their kinetics. Emond et al ( , 2004 estimated by a modification of the Wang et al (1997) model for some DLCs elimination rates 20-fold those of TCDD in rats while the relative potency factors can vary over 2 orders of magnitude.…”