The contribution of protein binding in the liver to the body burden of dibenzo-p-docins and dibenzo-p-furans: Analysis by means of PBPK modeling
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Open Access
Type
Report
Language
en
Date
1999-07-31
Research Projects
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Journal Issue
Title
The contribution of protein binding in the liver to
the body burden of dibenzo-p-docins and dibenzo-p-furans: Analysis by means
of PBPK modeling
Translated Title
De invloed van eiwitbinding in de lever op de
lichaamsbelasting met dibenzo-p-dioxinen en dibenzo-p-furanen: Een analyse
m.b.v. PBPK modellering
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Abstract
In een voorgaande studie is een "Physiologisch
gebaseerd PharmacoKinetisch" (PBPK) model gebruikt om de hoeveelheid van
dibenzo-p-dioxinen en dibenzo-p-furanen in moedermelk te beschrijven.
Hierbij zijn gehalten van dioxinen en furanen in moedermelk als maat genomen
voor de totale hoeveelheid van deze stoffen in het lichaam
(lichaamsbelasting of body burden). In het PBPK model wordt ervan uitgegaan
dat de verdeling van dioxinen en furanen in het lichaam bepaald wordt door
het lipide gehalte van het bloed en de verschillende organen. Echter, voor
de lever is bekend dat de opname van dioxinen en furanen vanuit het bloed
niet alleen bepaald wordt door de hoeveelheid lipide in dit orgaan maar ook
door de binding aan eiwitten. Wanneer deze eiwitbinding wezenlijk bijdraagt
aan de lichaamsbelasting van dioxinen en furanen dan zal genoemd PBPK model
de lichaamsbelasting substantieel onderschatte. Voor
octachloro-dibenzo-p-dioxine (OCDD) is onderzocht hoe groot de bijdrage van
levereiwitbinding is aan de lichaamsbelasting van deze stof. OCDD is
gekozen vanwege zijn eigenschap om specifiek in de lever van de mens te
accumuleren. Voor het berekenen van de lichaamsbelasting is een PBPK model
gebruikt dat de binding van OCDD aan levereiwit bevat. Na levenslange
blootstelling berekent het PBPK model dat de binding van OCDD aan levereiwit
voor minder dan 6% bijdraagt aan de lichaamsbelasting. Aangezien van de
dioxinen en furanen OCDD de duidelijkste stapeling in de lever te zien geeft
mag verwacht worden dat dit percentage voor andere dioxinen en furanen nog
kleiner is. Geconcludeerd wordt dat, bij de mens, de binding van dioxinen
en furanen aan levereiwit weinig bijdraagt aan de lichaamsbelasting van deze
stoffen.
In a previous study "Physiologically Based PharmacoKinetic" (PBPK) modeling was used to estimate the amount of dibenzo-p-dioxins and dibenzo-p-furans in mother's milk. This amount is considered to reflect the total amount of dibenzo-p-dioxins and dibenzo-p-furans in the body (body burden). In the PBPK model the distribution of dioxins and furans in the body is assumed to be determined by the lipid content of the blood and the organs. However, in the mammalian liver dioxins and furans not only accumulate by uptake in the liver's lipid fraction but also by binding to hepatic proteins. When this binding substantially contributes to the body burden of dioxins and furans the mentioned PBPK model may underestimate the latter entity. In this study the contribution of hepatic protein binding to the body burden of octachloro-dibenzo-p-dioxin (OCDD) was quantified. OCDD was chosen because of its property to preferentially accumulate in the human liver. The body burden of OCDD was simulated with a PBPK model which incorporates the binding of OCDD to hepatic proteins. After life-long exposure the PBPK model calculates that the contribution of hepatic protein binding to the body burden of OCDD was less than 6%. As, of all dioxins and furans, OCDD shows the most prominent accumulation in the liver this percentage is expected to be even lower for other dioxins and furans. It is concluded that, in humans, the contribution of the hepatic protein binding of dioxins and furans to the body burden of these compounds is limited.
In a previous study "Physiologically Based PharmacoKinetic" (PBPK) modeling was used to estimate the amount of dibenzo-p-dioxins and dibenzo-p-furans in mother's milk. This amount is considered to reflect the total amount of dibenzo-p-dioxins and dibenzo-p-furans in the body (body burden). In the PBPK model the distribution of dioxins and furans in the body is assumed to be determined by the lipid content of the blood and the organs. However, in the mammalian liver dioxins and furans not only accumulate by uptake in the liver's lipid fraction but also by binding to hepatic proteins. When this binding substantially contributes to the body burden of dioxins and furans the mentioned PBPK model may underestimate the latter entity. In this study the contribution of hepatic protein binding to the body burden of octachloro-dibenzo-p-dioxin (OCDD) was quantified. OCDD was chosen because of its property to preferentially accumulate in the human liver. The body burden of OCDD was simulated with a PBPK model which incorporates the binding of OCDD to hepatic proteins. After life-long exposure the PBPK model calculates that the contribution of hepatic protein binding to the body burden of OCDD was less than 6%. As, of all dioxins and furans, OCDD shows the most prominent accumulation in the liver this percentage is expected to be even lower for other dioxins and furans. It is concluded that, in humans, the contribution of the hepatic protein binding of dioxins and furans to the body burden of these compounds is limited.
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