TCDD ELIMINATION KINETICS: MODIFICATION OF THE CARRIER ET AL. (1995) MODEL TO INCLUDE AN ADDITIONAL ELIMINATION MECHANISM Robert C. Brunet 1 , Lesa L. Aylward 2 , Gaétan Carrier 3 , and Sean M. Hays 4 1 Département de mathématiques et de statistique and Centre de recherches mathématiques, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montreal, QC, Canada, H3C 3J7 2 Exponent, Inc., 1800 Diagonal Road, Suite 355, Alexandria, VA 22314 3 Département de santé environnementale et santé au travail, Faculté de Médicine, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montréal, QC, Canada, H3C 3J7 4 Exponent, Inc., 4940 Pearl East Circle, Suite 300, Boulder, CO 80301 Introduction The object of this paper is to present a modification to a previously developed physiologically based model 1,2 by Carrier and coworkers for simulating the metabolism and elimination of TCDD. Recent reports on three patients from Austria with moderate to extremely high body burdens of TCDD 3,4 and on the Seveso population 5 confirm the existence of a concentration dependence for the elimination of TCDD from the body. These data demonstrate that at substantially elevated body burdens, elimination rates for TCDD are much higher than previously estimated based on data from persons with body burdens below about 500 ppt. Average elimination half-lives of <1 to 3.6 years were observed in two women and one man exposed to very high or moderate levels of TCDD in Vienna, Austria, in 1997 (peak measured serum lipid levels of 144,000, 26,000, and 856 ppt) 3,4 and in adults exposed in Seveso, Italy, where multiple measurements of serum lipid TCDD levels were carried out beginning within two weeks after the accident (initial levels were over 2,000 ppt for many persons). 5,6 A dependence of TCDD elimination rate on body burden has been observed in rodents (reviewed by Carrier et al.), 1 and a similar increased elimination rate at high concentrations was reported for polychlorinated dibenzofurans in humans. 7 The dose dependence of elimination rate in rodents has been hypothesized to occur secondary to induction of the TCDD binding protein CYP1A2 in the liver, and data demonstrating CYP1A2 induction suggest a similar possibility in the Austrian patients. 3 The original Carrier et al. model postulated that, at any moment, the amount of TCDD elimination is proportional to the current concentration in the liver. However, the proportion of body burden in liver was modeled to increase in a non-linear, saturable manner as body concentration increases (following a Michaelis-Menten relationship), theoretically as a result of the induction of the binding protein CYP1A2 in the liver. The key parameters for the model are k e , the liver elimination rate; f min and f max , the minimum and maximum fractions of body burden that distribute to the liver; and K, the concentration at which the proportion distributing to liver reaches half- maximum. The model predicts the time-dependent TCDD concentrations in the body and in liver and fat tissue, and can incorporate changes in body weight and body composition, which can have significant effects on tissue concentrations. Organohalogen Compounds, Volumes 60-65, Dioxin 2003 Boston, MA Organohalogen Compounds 65, 226-229 (2003) 226