A Physiologically Based Pharmacokinetic (PB-PK) Model for 1,2-Dichlorobenzene Linked to Two Possible Parameters of Toxicity

Hissink, A.M.; Ommen, Ben van; Krüse, Jacob; Bladeren, P.J. van

doi:10.1006/taap.1997.8184

Cited by 20 publications

(9 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Model predictions for TC deviated on average less than 40% from experimentally observed values, which is relatively good compared with the current state of the art for PBK models of exogenous substances (26)(27)(28)45 ). This is all the more remarkable because the model was obtained via a relatively straightforward translational adaptation of our previously developed mouse model.…”

Section: Discussionsupporting

confidence: 55%

“…The average relative deviations between model predictions and experimental data were 36%, 49%, and 43% for TC, HDL-C, and non-HDL-C, respectively. This is considered successful within the present state-of-the-art of PBK modeling, where quantitative predictions may generally be correct within one order of magnitude (25)(26)(27)(28). These model predictions are generally within the experimental error margin given the small patient groups sizes (generally n < 20).…”

Section: Model Validationmentioning

confidence: 94%

See 1 more Smart Citation

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

Pas

Woutersen

Ommen

et al. 2012

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org these cholesterol modeling studies present models that focus on LDL cholesterol (LDL-C) metabolism in plasma ( 4-6 ) or on cellular cholesterol metabolism ( 7 ). These models do not represent all relevant components of whole body cholesterol homeostasis because they lack reactions such as cholesterol absorption and biosynthesis in organs, which are the reactions targeted by important cholesterol-lowering drugs, such as statins. This implies that the models cannot fully explain how relevant plasma cholesterol-associated biomarkers are infl uenced by these drug interventions.We have, therefore, developed an in silico physiologically based kinetic (PBK) model for plasma cholesterol in the mouse that includes all relevant reactions and that correctly predicts the plasma cholesterol levels of a large variety of mouse strains with gene knockouts related to cholesterol metabolism ( 11 ). The model, of which the structure is given in Fig. 1 , is able to predict HDL cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), and total plasma cholesterol (TC) concentrations ( 12 ) as well as the intra-organ pools representing hepatic free cholesterol (Liv-FC), peripheral cholesterol (Per-C), intestinal cholesterol ester (Int-CE), hepatic cholesterol ester (Liv-CE), and intestinal free cholesterol (Int-FC) in the mouse. A similar model for humans will be of considerable value in predicting effects of drugs and genetic variations on plasma cholesterol concentrations. Therefore, the aim of this work is to adapt our model to a human version.Turnover of cholesterol in humans is quantitatively and qualitatively different from that in mice ( 13 ). Qualitative difference resides mainly in the protein cholesteryl ester In silico modeling has proven to be a useful tool in biology because it allows the study of interspecies variation and regulation of homeostasis and allows the integration of information from various sources ( 1-3 ). There are several modeling efforts on cholesterol ( 4-7 ), an important biomarker for the risk for cardiovascular events ( 8-10 ). Most of Manuscript received 4 September 2012 and in revised form 28 September 2012. Published, JLR Papers in Press, September 29, 2012 DOI 10.1194 A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans Abbreviations: C, cholesterol (sum of FC and CE); CE, cholesterol ester; CETP, cholesterol ester transfer protein; FC, free cholesterol; FH, familial hypercholesterolemia; GWAS, genome-wide association study; PBK, physiologically based kinetic; SC, sensitivity coeffi cient; SLOS, Smith-Lemli-Opitz syndrome; TC, total plasma cholesterol (sum of HDL-C and non-HDL-C).

show abstract

Section: Discussionsupporting

confidence: 55%

Section: Model Validationmentioning

confidence: 94%

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

Pas

Woutersen

Ommen

et al. 2012

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…The predicted formation of 4-allylphenol and 1′-hydroxyestragole glucuronide were in the same order of magnitude as the reported levels of these metabolic routes in humans exposed to estragole (Sangster et al , 1987), which can be considered acceptable within the present state-of-the-art of integrating in vitro data and PBBK modeling (Hissink et al , 1997; Lupfert and Reichel, 2005; Quick and Shuler, 1999), and which might provide an indication that the critical metabolic pathways have been captured in the model. For a more complete evaluation of the performance of the model, however, additional in vivo data are needed, especially on the plasma levels of estragole and/or its metabolites.…”

Section: Discussionmentioning

confidence: 55%

Use of Physiologically Based Biokinetic (PBBK) Modeling to Study Estragole Bioactivation and Detoxification in Humans as Compared with Male Rats

Punt

Paini

Boersma

et al. 2009

Toxicological Sciences

150

View full text Add to dashboard Cite

The extent of bioactivation of the herbal constituent estragole to its ultimate carcinogenic metabolite 1′-sulfooxyestragole depends on the relative levels of bioactivation and detoxification pathways. The present study investigated the kinetics of the metabolic reactions of both estragole and its proximate carcinogenic metabolite 1′-hydroxyestragole in humans in incubations with relevant tissue fractions. Based on the kinetic data obtained a physiologically based biokinetic (PBBK) model for estragole in human was defined to predict the relative extent of bioactivation and detoxification at different dose levels of estragole. The outcomes of the model were subsequently compared with those previously predicted by a PBBK model for estragole in male rat to evaluate the occurrence of species differences in metabolic activation. The results obtained reveal that formation of 1′-oxoestragole, which represents a minor metabolic route for 1′-hydroxyestragole in rat, is the main detoxification pathway of 1′-hydroxyestragole in humans. Due to a high level of this 1′-hydroxyestragole oxidation pathway in human liver, the predicted species differences in formation of 1′-sulfooxyestragole remain relatively low, with the predicted formation of 1′-sulfooxyestragole being twofold higher in human compared with male rat, even though the formation of its precursor 1′-hydroxyestragole was predicted to be fourfold higher in human. Overall, it is concluded that in spite of significant differences in the relative extent of different metabolic pathways between human and male rat there is a minor influence of species differences on the ultimate overall bioactivation of estragole to 1′-sulfooxyestragole.

show abstract

“…Technical-grade o-DCB contains p-dichlorobenzene (p-DCB; 17%) and m-dichlorobenzene (m-DCB; 2%) [12,13]. Technical-grade o-DCB contains p-dichlorobenzene (p-DCB; 17%) and m-dichlorobenzene (m-DCB; 2%) [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…o-Dichlorobenzene (o-DCB) is used in the production of pesticides and other chlorinated compounds such as solvents, fumigants, industrial odor-control agents, and metal polishes. Technical-grade o-DCB contains p-dichlorobenzene (p-DCB; 17%) and m-dichlorobenzene (m-DCB; 2%) [12,13]. O-dichlorobenzene did not show any estrogenic activity in a yeast two-hybrid assay up to a concentration of 1 mM [14].…”

Section: Introductionmentioning

confidence: 99%

IN VITRO AND IN VIVO ESTROGENICITY AND TOXICITY OF o-, m-, AND p-DICHLOROBENZENE

Versonnen¹,

Arijs²,

Verslycke³

et al. 2003

Environ Toxicol Chem

View full text Add to dashboard Cite

The estrogenicity of o-, m-, and p-dichlorobenzene (DCB) was evaluated with a yeast estrogen screen (YES) and zebrafish (Danio rerio) vitellogenin (VTG) assays. With the YES, p-DCB and m-DCB were found to be estrogenic in a concentration-responsive manner. The relative potency measured with the YES (relative to 17beta-estradiol) was 2.2 x 10(-7) for p-DCB and 1.04 x 10(-8) for m-DCB. Following acute toxicity tests with the zebrafish, plasma VTG production was measured to examine the in vivo estrogenic activity of the three compounds after a 14-d exposure. Adult zebrafish were exposed to different concentrations of o-, m- and p-DCB, ranging from 0.1 to 32 mg/L; ethynylestradiol ([EE2]; 5 ng/L, 10 ng/L, 50 ng/L, and 100 ng/L) was used as a positive control. After exposure, blood samples were taken and protein electrophoresis was performed to determine the relative VTG content. Gonadosomatic indices (GSI) and condition factors (CF) were also calculated. Elevated VTG levels and decreased female GSIs were found in fish exposed to > or = 5 ng EE2/L and in fish exposed to > or = 10 mg p-DCB/L. Low GSIs coincided with high levels of VTG in the blood of female zebrafish. This relation was not only found in fish exposed to EE2 but also in controls and fish exposed to DCB. Therefore, a direct or indirect effect of VTG on the GSI is suggested rather than a direct toxic effect of the tested compounds on the gonads.

show abstract

A Physiologically Based Pharmacokinetic (PB-PK) Model for 1,2-Dichlorobenzene Linked to Two Possible Parameters of Toxicity

Cited by 20 publications

References 29 publications

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans

Use of Physiologically Based Biokinetic (PBBK) Modeling to Study Estragole Bioactivation and Detoxification in Humans as Compared with Male Rats

IN VITRO AND IN VIVO ESTROGENICITY AND TOXICITY OF o-, m-, AND p-DICHLOROBENZENE

Contact Info

Product

Resources

About