Pharmacokinetics of [125I]-2-lodo-3,7,8-trichlorodibenzo-p-dioxin in mice: Analysis with a physiological modeling approach

Hw, Leung; Poland, Alan; Dj, Paustenbach; Fj, Murray; Andersen, Melvin E.

doi:10.1016/0041-008x(90)90314-k

Cited by 50 publications

(14 citation statements)

References 16 publications

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“…Biotransformation of TCDD is regarded as a detoxification process (Beatty et al., ; Ramsey et al., ; Weber et al., ; Mason and Safe, ), and TCDD toxicity is ascribed to the unchanged parent compound. As TCDD‐inducible CYPs appear to be involved in the biotransformation step, TCDD may generally be able to induce its own metabolism at high doses (Neal et al., ; Poiger and Buser et al., ; Poiger and Schlatter, ; Wroblewski and Olson, , ; Leung et al., ; Shinkyo et al., ; Inui et al., ). However, although at least guinea pigs seem to be incapable of this autoinduction (Wroblewski and Olson, ).…”

Section: Assessmentmentioning

confidence: 99%

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

143

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The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL‐PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre‐ and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005‐TEQ/g fat in blood sampled at age 9 years based on PCDD/F‐TEQs. No association was observed when including DL‐PCB‐TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F‐TEQ only was on average 2.4‐ and 2.7‐fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL‐PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.

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Section: Assessmentmentioning

confidence: 99%

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

143

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“…Level 1 models by Lawrence and Gobas (1997) and Leung et al (1988) feature two specific binding proteins (i.e., cytosolic AhR and microsomal CYP1A2) in the liver, with or without consideration of CYP1A1/2 induction. The Leung et al (1988) model was later subjected to modifications, such as incorporation of extrahepatic AhR-binding sites (muscle and skin) (Leung et al 1990b) and CYP1A1/2 induction (Leung et al 1990a). Next in complexity are the level 2 models incorporating Hill-type interactions between the TCDD-AhR complex and DREs and induction of CYP1A1/2 at the gene and protein levels Kohn et al 1993;Santostefano et al 1998;Wang et al 1997a).…”

Section: Pbpk Models Of Tcdd In Rodentsmentioning

confidence: 99%

“…8.7b), indicating that lipid content based partitioning predominated in the absence of microsomal protein induction. Leung et al (1990b) then modeled the distribution of that small dose of ITCDD affected by microsomal protein induction in the mice. Most parameters were chosen to be consistent with the previous models (Leung et al 1988).…”

Section: Level 1 Models: Binding Of Tcdd To Ahr and Cyp1a2mentioning

confidence: 99%

“…To further explore the effect of microsomal protein induction on TCDD distribution, Leung et al (1990b) conducted a pharmacokinetic experiment on 125 I-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD), which was developed as a substitute for TCDD, due to its ease of quantification even at very low doses. In their study, one group of female C57BL/6J mice was pretreated with TCDD, while a second group was pretreated with the vehicle only.…”

Section: Level 1 Models: Binding Of Tcdd To Ahr and Cyp1a2mentioning

confidence: 99%

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Dioxin and Related Compounds

2005

Physiologically Based Pharmacokinetic Modeling

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“…Two recent reports on the application of physiologically based pharmacokinetics of 1,4-dioxane (8,46) incorporated the kinetic constants for the formation of the principal metabolite (P-hydroxy ethylacetic acid). The model accommodated the administration of 1,4-dioxane by the iv, inhalation, and oral routes and allowed the calculation of the surrogate delivered doses to various organs, particularly the liver.…”

Section: Ethylene Oxidementioning

confidence: 99%

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

Krewski

Withey

et al. 1994

Environ Health Perspect

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The use of physiologically based pharmacokinetic (PBPK) models has been proposed as a means of estimating the dose of the reactive metabolites of carcinogenic xenobiotics reaching target tissues, thereby affording an opportunity to base estimates of potential cancer risk on tissue dose rather than external levels of exposure. In this article, we demonstrate how a PBPK model can be constructed by specifying mass-balance equations for each physiological compartment included in the model. In general, this leads to a system of nonlinear partial differential equations with which to characterize the compartmental system. These equations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the special case of a linear pharmacokinetic system, we present simple closed-form expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore be the primary focus of sensitivity analyses. Applications of PBPK modeling for purposes of tissue dosimetry are reviewed, including models developed for methylene chloride, ethylene oxide, 1,4-dioxane, 1-nitropyrene, as well as polychlorinated biphenyls, dioxins, and furans. Special considerations in PBPK modeling related to aging, topical absorption, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic models for neoplastic transformation of stem cells in the target tissue is explored. Environ Health Perspect 1 02(Suppl 1 1): 37-50 (1994)

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Pharmacokinetics of [125I]-2-lodo-3,7,8-trichlorodibenzo-p-dioxin in mice: Analysis with a physiological modeling approach

Cited by 50 publications

References 16 publications

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Dioxin and Related Compounds

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

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