Physiologically Based Pharmacokinetic Model for Tetrachlorobenzyltoluenes in Rat: Comparison of in Vitro and in Vivo Metabolic Rates

H. J. Kramer*,1, H. Drenth*, M. vandenBerg*, W. Seinen*,2 and J. DeJongh{dagger}

* Research Institute of Toxicology, Utrecht University, P.O. Box 80176, 3508-TD Utrecht, The Netherlands; and {dagger} Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, Archimedesweg 31, 2333 CM Leiden, The Netherlands

Received January 9, 2001; accepted June 1, 2001


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Ugilec 141 is a technical mixture of tetrachlorobenzyltoluenes (TCBTs). It was introduced in the early 1980s as a replacement for polychlorinated biphenyls (PCBs). Based on physicochemical properties and accumulation in the environment, the use of this mixture was prohibited. To gain more insight in the toxicokinetics of these compounds in mammals, rats were exposed to a single iv bolus injection of a mixture of 3 TCBTs. At different time points after dosing, the tissue and blood concentrations of the TCBTs were determined. The adipose tissue is the main storage compartment, followed by skin and muscle. The TCBTs were rapidly eliminated from the liver and the blood, with half lives ranging from 65 to 72 h. Additionally, the tissue concentration data for all 3 TCBTs were analyzed using a physiologically based pharmacokinetic (PB-PK) model. Sensitivity analysis illustrated that the elimination of the TCBTs was not influenced by metabolism only, but also by the blood flow through the liver. Furthermore, the metabolic rates derived from the model were compared to previously reported in vitro metabolic rates. The in vitro values for the TCBTs were only a factor 2 to 3 smaller than the in vivo metabolic rates, indicating the value of in vitro techniques for a priori parameterization of PB-PK models.

Key Words: PB-PK; PCB; rat; in vitro-in vivo extrapolation; partition coefficients; metabolism; toxicokinetics.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
The technical mixture Ugilec 141 consists of tetrachlorobenzyltoluene (TCBT) isomers (Fig. 1Go). It was developed in the early 1980s as a replacement for mixtures of polychlorobiphenyls (PCBs), especially in the mining industry. Similarities have been reported between TCBTs and PCBs with respect to physicochemical properties (van Haelst, 1996Go), biochemical changes in mice (Murk et al., 1991Go), and accumulation in fish (Fuerst et al., 1987Go; Wammes et al., 1997Go). Due to the unwanted presence of Ugilec 141 in the environment and biota, the application of Ugilec 141 in new systems was prohibited by the European Union in 1994.



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FIG. 1. Chemical structure of 3 tetrachlorobenzyltoluenes (TCBTs): 3,3',4,4'-Cl4-2-Me- (TCBT 87), 3,3'4,4'-Cl4-5-Me- (TCBT 88), and 3,3',4',5-Cl4-4-Me-Tetrachlorobenzyltoluene (TCBT 94). Numbering according to Ehmann and Balschmitter (1989).

 
Presently, information of possible accumulation of TCBTs in mammals is limited. One study indicated that the mixture Ugilec 141 was eliminated faster from rat liver tissue than 2,2',4,5'5-PnCB (Bouraly, 1989).

Physiologically based pharmacokinetic (PB-PK) models have been used successfully to analyze the pharmacokinetic behavior of lipophilic substances like PCBs and dioxins (Andersen et al., 1993Go; Kedderis et al., 1993Go; Lutz et al., 1977Go, 1984Go). The parameters of such models may be obtained a priori, either from literature, in vitro studies, or by fitting the model to the experimental data or from in vivo experiments (Yang and Andersen, 1994Go). Extrapolation of in vitro metabolic rates resulted in good estimates for the in vivo metabolism of volatile and nonvolatile organic chemicals (Carlile et al., 1998Go; Houston, 1994Go; Houston and Carlile, 1997Go; Krishnan and Andersen, 1994Go), but lipophilic substances, like TCBTs have not been studied in this respect.

The aim of the present study was to determine the kinetics of TCBTs and to determine the potential of these compounds to accumulate in mammals. Hence, rats were intravenously injected with a single bolus dose of a mixture of 3 TCBT isomers (Fig. 1Go). The tissue concentrations were determined at various time points after dosing, and analyzed using a PB-PK model. Furthermore, in vitro metabolic rates were compared to in vivo metabolic rate constants.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Chemicals.
TCBT isomers 3,3',4,4'-Cl4-2-Me- (TCBT 87), 3,3'4,4'-Cl4-5-Me- (TCBT 88), and 3,3',4',5-Cl4-4-Me-Tetrachlorobenzyltoluene (TCBT 94) were kindly provided by Prof. L. Brandsma, from the department of Preparative Organic Synthesis of the Chemistry Faculty of Utrecht University, The Netherlands. The isomers are numbered according to Ehmann and Ballschmiter (1989). The purity of the isomers is > 95% (De Lang et al., 1998Go). 2,2',4,4',5,5'-HxCB (PCB 153) was obtained from Dr. Ehrenstorfer (Augsburg, Germany). The purity was > 98%. Analytical grade n-hexane and acetone were obtained from J. Baker (Deventer, The Netherlands).

Animals.
Adult male CPB:UwU rats (250–300 g) obtained from the Central Animal Laboratory Utrecht University were acclimatized for 5 days. Rats were housed individually in Macrolon III cages with filter top. Animals were maintained on a 12-h light/dark cycle under conditions of constant temperature and humidity. The rats were provided with rodent chow and tap water ad libitum. After 5 days the rats were weighed and dosed intravenously with a mixture of TCBT 87 (0.43 mg/kg), TCBT 88 (0.45 mg/kg), and TCBT 94 (0.48 mg/kg). The mixture was dissolved in a 20% tween/water (v/v) solution (polyethylenesorbitanmonooleate, Sigma, St. Louis, MO) and administered via the tail vein at a constant volume of 1 ml/kg. In vitro studies demonstrated that no interactions with respect to metabolism (Kramer et al., 2000Go) occurred at the blood concentrations obtained after application of this dose.

Animals were killed in groups of 3 over a period of 168 h (t = 6, 10, 24, 48, 96, and 168 h) after sedation with CO2 (g), which was followed by exsanguination by aorta punction. Blood was collected in glass tubes with EDTA as anticoagulant and stored at 4°C until further use. About 1 to 4 g of liver, abdominal skin, abdominal adipose tissue, and muscle from the hind leg were collected. The tissues and organs were weighed and stored at –80°C until further use. Blood from the liver was removed by perfusing with saline.

Extraction of tissues.
The frozen tissues and organs (except for blood samples) were freeze dried for 48 h. The dried samples were placed in a paper cartridge and spiked with 100 µl of PCB 153 (1.6 mg/l; internal standard) in n-hexane. Subsequently the samples were extracted with 80 ml n-hexane under reflux for 16 h (Bouraly, 1989). The recovery of the extraction was 90 ± 5.6 %. The extract was collected in preweighed flasks and the n-hexane was evaporated under nitrogen. The n-hexane extractable fat was then determined gravimetrically.

Cleanup.
Glass columns (1 cm, 20 cm length) were filled with 4 grams Florisil (mesh 60–200) deactivated with 5% water (w/w) to remove the n-hexane extractable fat (Bouraly, 1989). The column was pre-eluted with 5 ml n-hexane before adding 1 ml of the tissue sample containing maximally 100 mg fat extract. The samples were eluted with 30 ml n-hexane. The recovery of the cleanup over the column was 70 ± 3.7 %. The eluates were concentrated prior to gas chromatographic analysis to a volume of ca. 500 µl.

Blood sample cleanup.
Blood was extracted using 2 ml acetone and 2 ml n-hexane per gram blood (De Boer and Wester, 1993Go). Prior to the extraction PCB153 (1.6 mg/l) was added as an internal standard. The mixture was shaken for 30 s and centrifuged for 1 min at 3000 rpm. The extraction was repeated 3 times. The organic phase was collected in preweighed vials and evaporated at room temperature under nitrogen. The n-hexane:acetone extractable fat content was determined gravimetrically. The recovery was 101 ± 10%.

GC analysis.
The extracts were analyzed on a Carlo Erba Mega 5360 HR-GC-63Ni-Electron Capture Detector equipped with a 15 m DB5 column (ID 0.32 mm, film thickness 0.25 µm). Samples were analyzed using splitless injection according to the following temperature program. The analysis started at 70°C, after 2 min temperature increased to 255°C at 20°C/min temperature. After 5 min at 255°C, temperature increased to 280°C at a rate of 30°C/min. After 4 min at 280°C the analysis stopped. The injector temperature was set at 250°C. Splitless closing times were 30 s preinjection and 99 s postinjection. The injection volume was 2 µl. The peak areas of the different compounds were determined relative to the peak area of PCB 153. Calibration curves for each compound using the internal standard PCB153 (1.6 mg/l) were used to quantify the amount per sample. This amount was divided by the wet weight of the tissue or blood sample.

Model description.
The general model structure (Fig. 2Go) was based on a model for PCBs (Lutz et al., 1977Go, 1984Go).



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FIG. 2. Physiologically based pharmacokinetic model for the kinetics of the TCBTs in rat. V, Q, and C represent volume, blood flow, and concentration of the different compartments, respectively. PAf, PAs, and PAm represent the diffusional clearance.

 
The chemical uptake by the liver, and the remaining tissue were modeled as a flow limited process. The tissue uptake by adipose tissue, muscle, and skin was described by a diffusion limited process (Wang et al., 1997Go). It was assumed that TCBTs are eliminated by first-order metabolism in the liver only.

Model parameterization.
The physiological parameters are presented in Table 1Go. The whole body volume has been taken into account except for the bone tissue (8%) because of its limited perfusion (Brown et al., 1994Go). Tissue to blood partition coefficients (PC) were calculated according to Gallo et al. (1987). The PC for remaining tissue was set equal to the value for muscle (Table 2Go).


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TABLE 1 Physiological Parameter Values
 

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TABLE 2 Parameter Values for Calculated Partition Coefficients (Px), Fitted Diffusional Clearance Constants, and Fitted Metabolic Rate Constants after iv Injection
 
The diffusional clearance constants for the adipose tissue (PafC), muscle (PamC), skin (PasC), as well as the metabolic rate constant (Kmet) were optimized to the tissue and blood concentration data (Table 2Go) monitoring the correlations between the individual optimized parameters. A normalized sensitivity analysis was performed to determine sensitivity of the model forecast to the parameters (Evans et al., 1994Go; Ploeger et al., 2000Go) with special emphasis on the blood concentrations and the total amount metabolized, because blood can easily be sampled and the total amount metabolized provides insight in the elimination.

Simulation software.
The model equations (Appendix) were implemented in ACSL for Windows (version 11.4.1., MGA Software Inc., Concord, MA). Nelder-Mead (simplex) algorithm was used to optimize the model parameters in ACSL math (version 1.2, MGA Software Inc.).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
The highest tissue concentrations were found in the adipose tissue followed by skin, muscle, liver, and blood for all 3 TCBTs (Fig. 3Go). For blood and liver, a rapid initial decline in tissue concentration was followed by a slower terminal elimination phase (Fig. 3Go), which could be described by a first-order process. The estimated terminal half-lives from the blood were 71, 62, and 65 h for TCBT 87, 88, and 94, respectively. All tissue concentration data were described adequately with the PB-PK model (Figs. 3A, 3B, and 3CGo) using the optimized parameter values (Table 2Go). Slight overestimation of the skin and muscle concentration of TCBT 87 and TCBT 88 between 6 and 48 h after exposure was observed.



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FIG. 3. Concentration of TCBT 87 (A), TCBT 88 (B), and TCBT 94 (C) in whole blood, liver adipose tissue, skin, and muscle of the rat. The lines represent the optimized model outcome. The scatter represent mean values and standard deviation (N = 3).

 
TCBT 87 deviated from the other 2 TCBTs with respect to tissue distribution as reflected in the PCs, metabolic rate, and diffusional clearance. The partitioning to the liver (Pl) of TCBT 87 was approximately 7 times higher than for TCBT 88 and 94. The relative distribution over the adipose tissue and the liver as indicated by the ratio Pf/Pl, appeared to depend on the isomer as well. The ratios were 12, 45, and 36 for TCBT 87, 88, and 94, respectively.

The metabolic rate constant of TCBT 87 was about 5 times lower than the metabolic rates of TCBT 88 and 94. The precision of the estimation of the metabolic rates, as indicated by the coefficient of variation (CV), ranged from 6–10%, and was comparable among the isomers. The diffusional clearance constants for TCBT 87 in each tissue tended to be higher than for the other 2 compounds. These estimates were less precise relative to the metabolic rate constants for all 3 isomers, with CVs ranging from 0.5 to 35%.

In vitro metabolic rate constants, as previously determined in hepatic microsomes from male rat (Kramer et al., 2000Go) were compared to in vivo metabolic rate constants (Table 3Go). The in vitro values were a factor 2 to 3 smaller than the metabolic rate constants, obtained after optimizing the model to the in vivo data. Alternatively, optimizing the diffusional clearance only, while fixing the metabolic rate to the in vitro values, overestimates systematically the tissue and blood concentrations (data not shown).


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TABLE 3 Comparison of in Vitro (Kin vitro) and in Vivo (Kmet) Derived Metabolic Rate Constants
 
The sensitivity of the PB-PK model forecast to the parameters is depicted in Figures 4 and 5GoGo. It appeared that the blood concentrations were most sensitive to the metabolic rate (Kmet) during the distribution phase (Fig. 4Go). In addition, liver blood flow (Ql) was also a major determinant of blood concentration. An increase in the flow through the adipose tissue resulted in a slight increase in the blood concentrations (Fig. 4Go). Figure 5Go shows that Kmet and the perfusion rate of the liver played a major role in the model predictions of the total amount metabolized. The sensitivity of the model to the diffusional clearance and the flow through the fat was only marginal as indicated by the small normalized sensitivity coefficients. Similar results from the sensitivity analysis were obtained for TCBT 88 and 94 (results not shown).



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FIG. 4. Sensitivity of model predictions to the metabolic rate (Kmet), and the perfusion rates of the adipose tissue (qf), and the liver (ql). The normalized predicted change in the concentration of TCBT 87 in blood concentration upon a 1% change in the parameter values is plotted against time.

 


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FIG. 5. Sensitivity of Kmet, PAFC, Qf, and Ql on the total amount metabolized using the PB-PK models for TCBT 87. The normalized predicted change in the total amount metabolized upon a 1% change in the parameter values is plotted against time.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
The present study showed that all 3 TCBTs reached the highest concentrations in the adipose tissue followed by skin, muscle, liver, and blood. This tissue distribution of TCBTs is comparable to that of PCBs and other lipophilic compounds in rat (Jordan and Feeley, 1999Go; Moir et al., 1996Go; Van den Berg et al., 1994Go). Furthermore, the first-order elimination of the TCBTs from the liver has also been observed for PCBs (Heinrich-Hirsch et al., 1997Go; Matthews and Dedrick, 1984Go; Ryan et al., 1993Go). This confirms, in a qualitative way, our initial assumption about the comparability of the kinetics of PCBs and TCBTs. The uptake of TCBTs by the adipose tissue, muscle, and skin was presently modeled as a diffusion limited process, similar to previously reported models for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrabromodibenzo-p-dioxin (Andersen et al., 1997Go; Kedderis et al., 1993Go; Wang et al., 1997Go). Initially, Lutz and coworkers (1977) used relatively low blood flows for adipose tissue and muscle, e.g., 2.2 ml/min/100 g adipose tissue while Brown and coworkers (1994) reported a range of 18 to 48 ml/min/100 g. A reduction of the blood flow resembled the effect of a diffusion limitation, but is not fully in agreement with the physiology. The diffusional clearance constants of closely related chemicals like for TCDD and tetrabromodibenzo-p-dioxin ranged between 0.08 and 0.1 for adipose tissue, for muscle between 0.03 and 0.05, and for skin between 0.015 and 0.09 (Andersen et al., 1997Go; Kedderis et al., 1993Go; Wang et al., 1997Go). These parameter values agree with our results, suggesting a similar distribution process for TCBTs and dioxins.

Although the octanol to water partition coefficients of the TCBTs lie in the same range (log Kow 7.3–7.4), large differences in partition coefficients between the individual isomers were presently observed. TCBT 87 appeared to have the largest PCs for all tissues and the lowest fat to liver concentration ratio. The partitioning of TCBT 87 to the liver is relatively high (Pl = 25), compared to Pls used in PB-PK models for related compounds. These Pls ranged from 3 to 17 (Kedderis et al., 1993Go; Lutz et al., 1977Go; Tuey and Matthews, 1980Go). TCDD and related compounds, like some PCBs, are selectively retained by CYP1A2 in the liver, causing alterations in the fat to liver concentration ratios, comparable to that observed for TCBT 87 (Andersen et al., 1997Go, 1993Go; DeVito et al., 1998Go; Van den Berg et al., 1994Go). This suggests that the differences in tissue partitioning among the TCBTs could be explained by selective retention of TCBT 87 by CYP1A2 in the liver.

TCBT 87 also differs from the other 2 isomers with respect to its metabolic rate. TCBT 87 was metabolized slower than TCBT 88 and TCBT 94. This agrees with the results of the in vitro study (Kramer et al., 2000Go). The present study showed that in vitro metabolic rate constants were 2- to 3-fold lower than the estimated in vivo metabolic rate constants. This could be explained by the possible contribution of other tissues to the metabolism in vivo, since the in vitro data were based on metabolism in the liver only. Another aspect could be the simultaneous estimation, which could confound the values. Since the correlation matrix did not reveal significant correlations, this effect was considered limited. However, differences in binding characteristics between in vitro and in vivo may be more likely, as was demonstrated for various drugs by Obach (1997). In this study, the extrapolation of in vitro data from experiments with microsomal fractions was improved when the free fractions of the substrate in the in vitro system and in vivo were taken into account. Thus, the factor of 2 to 3 between in vitro and in vivo might reflect the differences in the free fraction.

The direct insertion of these in vitro values in the PB-PK model resulted in an overestimation of the tissue concentrations.

Sensitivity of the metabolic rate constant on the model predictions of the amount metabolized showed that this parameter played an important role during the distribution phase of the TCBTs. This observation was substantiated by the almost similar terminal half-lives of the TCBTs, while the in vivo metabolic rate constants of the TCBTs differed maximally by a factor of 5 (Table 3Go). The blood flow through the liver also contributed substantially to the elimination as indicated by the normalized sensitivity coefficient (Fig. 4Go). These findings suggest that processes other than the metabolism become rate limiting during the terminal elimination phase, e.g., redistribution from the adipose tissue.

In summary, the in vivo kinetics of TCBTs were comparable to that of PCBs, with the highest tissue concentrations in the adipose tissue. Furthermore, it was demonstrated that the tissue concentration data were adequately described by the PB-PK model. This model showed that TCBT 87 was distinct from the other 2 TCBTs with respect to tissue partitioning and metabolic rates. Additionally, the model illustrated that during the distribution phase, metabolism played an important role in the elimination of the TCBTs, while during the terminal elimination phase possible redistribution from tissue to blood becomes rate limiting.


    APPENDIX
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Mass Balance Differential Equations
For adipose tissue, skin and muscle the amount in the tissue (Ax) and tissue blood (Axb) are described by the following differential equations where CA denotes the blood concentration, Qx, Cvx, PAx, Cx, and Px denote the blood flow, venous blood concentration, diffusional clearance, and tissue: blood partition coefficient, respectively, associated with tissue x:

(1)


(2)

The amount in kidney and remaining tissue are described as follows:

(3)

Concentrations in these tissues are represented by the amount divided by the tissue volume:


(4)

Metabolism is described as a first-order process, which occurs in the liver. The liver compartment is therefore described as:

(5)

where Kmet represents the metabolic rate constant.


(6)

where Qx is the blood flow through tissue x and PAxC is a constant representing part of the diffusional clearance (PAx).


    NOTES
 
1 Present address: ILSI Europe, Av. E. Mounier 83, Box 6, B-1200 Brussels, Belgium. Back

2 To whom correspondence should be addressed at Gebouw Nieuw Gildestein, Yalelaan 2, 3584 CL Utrecht, The Netherlands. E-mail: w.seinen{at}iras.uu.nl. Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Andersen, M. E., Birnbaum, L. S., Barton, H. A., and Eklund, C. R. (1997). Regional hepatic CYP1A1 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation. Toxicol. Appl. Pharmacol. 144, 145–155.[ISI][Medline]

Andersen, M. E., Mills, J. J., Gargas, M. L., Kedderis, L., Birnbaum, L. S., Neubert, D., and Greenlee, W. F. (1993). Modeling receptor-mediated processes with dioxin: Implications for pharmacokinetics and risk assessment. Risk Anal. 13, 25–36.[ISI][Medline]

Bouraly, M., and Millischer, R. J. (1989). Bioaccumulation and elimination of tetrachlorobenzyltoluene (TCBT) by the rat and by fish. Chemosphere 18, 2051–2063.[ISI]

Brown, R., Foran, J., Olin, S., and Robinson, D. (1994). Physiological Parameter Values for PBPK Models. International Life Sciences Institute and Risk Science Institute, Washington D. C.

Carlile, D. J., Stevens, A. J., Ashforth, E. I., Waghela, D., and Houston, J. B. (1998). In vivo clearance of ethoxycoumarin and its prediction from in vitro systems. Use of drug depletion and metabolite formation methods in hepatic microsomes and isolated hepatocytes. Drug Metab. Dispos. 26, 216–221.[Abstract/Free Full Text]

De Boer, J., and Wester, P. G. (1993). Determination of toxaphene in human milk from Nigaragua and in fish and marine mammals from the northeastern Atlantic and the North Sea. Chemosphere 27, 1879–1890.[ISI]

De Lang, R. -J., van Hooijdonk, M. J. C. M., Brandsma, L., Kramer, H., and Seinen, W. (1998). Transition metal catalysed cross-coupling between benzylic halides and aryl nucleophiles. Synthesis of some toxicologically interesting tetrachlorobenzyltoluenes. Tetrahedron 54, 2953–2966.[ISI]

DeVito, M. J., Ross, D. G., Dupuy, A. E., Jr., Ferrario, J., McDaniel, D., and Birnbaum, L. S. (1998). Dose-response relationships for disposition and hepatic sequestration of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice. Toxicol. Sci. 46, 223–234.[Abstract]

Ehmann, J., and Ballschmiter, K. (1989). Isomer-specific determination of tetrachlorobenzyltoluenes (TCBT) in the technical mixture Ugilec 141 by capillary gas chromatography. Fresenius Z. Anal. Chem. 332, 904–911.

Evans, M. V., Crank, W. D., Yang, H. -M., and Simmons, J. E. (1994). Applications of sensitivity analysis to a physiologically based pharmacokinetic model for carbon tetrachloride in rats. Toxicol. Appl. Pharmacol. 128, 36–44.[ISI][Medline]

Fuerst, P., Krueger, C., Meemken, H. -A. and Groebel, W. (1987). Levels of PCB-substitute Ugilec (tetrachlorobenzyltoluenes) in fish from areas with extensive mining. Z. Lebensm. Unters. Forsch. 185, 394–397.[ISI][Medline]

Gallo, J. M., Lam, F. C., and Perrier, D. G. (1987). Area method for the estimation of partition coefficients for physiological pharmacokinetic models. J. Pharmacokinet. Biopharm. 15, 271–280.[ISI][Medline]

Heinrich-Hirsch, B., Beck, H., Chahoud, I., Grote, K., Hartmann, J., and Mathar, W. (1997). Tissue distribution, toxicokinetics and induction of hepatic drug metabolizing enzymes in male rats after a single s.c. dose of 3,4,3',4'-tetrachlorobiphenyl (PCB-77). Chemosphere 34, 1523–1534.[ISI][Medline]

Houston, J. B. (1994). Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47, 1469–1479.[ISI][Medline]

Houston, J. B., and Carlile, D. J. (1997). Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metab. Rev. 29, 891–922.[ISI][Medline]

Jordan, S. A., and Feeley, M. M. (1999). PCB congener patterns in rats consuming diets containing Great Lakes salmon: Analysis of fish, diets, and adipose tissue. Environ. Res. 80, S207–S212.[ISI][Medline]

Kedderis, L. B., Mills, J. J., Andersen, M. E., and Birnbaum, L. S. (1993). A physiologically based pharmacokinetic model for 2,3,7,8- tetrabromodibenzo-p-dioxin (TBDD) in the rat: Tissue distribution and CYP1A induction. Toxicol. Appl. Pharmacol. 121, 87–98.[ISI][Medline]

Kramer, H. J., van den Berg, M., De Lang, R. J., Brandsma, L., and Dejongh, J. (2000). Biotransformation rates of Ugilec 141 (tetrachlorobenzyltoluenes) in rat and trout microsomes. Chemosphere 40, 1283–1288.[ISI][Medline]

Krishnan, K., and Andersen, M. E. (1994). Physiologically based pharmacokinetic modeling in toxicology. In Principles and Methods of Toxicology (A. W. Hayes, Ed.), pp. 149–188. Raven Press, Ltd., New York.

Lutz, R. J., Dedrick, R. L., Matthews, H. B., Eling, T. E., and Anderson, M. W. (1977). A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. Drug Metab. Dispos. 5, 386–396.[Abstract]

Lutz, R. J., Dedrick, R. L., Tuey, D., Sipes, I. G., Anderson, M. W., and Matthews, H. B. (1984). Comparison of the pharmacokinetics of several polychlorinated biphenyls in mouse, rat, dog, and monkey by means of a physiological pharmacokinetic model. Drug Metab. Dispos. 12, 527–535.[Abstract]

Matthews, H. B., and Dedrick, R. L. (1984). Pharmacokinetics of PCBs. Annu. Rev. Pharmacol. Toxicol. 24, 85–103.[ISI][Medline]

Moir, D., Viau, A., Chu, I., Wehler, E. K., Morck, A., and Bergman, A. (1996). Tissue distribution, metabolism, and excretion of 2,4,4'-trichlorobiphenyl (CB-28) in the rat. Toxicol. Ind. Health 12, 105–121.[ISI][Medline]

Murk, A. J., VandenBerg, J. H. J., Koeman, J. H., and Brouwer, A. (1991). The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorinated bifenyls (Arochlor 1254 and PCB 77) copared in Ah-responsive and Ah-nonresponsive mice. Environ. Pollut. 72, 57–68.[ISI][Medline]

Obach, R. S. (1997). Nonspecific binding to microsomes: Impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol. Drug Metab. Dispos. 25, 1359–1369.[Abstract/Free Full Text]

Ploeger, B. A., Meulenbelt, J., and DeJongh, J. (2000). Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound subject to presystemic metabolism and enterohepatic cycling. Toxicol. Appl. Pharmacol. 162, 177–188.[ISI][Medline]

Ryan, J. J., Levesque, D., Panopio, L. G., Sun, W. F., Masuda, Y., and Kuroki, H. (1993). Elimination of polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) from human blood in the Yusho and Yu-Cheng rice oil poisonings. Arch. Environ. Contam. Toxicol. 24, 504–512.[ISI][Medline]

Tuey, D. B., and Matthews, H. B. (1980). Distribution and excretion of 2,2',4,4',5,5'-hexabromobiphenyl in rats and man: Pharmacokinetic model predictions. Toxicol. Appl. Pharmacol. 53, 420–431.[ISI][Medline]

Van den Berg, M., De Jongh, J., Poiger, H., and Olson, J. R. (1994). The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity. Crit. Rev. Toxicol. 24, 1–74.[ISI][Medline]

van Haelst, A. G. (1996). Environmental chemistry of tetrachlorobenzyltoluenes. Thesis, University of Amsterdam, The Netherlands.

Wammes, J. I. J., Linders, S. H. M. A., Liem, A. K. D., and Gerrits, V. E. (1997). Ugilec 141, PCBs and Dioxins in Eel from the River Rur. RIVM, Bilthoven.

Wang, X., Santostefano, M. J., Evans, M. V., Richardson, V. M., Diliberto, J. J., and Birnbaum, L. S. (1997). Determination of parameters responsible for pharmacokinetic behavior of TCDD in female Sprague-Dawley rats. Toxicol. Appl. Pharmacol. 147, 151–168.[ISI][Medline]

Yang, R., and Andersen, M. E. (1994). Pharmacokinetics. In Principles and Methods of Toxicology (A. W. Hayes, Ed.), pp. 49–73. Raven Press, Ltd., New York.





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Articles by Kramer, H. J.
Articles by DeJongh, J.