Modeling of the Toxicokinetics of Polychlorinated Dibenzo-p-dioxins and Dibenzofurans in Mammalians, Including Humans

Carrier, Gaétan; Brunet, Robert C.; Brodeur, Jean‐Paul

doi:10.1006/taap.1995.1069

Cited by 66 publications

(58 citation statements)

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“…The fast elimination within the first 0.27 years followed by a slower rate after 3 years is consistent with the expected pattern in a two-compartment open model (Shargel and You, 1985 ), with a distribution phase of rapid elimination followed by a slower elimination phase. This pattern is also consistent with changes in the rate of whole -body elimination of TCDD observed in rats (Carrier et al, 1995 ); in animals receiving a single dose of 300 ng TCDD /kg body weight, the simulated half -life 3 days after exposure was 9.4 days and the half -life increased to 61.01 days at 91 days after exposure. The same authors observed a similar phenomenon in a Yu-Cheng patient exposed to 2,3,4,7,8 -pentaCDF for 38 weeks; the simulated half -life was 1.66 years 4 years after exposure and 31.05 years 50 years after exposure.…”

Section: Discussionsupporting

confidence: 85%

Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of operation Ranch Hand

Michalek¹,

Pirkle

Needham

et al. 2002

J Expo Sci Environ Epidemiol

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A combined analysis of 2,3,7,8 -tetrachlorodibenzo -p -dioxin ( TCDD ) elimination in Seveso adults and Ranch Hand veterans found a period of fast elimination within the first 0.27 years after exposure in Seveso, followed by a period of slower elimination between 3 and 16.35 years from exposure. The mean TCDD elimination rate within the first 0.27 years after exposure among six adult males in the Seveso cohort was 2.0646 year À 1 ( half -life = 0.34 years ). The mean rate from 3 to 16.35 years was 0.1011 year À 1 ( half -life = 6.9 years ). The mean Ranch Hand elimination rate, 00924 year À 1 ( half -life = 6.9 years ), measured between 9 and 33 years after exposure, was significantly less than the Seveso mean in the first 0.27 years after exposure, but not significantly different from the Seveso mean between 3 and 16.35 years after exposure. The fast elimination within the first 0.27 years followed by a slower rate after 3 years is consistent with the expected pattern in a two -compartment open model, with a distribution phase of rapid elimination followed by a slower elimination phase.

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Section: Discussionsupporting

confidence: 85%

Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of operation Ranch Hand

Michalek¹,

Pirkle

Needham

et al. 2002

J Expo Sci Environ Epidemiol

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“…Human data are insufficient at present to determine the exact shape and parameters of the dose-response curve for the liver fraction due to induction of CYP1A2 in the liver. The values for f h min , f h max , and K used in this modeling were those based on fits to animal data and previous modeling of human data (Carrier et al, 1995b(Carrier et al, , 1999; the fitting procedure in this paper varied only the basic hepatic elimination rate k e . However, due to the structure of the model, similar results (in terms of elimination behavior and fits to the serial sampling data) could be obtained by covarying k e and K. Similarly, f h max and k e could be adjusted in opposite directions to result in similar elimination behavior.…”

Section: Discussionmentioning

confidence: 99%

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

Aylward

Brunet

Carrier

et al. 2004

J Expo Sci Environ Epidemiol

133

103

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Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order backextrapolations with half-lives of 7-9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDD's carcinogenic potency based on such data.

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“…There is evidence from observations in rodents that, with increasing TCDD dosage, increasing amounts of the applied substance accumulate in the liver, leading to an increased hepatic/adipose tissue concentration ratio (Abraham et al 1988) as a result of the dose-dependent hepatic binding of TCDD to CYP1A2 (Diliberto et al 1997). Based on these observations, a kinetic model was developed by Carrier and coworkers (Carrier et al 1995a(Carrier et al , 1995b, assuming two compartments (liver and fat), increasing fractionating of TCDD in liver with increasing body burdens, and with elimination by the liver depending on its TCDD burden. This model predicts a non-linear elimination with shorter half-lives in hepatic than in adipose tissue, which increase with time after acute exposure.…”

Section: Hepatic Metabolism and Non-linear Kinetics?mentioning

confidence: 97%

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

Geusau

Schmaldienst

Derfler

et al. 2002

Archives of Toxicology

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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.

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Modeling of the Toxicokinetics of Polychlorinated Dibenzo-p-dioxins and Dibenzofurans in Mammalians, Including Humans

Cited by 66 publications

References 0 publications

Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of operation Ranch Hand

Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of operation Ranch Hand

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

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

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