Severe 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) intoxication: kinetics and trials to enhance elimination in two patients

Abstract

In spring 1998, two women were diagnosed with severe 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) intoxication. Over the following 3 years, TCDD levels were monitored under various attempts to enhance its elimination, and the half-lives were evaluated. Olestra, a non-digestible, non-absorbable dietary fat substitute, was continuously administered to the patients either as pure substance or in potato-chips. Additionally, in the more severely contaminated patient, we studied whether low-density lipoprotein (LDL)-apheresis, an extracorporeal means of blood lipid elimination, was effective in reducing the TCDD body burden. The blood concentrations initially measured in spring 1998 were 144,000 pg/g blood fat in patient 1 and 26,000 pg/g in patient 2, the highest levels ever measured in adults. In March 2001, concentrations in blood fat were 35,900 and 9,500 pg/g, corresponding to overall elimination half-lives of 560 days (1.5 years) in patient 1 and 1050 days (2.9 years) in patient 2, which are considerably shorter than median values of 7-9 years reported for background and moderate exposure levels. Calculations of the TCDD half-lives and measurements of TCDD elimination via different routes allowed the calculation of an unidentified route of elimination, representing 78 and 62% of the overall elimination in patient 1 and 2, respectively, probably due to an induced hepatic metabolism caused by the high TCDD exposure. As previously reported, administration of olestra was found to be effective in increasing the fecal excretion of TCDD. Due to the short half-lives in our patients, the effect of olestra on the overall elimination was relatively small, but is expected to be much greater for 'normal' half-lives. LDL-apheresis was shown to eliminate TCDD, corresponding to the eliminated blood fat. When employed twice a week, the amount of TCDD excreted by this method was comparable to fecal excretion. In view of costs and time involved, LDL-apheresis does not seem to be justified for enhancement of TCDD elimination.

Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort

“…(Schlummer et al, 1998;Rohde et al, 1999;Kitamura et al, 2001a;Moser and McLachlan, 2001;Geusau et al, 2002). This model assumes that unchanged fecal TCDD stems from two sources: (1) elimination from circulating blood lipid through partitioning in the larger intestine (proportional to the adipose TCDD burden Q a in ng), and (2) pass-through elimination of unabsorbed TCDD from dietary intake ( Figure 2).…”

“…Elimination half-lives of less than 1 to 3.6 years were estimated in two women and one man who were exposed to very high levels of TCDD in Vienna, Austria, in 1997 (peak measured serum lipid levels of 144,000, 26,000, and 856 ppt) Geusau et al, 2002) and in adults during the first 3 years after the Seveso, Italy, accident (initial levels typically over 2,000 ppt) (Michalek et al, 2002). Previous estimates of the half-life of elimination for TCDD have ranged from about 7 to 9 years based on serial measurements in the Ranch Hand population or occupationally exposed workers (Flesch-Janys et al, 1996;Michalek and Tripathi, 1999;Rohde et al, 1999).…”

“…In addition, there is evidence that unchanged TCDD partitions on a lipid basis into bile and thus is excreted into feces as well (Kitamura et al, 2001b). Five recent studies provide data that allow assessment of the rate of partitioning of TCDD from circulating lipids into fecal contents (Schlummer et al, 1998;Rohde et al, 1999;Kitamura et al, 2001a;Moser and McLachlan, 2001;Geusau et al, 2002).…”

“…However, recent data from human populations (Rohde et al, 1999;Geusau et al, 2002;Moser and McLachlan, 2002) suggest that the amount of unchanged TCDD eliminated cannot account for the rate of disappearance of TCDD in moderately to highly exposed persons. In combination with data that show inducible hepatic metabolism of TCDD in animals (Olson et al, 1994;Hu and Bunce, 1999), these data suggest that the hepatic elimination of TCDD modeled in the Carrier et al (1995a, b) model is through hepatic metabolism and not elimination of the unchanged parent compound.…”

“…This paper describes a modification to the original Carrier et al (1995a, b) toxicokinetic model structure to account for lipid-based elimination. The modified model was fit to serial serum lipid TCDD sampling data for three persons from Vienna, Austria, whose TCDD exposure has been described in the literature Geusau et al, 2002) and to 36 adults exposed during the Seveso accident. The resulting range of fitted parameters for all 39 adults provides an indication of the variability in elimination behavior of TCDD in the adult population.…”