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PubMed2005

Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling.

Under OSHA and American Conference of Governmental Industrial Hygienists (ACGIH) guidelines, the mixture formula (unity calculation) provides a method for evaluating exposures to mixtures of chemicals that cause similar toxicities. According to the formula, if exposures are reduced in proportion to the number of chemicals and their respective exposure limits, the overall exposure is acceptable. This approach assumes that responses are additive, which is not the case when pharmacokinetic interactions occur. To determine the validity of the additivity assumption, we performed unity calculations for a variety of exposures to toluene, ethylbenzene, and/or xylene using the concentration of each chemical in blood in the calculation instead of the inhaled concentration. The blood concentrations were predicted using a validated physiologically based pharmacokinetic (PBPK) model to allow exploration of a variety of exposure scenarios. In addition, the Occupational Safety and Health Administration and ACGIH occupational exposure limits were largely based on studies of humans or animals that were resting during exposure. The PBPK model was also used to determine the increased concentration of chemicals in the blood when employees were exercising or performing manual work. At rest, a modest overexposure occurs due to pharmacokinetic interactions when exposure is equal to levels where a unity calculation is 1.0 based on threshold limit values (TLVs). Under work load, however, internal exposure was 87%higher than provided by the TLVs. When exposures were controlled by a unity calculation based on permissible exposure limits (PELs), internal exposure was 2.9 and 4.6 times the exposures at the TLVs at rest and workload, respectively. If exposure was equal to PELs outright, internal exposure was 12.5 and 16 times the exposure at the TLVs at rest and workload, respectively. These analyses indicate the importance of (1) selecting appropriate exposure limits, (2) performing unity calculations, and (3) considering the effect of work load on internal doses, and they illustrate the utility of PBPK modeling in occupational health risk assessment.

Animals↗
PubMed2000

Extrapolation of a PBPK model for dioxins across dosage regimen, gender, strain, and species.

A physiologically based pharmacodynamic (PBPK) model for 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) was developed based on pharmacokinetic data from acute oral exposures of TCDD to female Sprague-Dawley rats (Wang et al., 1997, Toxicol Appl. Pharmacol 147, 151-168). In the present study, the utility of this model to predict the disposition of TCDD in male and female Sprague-Dawley and female Wistar rats exposed to TCDD through different dosage regimens was examined. The ability of the model to predict the disposition of 2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITrCDD) in mice (Leung, et al., 1990, Toxicol. Appl. Pharmacol. 103, 399-410) was also examined. The ability of the model to predict across routes of exposure was assessed with intravenous injection data (5.6 microg/kg bw) (Li et al., 1995, Fundam. Appl. Toxicol. 27, 70-76) in female rats. Analysis across gender extrapolations used data for male Sprague-Dawley rats exposed intravenously to 9.25 microg TCDD/kg bw (Weber et al., 1993, Fundam. Appl. Toxicol. 21, 523-534). The analysis of across-dosage regimen and stains of rats extrapolations were assessed using data from rats exposed to TCDD through a loading/maintenance dosage regimen (Krowke et al., 1989, Arch. Toxicol. 63, 356-360). The physiological differences between gender, strain, and species were taken into account when fitting the PBPK model to these data sets. The results demonstrate that the PBPK model for TCDD developed for female Sprague-Dawley rats exposed by acute oral dosing accurately predicts the disposition of TCDD, for different gender and strain of rats across varying dosage regimens, as well as in a strain of mice. Minimal changes in fitted parameters were required to provide accurate predictions of these data sets. This study provides further confirmation of the potential use of physiological modeling in understanding pharmacokinetics and pharmacodynamics.

Administration, Oral↗
PubMed2001

A PBPK modeling-based approach to account for interactions in the health risk assessment of chemical mixtures.

The objectives of the present study were: (1) to develop a risk assessment methodology for chemical mixtures that accounts for pharmacokinetic interactions among components, and (2) to apply this methodology to assess the health risk associated with occupational inhalation exposure to airborne mixtures of dichloromethane, benzene, toluene, ethylbenzene, and m-xylene. The basis of the proposed risk assessment methodology relates to the characterization of the change in tissue dose metrics (e.g., area under the concentration-time curve for parent chemical in tissues [AUCtissue], maximal concentration of parent chemical or metabolite [Cmax], quantity metabolized over a period of time) in humans, during mixed exposures using PBPK models. For systemic toxicants, an interaction-based hazard index was calculated using data on tissue dose of mixture constituents. Initially, the AUCtarget tissue (AUCtt) corresponding to guideline values (e.g., threshold limit value [TLV]) of individual chemicals were obtained. Then, the AUCtt for each chemical during mixed exposure was obtained using a mixture PBPK model that accounted for the binary and higher order interactions occurring within the mixture. An interaction-based hazard index was then calculated for each toxic effect by summing the ratio of AUCtt obtained during mixed exposure (predefined mixture) and single exposure (TLV). For the carcinogenic constituents of the mixture, an interaction-based response additivity approach was applied. This method consisted of adding the cancer risk for each constituent, calculated as the product of q*tissue dose and AUCtt. The AUCtt during mixture exposures was obtained using an interaction-based PBPK model. The approaches developed in the present study permit, for the first time, the consideration of the impact of multichemical pharmacokinetic interactions at a quantitative level in mixture risk assessments.

Air Pollutants, Occupational↗
PubMed2002

PBPK modeling of the percutaneous absorption of perchloroethylene from a soil matrix in rats and humans.

Perchloroethylene (PCE) is a widely used volatile organic chemical. Exposures to PCE are primarily through inhalation and dermal contact. The dermal absorption of PCE from a soil matrix was compared in rats and humans using real-time MS/MS exhaled breath technology and physiologically based pharmacokinetic (PBPK) modeling. Studies with rats were performed to compare the effects of loading volume, concentration, and occlusion. In rats, the percutaneous permeability coefficient (K(P)) for PCE was 0.102 +/- 0.017, and was independent of loading volume, concentration, or occlusion. Exhaled breath concentrations peaked within 1 h in nonoccluded exposures, but were maintained over the 5 h exposure period when the system was occluded. Three human volunteers submerged a hand in a container of PCE-laden soil for 2 h and their exhaled breath was continually monitored during and for 2.5 h following exposure. The absorption and elimination kinetics of PCE were slower in these subjects than initially predicted based upon the PBPK model developed from rat dermal kinetic data. The resulting K(P) for humans was over 100-fold lower than for the rat utilizing a single, well-stirred dermal compartment. Therefore, two additional PBPK skin compartment models were evaluated: a parallel model to simulate follicular uptake and a layered model to portray a stratum corneum barrier. The parallel dual dermal compartment model was not capable of describing the exhaled breath kinetics, whereas the layered model substantially improved the fit of the model to the complex kinetics of dermal absorption through the hand. In real-world situations, percutaneous absorption of PCE is likely to be minimal.

Administration, Cutaneous↗
PubMed2003

Route-specific differences in distribution characteristics of octamethylcyclotetrasiloxane in rats: analysis using PBPK models.

Octamethylcyclotetrasiloxane (D(4)) is used in selected consumer products and has a potential for human exposure from multiple routes. Here we develop a physiologically based pharmacokinetic (PBPK) model to describe the tissue dosimetry, plasma concentration, and clearance in the rat following inhalation and dermal, oral, and iv exposure. An initial multiroute PBPK model, based on a previously published inhalation PBPK model for D(4), provided excellent fits to the observed concentration time course of D(4) metabolites in urine and D(4) exhalation rate following dermal exposures. However, the pharmacokinetics of D(4), following oral and iv exposure, were sensitive to the mode of entry into the blood compartment. A refined model, describing delivery of D(4) from the GI tract to the nonexchangeable/deep blood compartment, provided the best fits to observed plasma D(4), exhaled D(4), and D(4) metabolites excreted in the urine following oral exposure. Pharmacokinetics following iv administration was best described by delivery of D(4) directly into the deep blood compartment, possibly reflecting a kinetically identifiable characteristic of the administration of D(4) as an emulsion for the intravenous route of exposure. This model-based analysis indicates that the pharmacokinetics of D(4) delivered by the inhalation or dermal routes is similar, and is different from the iv or oral delivery routes.

Adjuvants, Immunologic↗
PubMed2005

Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs.

AIMS: To create a general physiologically based pharmacokinetic (PBPK) model for drug disposition in infants and children, covering the age range from birth to adulthood, and to evaluate it with theophylline and midazolam as model drugs. METHODS: Physiological data for neonates, 0.5-, 1-, 2-, 5-, 10- and 15-year-old children, and adults, of both sexes were compiled from the literature. The data comprised body weight and surface area, organ weights, vascular and interstitial spaces, extracellular body water, organ blood flows, cardiac output and glomerular filtration rate. Tissue: plasma partition coefficients were calculated from rat data and unbound fraction (f u) of the drug in human plasma, and age-related changes in unbound intrinsic hepatic clearance were estimated from CYP1A2 and CYP2E1 (theophylline) and CYP3A4 (midazolam) activities in vitro. Volume of distribution (V dss), total and renal clearance (CL and CL R) and elimination half-life (t(1/2)) were estimated by PBPK modelling, as functions of age, and compared with literature data. RESULTS: The predicted V dss of theophylline was 0.4-0.6 l kg(-1) and showed only a modest change with age. The median prediction error (MPE) compared with literature data was 3.4%. Predicted total CL demonstrated the time-course generally reported in the literature. It was 20 ml h(-1) kg(-1) in the neonate, rising to 73 ml h(-1) kg(-1) at 5 years and then decreasing to 48 ml h(-1) kg(-1) in the adult. Overall, the MPE was - 4.0%. Predicted t(1/2) was 18 h in the neonate, dropping rapidly to 4.6-7.2 h from 6 months onwards, and the MPE was 24%. The predictions for midazolam were also in good agreement with literature data. V dss ranged between 1.0 and 1.7 l kg(-1) and showed only modest change with age. CL was 124 ml h(-1) kg(-1) in the neonate and peaked at 664 ml h(-1) kg(-1) at 5 years before decreasing to 425 ml h(-1) kg(-1) in the adult. Predicted t(1/2) was 6.9 h in the neonate and attained 'adult' values of 2.5-3.5 h from 1 year onwards. CONCLUSIONS: A general PBPK model for the prediction of drug disposition over the age range neonate to young adult is presented. A reference source of physiological data was compiled and validated as far as possible. Since studies of pharmacokinetics in children present obvious practical and ethical difficulties, one aim of the work was to utilize maximally already available data. Prediction of the disposition of theophylline and midazolam, two model drugs with dissimilar physicochemical and pharmacokinetic characteristics, yielded results that generally tallied with literature data. Future use of the model may demonstrate further its strengths and weaknesses.

Adolescent↗
PubMed2002

Pharmacokinetics of toxic chemicals in breast milk: use of PBPK models to predict infant exposure.

Factors controlling the transfer of potentially toxic chemicals in the breast milk of nursing mothers include both chemical characteristics, such as lipophilicity, and physiologic changes during lactation. Physiologically based pharmacokinetic (PBPK) models can aid in the prediction of infant exposure via breast milk. Benefits of these quantitative models include the ability to account for changing maternal physiology and transfer kinetics, as well as the chemical-specific characteristics, in order to produce more accurate estimates of neonatal risk. A recently developed PBPK model for perchlorate and iodide kinetics in the lactating and neonatal rat demonstrates the utility of PBPK modeling in predicting maternal and neonatal distribution of these two compounds. This model incorporates time-dependent changes in physiologic characteristics and includes interactions between iodide and perchlorate that alter the distribution and kinetics of iodide.

Adult↗
PubMed1998

A CFD-PBPK hybrid model for simulating gas and vapor uptake in the rat nose.

In laboratory studies of rodents, the inhalation of organic vapors often results in preferential damage to olfactory epithelium. Such focal lesion formation may be due either wholly or in part to a corresponding nonuniformity in the spatial distribution of vapor uptake within the nasal cavities. As a tool for determining this dose distribution, a mathematical model based on a combination of computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) modeling was developed for simulating toxicant vapor uptake in the rat nose. The nasal airways were subdivided into four distinct meatuses selected such that each contained a major air flow stream. Each meatus was further divided into four serial regions attached to separate tissue stacks containing mucus, epithelial, and subepithelial compartments. Values for the gas-phase mass transfer coefficients and gas flows in the 16 airway regions were determined by a solution of the Navier-Stokes and convection-diffusion equations using commercially available CFD software. These values were then input to a PBPK simulation of toxicant transport through the 16 tissue stacks. The model was validated by using overall uptake data from rodent inhalation studies for three "unreactive" vapors that were either completely inert (i.e., acetone), reversibly ionized in aqueous media (i.e., acrylic acid), or prevented from being metabolized by an enzyme inhibitor (i.e., isoamyl alcohol). A sensitivity analysis revealed that accurate values of the mass transfer coefficient were not necessary to simulate regional concentrations and uptake of unreactive vapors in the rat nose, but reliable estimates of diffusion coefficients in tissue were crucial for accurate simulations.

Air Pollutants↗
PubMed2005

Kinetic and mechanistic data needs for a human phsiologically based pharmacokinetic (PBPK) model for acrylamide: pharmacokinetic model for acrylamide.

A pharmacokinetic (PBPK) model has been developed for acrylamide (AMD) and its oxidative metabolite, glycidamide (GLY), in the rat based on available information. Despite gaps and limitations to the database, model parameters have been estimated to provide a relatively consistent description of the kinetics of acrylamide and glycidamide using a single set of values (with minor adjustments in some cases). Future kinetic and mechanistic studies will need to focus on the collection of key data for refining certain model parameters and for model validation, as well as for conducting studies that elucidate the mechanism of action. Development of a validated human AMD/GLY PBPK model capable of predicting target tissue doses at relevant dietary AMD exposures, in combination with expanding data on modes of action, should allow for a substantive improvement in the risk assessment of acrylamide in food.

Acrylamide↗
PubMed2001

Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model.

Vinyl chloride (VC) is a trans-species carcinogen, producing tumors in a variety of tissues, from both inhalation and oral exposures, across a number of species. In particular, exposure to VC has been associated with a rare tumor, liver angiosarcoma, in a large number of studies in mice, rats, and humans. The mode of action for the carcinogenicity of VC appears to be a relatively straightforward example of DNA adduct formation by a reactive metabolite, leading to mutation, mistranscription, and neoplasia. The objective of the present analysis was to investigate the comparative potency of a classic genotoxic carcinogen across species, by performing a quantitative comparison of the carcinogenic potency of VC using data from inhalation and oral rodent bioassays as well as from human epidemiological studies. A physiologically-based pharmacokinetic (PBPK) model for VC was developed to support the target tissue dosimetry for the cancer risk assessment. Unlike previous models, the initial metabolism of VC was described as occurring via two saturable pathways, one representing low capacity-high affinity oxidation by CYP2E1 and the other (in the rodent) representing higher capacity-lower affinity oxidation by other isozymes of P450, producing in both cases chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) as intermediate reactive products. Depletion of glutathione by reaction with CEO and CAA was also described. Animal-based risk estimates for human inhalation exposure to VC using total metabolism estimates from the PBPK model were consistent with risk estimates based on human epidemiological data, and were lower than those currently used in environmental decision-making by a factor of 80.

Air Pollutants↗
PubMedDate not supplied

New PBPK model applied to old occupational exposure to benzene.

An intensive program of benzene monitoring using new techniques was undertaken in Western Europe in the late 1960s and early 1970s. Significant exposure was found in the transport of benzene and gasoline, particularly during the loading of barges, and during the loading and operation of sea-going vessels. The ceiling threshold limit value of 25 ppm recommended at that time generated problems in assessing exposure, so alternative criteria were proposed. During that period some shore-based exposures were reported, and their significance was discussed in several articles. The information gained at that time is reexamined by physiologically based pharmacokinetic (PBPK) modeling and is used to help validate an improved PBPK model, which is described and tested on results from experimental exposure in a companion article. The old field data, comprising five specific studies, confirm the relevance of modeling to assessment of occupational exposure, and demonstrate its value for interpretation of field data, which is seldom as complete, systematic, or accurate as that obtained in experimental work. The model suggests that metabolism of benzene in humans may not be restricted to the liver. Sites and processes of metabolism merit further investigation.

Air Pollutants, Occupational↗
PubMed2001

Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations.

Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.

Administration, Inhalation↗
PubMed1997

Structural identifiability of PBPK models: practical consequences for modeling strategies and study designs.

Physiologically based pharmacokinetic (PBPK) models usually contain unknown parameters that need to be estimated by calibration to concentration-time profiles from in vivo experiments. However, even with error-free data, the number of parameters that can be estimated in this way is limited, depending on the particular situation. This paper introduces the concept of structural identifiability of a model, a requirement to make the estimation of parameters by calibration a meaningful undertaking. We briefly discuss the techniques-available from systems analysis-for examining the identifiability of models. Two conditions of uniqueness are involved, one relating to the model's equations and its parameters, the other to the number of available observations in time. The assessment of the first uniqueness condition involves rather tedious matrix algebra, requiring the appropriate mathematical expertise. We therefore give some general results for a particular class of PBPK models, indicating in what situations the first uniqueness condition either holds or does not. The assessment of the second uniqueness condition does not require specialized skills, and the minimum number of observations in time necessary can be easily determined for any particular situation. The practical implications for both modeling strategies and experimental protocols are discussed.

Animals↗
PubMed2003

Modeling interindividual variation in physiological factors used in PBPK models of humans.

Modeling interindividual variation in internal doses in humans using PBPK models requires data on the variation in physiological parameters across the population of interest. These data should also reflect the correlations between the values of the various parameters in a person. In this project, we develop a source of data for human physiological parameters where (1) the parameter values for an individual are correlated with one another, and (2) values of parameters capture interindividual variation in populations of a specific gender, race, and age range. The parameters investigated in this project include: (1) volumes of selected organs and tissues; (2) blood flows for the organs and tissues; and (3) the total cardiac output under resting conditions and average daily inhalation rate. These parameters are expressed as records of correlated values for the approximately 30,000 individuals evaluated in the NHANES III survey. A computer program, Physiological Parameters for PBPK Modeling (P3M), is developed that allows records to be retrieved randomly from the database with specification of constraints on age, sex, and ethnicity. P3M is publicly available. The database and accompanying software provide a convenient tool for parameterizating models of interindividual variation in human pharmacokinetics.

Computer Simulation↗
PubMedDate not supplied

Determination of the rat tissue partitioning of endotoxin in vitro for physiologically-based pharmacokinetic (PBPK) modeling.

The biosynthetically double-labeled lipopolysaccharide (LPS), containing (3)H-labeled on the fatty acyl-chains and (14)C-labeled on the glucosamine of Salmonella enterica serotype typhimurium, was isolated from bacteria grown in proteose peptone-beef extract (PPBE) medium in the presence of labeled precursors; 133 micro Ci/ml of [2-(3)H] acetate sodium salt and 0.167 micro Ci/ml of N-acetyl[D-1-(14)C]glucosamine. The LPS was extracted from the bacteria with 90% phenol/chloroform/petroleum ether, purified and stored in 0.1% (v/v) triethylamine/10 mM Tris HCl at -70 degrees C. Tissue slices and portions of the meninges were prepared and incubated in artificial cerebrospinal fluid (CSF) or Krebs phosphate buffer (Krebs) containing 150 ng/ml LPS with [(3)H] LPS (0.004 micro Ci/ml, sp. act. 28 micro Ci/mg LPS). The tissues were incubated under 95% oxygen/5% carbon dioxide at 37 degrees C with constant agitation until steady-state uptake was reached (60 min). At the end of the incubation period, tissues were processed for radioactivity measurement. The rat tissue partitioning of LPS in artificial CSF for brain and Krebs for other organs was measured by using the ratio of tissue to medium at the steady state in vitro. The following results were obtained from the study: Heart, 0.15; liver, 0.19; spleen, 0.12; kidney, 0.18; stomach, 0.17; small intestine, 0.18; brain stem, 0.10; cerebellum, 0.11; meninges, 0.77; hippocampus, 0.12; hypothalamus, 0.12; frontal cortex, 0.09 and caudate nucleus, 0.10. This information, along with plasma or blood/buffer partition coefficients, is a requisite for constructing a physiologically-based pharmacokinetic (PBPK) model of endotoxins for quantitative risk assessment.

Animals↗
PubMed2002

Physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry of organic esters: assessing the state-of-knowledge and risk assessment applications with methyl methacrylate and vinyl acetate.

Mathematical models have been developed to describe nasal epithelial tissue dosimetry with two compounds, vinyl acetate (VA) and methyl methacrylate (MMA), that cause toxicity in these tissues These models couple computational fluid dynamics (CFD) calculations that map airflow patterns within the nose with physiologically based pharmacokinetic (PBPK) models that integrate diffusion, metabolism, and tissue interactions of these compounds. Dose metrics estimated in these models for MMA and VA, respectively, were rates of MMA metabolism per volume of tissue and alterations in pH in target tissues associated with VA hydrolysis and metabolism. In this article, four scientists who have contributed significantly to development of these models describe the many similarities and relatively few differences between the MMA and VA models. Some differences arise naturally because of differences in target tissues, in the calculated measures of tissue dose, and in the modes of action for highly extracted vapors (VA) compared with poorly extracted vapors (MMA). A difference in the approach used to estimate metabolic parameters from human tissues provides insights into interindividual extrapolation and identifies opportunities for studies with human nasal tissues to enhance current risk assessments. In general, the differences in model structure for these two esters were essential for describing the biology of the observed responses and in accounting for the different measures of target tissue dose. This article is intended to serve as a guide for understanding issues of optimum model structure and optimal data sources for these nasal tissue dosimetry models. We also hope that it leads to greater international acceptance of these hybrid CFD/PBPK modeling approaches for improving risk assessment for many nasal toxicants. In general, these models predict either equivalent (VA) or lower (MMA) nasal tissue doses in humans compared with tissue doses at equivalent exposure concentrations in rats.

Air Movements↗
PubMed2007

A delayed nonlinear PBPK model for genistein dosimetry in rats.

Genistein is an endocrine-active compound (EAC) found in soy products. It has been linked to beneficial effects such as mammary tumor growth suppression and adverse endocrine-related effects such as reduced birth weight in rats and humans. In its conjugated form, genistein is excreted in the bile, which is a significant factor in its pharmacokinetics. Experimental data suggest that genistein induces a concentration-dependent suppression of biliary excretion. In this article, we describe a physiologically based pharmacokinetic (PBPK) model that focuses on biliary excretion with the goal of accurately simulating the observed suppression. The mathematical model is a system of nonlinear differential equations with state-dependent delay to describe biliary excretion. The model was analyzed to examine local existence and uniqueness of a solution to the equations. Furthermore, unknown parameters were estimated, and the mathematical model was compared against published experimental data.

Animals↗
PubMed1996

PBPK model for butadiene metabolism to epoxides: quantitative species differences in metabolism.

We have developed a physiologically based pharmacokinetic (PBPK) model for 1,3-butadiene (BD) and its first reactive metabolite 1,2-epoxybutene-3 (EB). This model contrasts with other published ones, in that it incorporates three important features: (I) reduced alveolar ventilation, based on experimental observations on a number of vapors and gases; (II) intrahepatic first-pass hydrolysis of EB, based on experimental observations with BD-EB, ethylene-ethylene oxide, and styrene-styrene oxide; (III) a two-substrate Michealis-Menten kinetic description of EB conjugation with GSH. We believe these features are essential for a correct toxicokinetic description of BD. The model was validated against a number of published experimental observations on BD, EB, and liver glutathione (GSH), kinetics made in vivo with rats and mice, including EB exhalation upon BD exposure and liver GSH depletion at high exposure levels of BD. According to our model, the relative internal doses of EB (expressed as the relation between steady-state concentrations or AUCs in mixed venous blood) are: mouse 1.6, rat 1.0, man 0.3. In the mouse, GSH depletion occurs after 6-9 h exposure at high concentrations resulting in a shift of the relative internal dose from 1.6 to between 2 and 3. The clear but relatively small mouse-rat difference in internal EB doses can only partly explain the marked species difference in cancer response between mice and rats exposed to BD.

Animals↗