The elimination of TCDD in mammals depends on diffusion into and out of adipose tissue, metabolism, hepatic sequestration, and hepatic elimination rate. The present study examined the relationship between these factors using a PBPK model. The Emond et al. (2004)
PBPK model indicates that the t1/2
of TCDD increases with increasing exposure, which is inconsistent with some experimental () and human data suggesting that the t1/2
decreases with exposure. Modification of the Emond et al. (2004)
model to include inducible hepatic elimination better fits the experimental data of Santostefano et al. (1998)
and Walker et al. (1999)
. With an inducible elimination, the t1/2
of TCDD varies from approximately 75 days to 10 days after exposures ranging from 10−3
μg TCDD/kg, respectively.
The inducible elimination model describes the elimination rate as a function of CYP1A2 induction. TCDD induces several xenobiotic-metabolizing enzymes, including CYP1A1, CYP1A2, and CYP1B1. The role of these enzymes in the metabolism of TCDD is not clear because of limited data on in vitro
and in vivo
metabolism of TCDD. The role of CYP1A in the metabolism of TCDD is inferred from in vitro
metabolism of lesser chlorinated dioxins or 2,3,7,8-tetrachloro-dibenzofuran (Olson et al. 1995
; Shinkyo et al. 2003
; Tai et al. 1993
). In vivo
studies examining biliary elimination of radioactivity in rats treated with [H3
]TCDD have not been able to demonstrate inducible elimination of TCDD-derived radioactivity (Kedderis et al. 1991
). Poiger and Schlatter (1985)
observed a doubling of the biliary elimination of TCDD in dogs pretreated with TCDD, indicating a role for CYP1A in the elimination of TCDD.
One of the problems in quantifying the role of CYP1A2 in the metabolism and elimination of TCDD is that CYP1A2 both binds and metabolizes TCDD. TCDD inhibits rat and human CYP1A2 activity (Staskal et al. 2005
). In CYP1A2
knockout mice, there is no hepatic sequestration of TCDD, adipose tissue TCDD concentrations are higher, and the levels of metabolites in urine and feces are lower compared with wild-type mice (Diliberto et al. 1999
; Hakk and Diliberto 2002
). These studies as a whole indicate that CYP1A2 and other CYPs are involved in the metabolism and elimination of TCDD.
The inducible elimination model predicts that the terminal elimination t1/2
of TCDD increases approximately 10-fold, whereas the elimination rate from hepatic tissue increases > 40-fold. One possible explanation for this discrepancy is that diffusion into and out of adipose tissue is the rate-limiting step in the elimination of TCDD at low exposures and that metabolic elimination is the rate-limiting step at high exposures. The model predicts that estimates of the t1/2
are more sensitive to changes in BMI at low exposures than at higher exposures. When significant induction of CYP1A2 occurs, there is an increase in hepatic sequestration and elimination, which dampens the effects of changes in BMI. These observations are consistent with experimental data in the CYP1A2 knockout mouse (Diliberto et al. 1999
; Hakk and Diliberto 2002
Pharmacokinetic models for TCDD describe its elimination in a variety of ways. The Andersen et al. (1993)
model describes induction as a function of receptor occupancy multiplied by a species-specific adjustment factor designated as “fold.” For rats, this parameter was assigned a value of 1 (Andersen et al. 1993
), resulting in a doubling of TCDD metabolism over the basal rate. Carrier et al. (1995a
used a simple first-order elimination process that is a function of total hepatic TCDD concentrations. In the Carrier et al. model, hepatic concentrations increase with dose in a nonlinear manner because of hepatic sequestration. As the fraction of TCDD in the liver increases from 15 to 70%, there is a 5-fold maximum induction of the elimination rate in rats. For humans, the model estimates that the fraction of TCDD in the liver ranges from 1 to 70%, resulting in an approximately 70-fold induction of TCDD elimination at high exposures (Carrier et al. 1995a
). The Kohn et al. (1996)
model uses Hill kinetics to describe the elimination of TCDD with a Hill exponent of greater than unity. The Kohn et al. (1996)
model also includes a biliary elimination of TCDD that is a function of a TCDD-induced hepatic lytic rate (hepatotoxicity) and a measure of cumulative exposure. In the Kohn et al. (1996)
model, once the cells die, the TCDD is eliminated through the bile into the gut with a linear rate, implying diffusion. The difference in the description of the elimination pathways between these models is based on the lack of known metabolic processes involved in the elimination of TCDD.
TCDD metabolism may not be the only route of elimination of TCDD. Aylward et al. (2005)
extended the Carrier et al. (1995a
model to include lipid partitioning of TCDD from circulation into the large intestine followed by fecal elimination, based on the work of Moser and McLachlan (2001). Although this pathway is not described in the present model, the elimination of TCDD from the blood into the intestines is indirectly accounted for in the optimized elimination rate. Our ability to discriminate between these different modeling approaches is diminished by our lack of understanding of the enzymes metabolizing TCDD and the role of lipid partitioning and hepato-toxicity in the pharmacokinetics of TCDD.
The dose-dependent elimination of dioxins can influence exposure assessments in epidemiologic studies assessing the potential adverse health effects of dioxins. Several of the epidemiologic studies examine the relationship between dioxin exposure and adverse health effects. Some of these analyses use a first-order elimination rate from present measured body burdens to back-calculate TCDD body burdens at the initial exposure (Crump et al. 2003
; Steenland et al. 2001
). Aylward et al. (2005)
and Emond et al. (2005)
suggest that using a pharmacokinetic model with dose-dependent elimination results in nonlinear relationships between measured body burdens and predicted peak body burdens. Applying PBPK models that include inducible elimination rates to the epidemiologic data may result in quantitatively different relationships between exposure and adverse health effects observed in these studies.