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PubMed1993

Variability of physiologically based pharmacokinetic (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE).

When used in the risk assessment process, the output from physiologically based pharmacokinetic (PBPK) models has usually been considered as an exact estimate of dose, ignoring uncertainties in the parameter values used in the model and their impact on model predictions. We have collected experimental data on the variability of key parameters in a PBPK model for tetrachloroethylene (PCE) and have used Monte Carlo analysis to estimate the resulting variability in the model predictions. Blood/air and tissue/blood partition coefficients and the interanimal variability of these data were determined for tetrachloroethylene (PCE). The mean values and variability for these and other published model parameters were incorporated into a PBPK model for PCE and a Monte Carlo analysis (n = 600) was performed to determine the effect on model predicted dose surrogates for a PCE risk assessment. For a typical dose surrogate, area under the blood time curve for metabolite in the liver (AUCLM), the coefficient of variation was 25% and the mean value for AUCLM was within a factor of two of the maximum and minimum values generated in the 600 simulations. These calculations demonstrate that parameter uncertainty is not a significant potential source of variability in the use of PBPK models in risk assessment. However, we did not in this study consider uncertainties as to metabolic pathways, mechanism of carcinogenicity, or appropriateness of dose surrogates.

Administration, Inhalation↗
PubMed2000

The utility of PBPK in the safety assessment of chloroform and carbon tetrachloride.

Occupational exposure limits (OELs) for individual substances are established on the basis of the available toxicological information at the time of their promulgation, expert interpretation of these data in light of industrial use, and the framework in which they sit. In the United Kingdom, the establishment of specific OELs includes the application of uncertainty factors to a defined starting point, usually the NOAEL from a suitable animal study. The magnitude of the uncertainty factors is generally determined through expert judgment including a knowledge of workplace conditions and management of exposure. PBPK modeling may help in this process by informing on issues relating to extrapolation between and within species. This study was therefore designed to consider how PBPK modeling could contribute to the establishment of OELs. PBPK models were developed for chloroform (mouse and human) and carbon tetrachloride (rat and human). These substances were chosen for examination because of the extent of their toxicological databases and availability of existing PBPK models. The models were exercised to predict the rate (chloroform) or extent (carbon tetrachloride) of metabolism of these substances, in both rodents and humans. Monte Carlo analysis was used to investigate the influence of variability within the human and animal model populations. The ratio of the rates/extent of metabolism predicted for humans compared to animals was compared to the uncertainty factors involved in setting the OES. Predictions obtained from the PBPK models indicated that average rat and mouse metabolism of carbon tetrachloride and chloroform, respectively, are much greater than that of the average human. Application of Monte Carlo analysis indicated that even those people who have the fastest rates or most extensive amounts of metabolism in the population are unlikely to generate the levels of metabolite of these substances necessary to produce overt toxicity in rodents. This study highlights the value that the use of PBPK modeling may add to help inform and improve toxicological aspects of a regulatory process.

Administration, Inhalation↗
PubMedDate not supplied

Combining cell culture analogue reactor designs and PBPK models to probe mechanisms of naphthalene toxicity.

An alternative method of evaluating the toxicology of a chemical is to use cultured mammalian cells in a novel cell culture analogue reactor (CCA) together with a corresponding physiologically based pharmacokinetic model (PBPK). The PBPK is a mathematical model that divides the body into compartments representing organs, integrating the kinetic, thermodynamic, and anatomical parameters of the animal. The bioreactor is a physical replica of the PBPK; where the PBPK specifies an organ or tissue compartment, the bioreactor contains compartments with a corresponding cell type. The device is a continuous, dynamic system composed of multiple cell types that interact through a common circulating cell culture medium. The bioreactor and the model are coupled to evaluate the plausibility of the molecular mechanism that is input into the model. This concept is tested with naphthalene as a model of PAH (polycyclic aromatic hydrocarbons) toxicants. Two physically different CCA reactors were tested with naphthalene, and different results were observed. In the prototype system using cells attached to glass dilution bottles, naphthalene dosing resulted in generation of a circulating metabolite from the "liver" compartment (based on H4IIE cells from a rat hepatoma) that caused cell death in the "lung" compartment (L2 cells from a rat lung), as well as depletion of glutathione in the L2 cells. An improved CCA using packed bed reactors of microcarrier cultured cells did not show differences between naphthalene-dosed and nondosed controls. To explain the different responses of the two CCA designs, PBPKs of the two reactors were tested with variations in physical and kinetic parameters, and toxic mechanism. When the toxic metabolite of naphthalene was naphthoquinone rather than naphthalene epoxide as initially assumed, the PBPK results were consistent with the results of the two CCA designs. This result indicates that the mechanism of naphthalene toxicity in the CCAs may be mediated through naphthoquinone formation. The CCA-PBPK concept is demonstrated to be applicable to the study of toxic mechanisms. In particular, use of this approach suggests that in vitro naphthalene toxicity is mediated through the naphthoquinone metabolite.

Animals↗
PubMed1996

Exploration of an interaction threshold for the joint toxicity of trichloroethylene and 1,1-dichloroethylene: utilization of a PBPK model.

Physiologically based pharmacokinetic (PBPK) modeling and gas uptake experiments were utilized to verify the competitive inhibition mechanism of interaction between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE) and to investigate the presence of an interaction threshold between the two chemicals. Initially, gas uptake experiments were conducted on Fischer 344 rats where the initial concentrations of both DCE and TCE were 2000:0, 0:2000, 2000:2000, 1000:0, 1000:1000, and 500:500 ppm, respectively. When the different modes of inhibition interactions (competitive, uncompetitive and noncompetitive) were employed in the PBPK model, the model description of the competitive inhibition provided the best description of the declining concentrations in the gas uptake chamber. Furthermore, to predict the range at which the interaction threshold would be found, the PBPK model included a mathematical description of the percentage of enzyme sites occupied by either chemical in the presence or the absence of the other. By comparing the percentage of occupied sites by one chemical, in the presence of the other, to those sites occupied in the absence of the latter, the PBPK model predicted a range of concentrations (100 ppm or less) of either chemical where the competitive inhibition interaction would not be observed. Consequently, gas uptake experiments were designed where the initial concentration was selected at 2000 ppm for one chemical while the other chemical was set at 100 in one experiment and 50 ppm in another. Under these conditions, the best stimulation to the concentration depletion curves in the gas uptake system of the chemical in the higher concentration was obtained when the PBPK model was run under the assumption of no-interaction. This substantiated the model predictions of the presence of observable interaction only at concentrations higher than 100 ppm.

Animals↗
PubMed2001

Assessing the reliability of PBPK models using data from methyl chloride-exposed, non-conjugating human subjects.

Physiologically based pharmacokinetic (PBPK) models are often optimized by adjusting metabolic parameters so as to fit experimental toxicokinetic data. The estimates of the metabolic parameters are then conditional on the assumed values for all other parameters. Meanwhile, the reliability of other parameters, or the structural model, is usually not questioned. Inhalation exposures with human volunteers in our laboratory show that non-conjugators lack metabolic capacity for methyl chloride entirely, and that elimination in these subjects takes place via exhalation only. Therefore, data from these methyl chloride exposures provide an excellent opportunity to assess the general reliability of standard inhalation PBPK models for humans. A hierarchical population PBPK model for methyl chloride was developed. The model was fit to the experimental data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. In a Bayesian analysis, it is possible to merge a priori knowledge of the physiological, anatomical and physicochemical parameters with the information embedded in the experimental toxicokinetic data obtained in vivo. The resulting estimates are both statistically and physiologically plausible. Model deviations suggest that a pulmonary sub-compartment may be needed in order to describe the inhalation and exhalation of volatile adequately. The results also indicate that there may be significant intra-individual variability in the model parameters. To our knowledge, this is the first time that the toxicokinetics of a non-metabolized chemical is used to assess population PBPK parameters. This approach holds promise for more elaborate experiments in order to assess the reliability of PBPK models in general.

Adult↗
PubMed2006

Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM. Certain aspects of the OSHA model, however, are not consistent with current approaches or with the USEPA's current DCM cancer risk assessment. Therefore, Bayesian analysis of the mouse PBPK model and dose-response modeling was undertaken to support development of an improved cancer risk assessment for DCM. A hierarchical population model was developed and prior parameter distributions were selected to reflect parameter values that were considered the most appropriate and best available. Bayesian modeling was conducted using MCSim, a publicly available software program for Markov Chain Monte Carlo analysis. Mean posterior values from the calibrated model were used to develop internal dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day in the lung and liver using exposure concentrations and results from the NTP mouse bioassay, consistent with the approach used by the USEPA for its current DCM cancer risk assessment. Internal dose metrics were 3- to 4-fold higher than those that support the current USEPA IRIS assessment. A decrease of similar magnitude was also noted in dose-response modeling results. These results show that the Bayesian PBPK model in the mouse provides an improved basis for a cancer risk assessment of DCM.

Animals↗
PubMed2000

Application of a hybrid CFD-PBPK nasal dosimetry model in an inhalation risk assessment: an example with acrylic acid.

The available inhalation toxicity information for acrylic acid (AA) suggests that lesions to the nasal cavity, specifically olfactory degeneration, are the most sensitive end point for developing a reference concentration (RfC). Advances in physiologically based pharmacokinetic (PBPK) modeling, specifically the incorporation of computational fluid dynamic (CFD) models, now make it possible to estimate the flux of inhaled chemicals within the nasal cavity of experimental species, specifically rats. The focus of this investigation was to apply an existing CFD-PBPK hybrid model in the estimation of an RfC to determine the impact of incorporation of this new modeling technique into the risk assessment process. Information provided in the literature on the toxicity and mode of action for AA was used to determine the risk assessment approach. A comparison of the approach used for the current U.S. Environmental Protection Agency (U.S. EPA) RfC with the approach using the CFD-PBPK hybrid model was also conducted. The application of the CFD-PBPK hybrid model in a risk assessment for AA resulted in an RfC of 79 ppb, assuming a minute ventilation of 13.8 l/min (20 m(3)/day) in humans. This value differs substantially from the RfC of 0.37 ppb estimated for AA by the U.S. EPA before the PBPK modeling advances became available. The difference in these two RfCs arises from many factors, with the main difference being the species selected (mouse vs. rat). The choice to conduct the evaluation using the rat was based on the availability of dosimetry data in this species. Once these data are available in the mouse, an assessment should be conducted using this information. Additional differences included the methods used for estimating the target tissue concentration, the uncertainty factors (UFs) applied, and the application of duration and uncertainty adjustments to the internal target tissue dose rather than the external exposure concentration.

Acrylates↗
PubMed2006

Steady-state solutions to PBPK models and their applications to risk assessment I: Route-to-route extrapolation of volatile chemicals.

Although analysis of in vivo pharmacokinetic data necessitates use of time-dependent physiologically-based pharmacokinetic (PBPK) models, risk assessment applications are often driven primarily by steady-state and/or integrated (e.g., AUC) dosimetry. To that end, we present an analysis of steady-state solutions to a PBPK model for a generic volatile chemical metabolized in the liver. We derive an equivalent model that is much simpler and contains many fewer parameters than the full PBPK model. The state of the system can be specified by two state variables-the rate of metabolism and the rate of clearance by exhalation. For a given oral dose rate or inhalation exposure concentration, the system state only depends on the blood-air partition coefficient, metabolic constants, and the rates of blood flow to the liver and of alveolar ventilation. At exposures where metabolism is close to linear, only the effective first-order metabolic rate is needed. Furthermore, in this case, the relationship between cumulative exposure and average internal dose (e.g., AUCs) remains the same for time-varying exposures. We apply our analysis to oral-inhalation route extrapolation, showing that for any dose metric, route equivalence only depends on the parameters that determine the system state. Even if the appropriate dose metric is unknown, bounds can be placed on the route-to-route equivalence with very limited data. We illustrate this analysis by showing that it reproduces exactly the PBPK-model-based route-to-route extrapolation in EPA's 2000 risk assessment for vinyl chloride. Overall, we find that in many cases, steady-state solutions exactly reproduce or closely approximate the solutions using the full PBPK model, while being substantially more transparent. Subsequent work will examine the utility of steady-state solutions for analyzing cross-species extrapolation and intraspecies variability.

Area Under Curve↗
PubMed2003

Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans.

The objective of this study was to use in synergy physiologically based and empirical approaches to estimate the drug-specific input parameters of PBPK models of disposition to simulate the plasma concentration-time profile of epiroprim in human. The estimated input parameters were the tissue:plasma partition coefficients (Pt:p) for distribution and the blood clearance (CL) for the in vivo conditions. Epiroprim represents a challenge for such methods, because it shows large interspecies differences in its pharmacokinetic properties. Two approaches were used to predict the human Pt:p values: the tissue composition model (TCM) and the "Arundel approach" based on the volume of distribution at steady state (Vdss) determined in vivo in the rat. CL in human was predicted by (1) conventional allometric scaling of in vivo animal clearances (CAS), (2) physiologically based direct scaling up of in vitro hepatocyte data (DSU), and (3) allometric scaling of animal intrinsic in vivo blood CL normalized by the ratios of animal:human intrinsic clearances determined in vitro with hepatocytes (NAS). The performance of prediction was assessed by comparing separately the above pharmacokinetic parameters (Vdss estimated from the Pt:p values and blood CL) with the corresponding in vivo data obtained from the plasma kinetic profiles. These input parameters were used in PBPK models, and the resulting plasma concentration-time profiles of epiroprim were compared with those observed in rat and human. Previously to the construction of the human PBPK model, a model for the rat was also developed to gain more confidence on the model structure and assumptions. Overall, using the TCM and the NAS for the parameterization of the distribution and clearance, respectively, the PBPK model gave the more accurate predictions of epiroprim's disposition in human. This study represents therefore an attractive approach, which may potentially help the clinical candidate selection.

Animals↗
PubMed2001

Assessing interaction thresholds for trichloroethylene in combination with tetrachloroethylene and 1,1,1-trichloroethane using gas uptake studies and PBPK modeling.

The volatile organic solvents trichloroethylene (TCE), tetrachloroethylene (perchloroethylene, PERC), and 1,1,1-trichloroethane (methylchloroform, MC) are widely distributed environmental pollutants and common contaminants of many chemical waste sites. To investigate the mode of pharmacokinetic interactions among TCE, PERC, and MC and to calculate defined "interaction thresholds", gas-uptake experiments were performed using a closed-chamber exposure system. In each experiment, two rats (Fischer 344, male, 8-9 weeks old) were exposed to different initial concentrations of TCE, PERC, and MC, applied singly or as a mixture, and their concentration in the gas phase of the chamber was monitored over a period of 6 h. A physiologically based pharmacokinetic (PBPK) model was developed to test multiple mechanisms of inhibitory interactions, i.e., competitive, non-competitive, or uncompetitive. All mixture exposure data were accurately described by a system of equations in which a PBPK model was provided for each chemical and each was regarded as an inhibitor of the others' metabolism. Sensitivity-analysis techniques were used to investigate the impact of key parameters on model output and optimize experimental design. Model simulations indicated that, among these three chemicals, the inhibition was competitive. The PBPK model was extended to assess occupationally relevant exposures at or below the current threshold-limit values (TLVs). Based on 10% elevation in TCE blood levels as a criterion for significant interaction and assuming TCE exposure is set at TLV of 50 ppm, the calculated interaction thresholds for PERC and MC were 25 and 135 ppm, respectively. TLV exposures to binary TCE/PERC mixture were below the 10% significance level. The interaction threshold for TCE and MC co-exposure would be reached at 50 and 175 ppm, respectively. Such interactive PBPK models should be of value in risk assessment of occupational and environmental exposure to solvent mixtures.

Administration, Inhalation↗
PubMed2001

Quantitative exposure assessment: application of physiologically-based pharmacokinetic (PBPK) modeling of low-dose, long-term exposures of organic acid toxicant in the brain.

Our objective was to construct a physiologically-based pharmacokinetic (PBPK) model describing the kinetic behavior of 2,4-dichlorophenoxyacetic acid (2,4-D) on rats after long-term exposures to low doses. Our study demonstrated the model's ability to simulate uptake of 2,4-D in discrete areas of the rat brain. The model was derived from the generic PBPK model that was first developed for high-dose, single exposures of 2,4-D to rats or rabbits (Kim, C.S., Gargas, M.L., Andersen, M.E., 1994. Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats and rabbits brain following single dose administration. Toxicol. Lett. 74, 189-201; Kim, C.S., Slikker, W., Jr., Binienda, Z., Gargas, M.L., Andersen, M.E., 1995. Development of a physiologically based pharmacokinetic (PBPK) model for 2,4-dichlorophenoxyacetic acid (2,4-D) dosimetry in discrete areas of the brain following a single intraperitoneal or intravenous dose. Neurotox. Teratol. 17, 111-120.), to which a subcutaneous (hypodermal) compartment was incorporated for low-dose, long-term infusion. It consisted of two body compartments, along with compartments for venous and arterial blood, cerebrospinal fluid, brain plasma and six brain regions. Uptake of the toxin was membrane-limited by the blood-brain barrier with clearance from the brain provided by cerebrospinal fluid 'sink' mechanisms. This model predicted profiles of 2,4-D levels in brain and blood over a 28-day period that compared well with concentrations measured in vivo with rats that had been given 2,4-D (1 or 10 mg/kg per day) with [14C]-2,4-D subcutaneously (s.c.) for 7, 14, or 28 days, respectively. This PBPK model should be an effective tool for evaluating the target tissue doses that may produce the neurotoxicity of organic acid toxicants after low-dose, long-term exposures to contaminated foods or the environment.

Journal Article↗
PubMed2003

Characterization of the pharmacokinetics of gasoline using PBPK modeling with a complex mixtures chemical lumping approach.

Gasoline consists of a few toxicologically significant components and a large number of other hydrocarbons in a complex mixture. By using an integrated, physiologically based pharmacokinetic (PBPK) modeling and lumping approach, we have developed a method for characterizing the pharmacokinetics (PKs) of gasoline in rats. The PBPK model tracks selected target components (benzene, toluene, ethylbenzene, o-xylene [BTEX], and n-hexane) and a lumped chemical group representing all nontarget components, with competitive metabolic inhibition between all target compounds and the lumped chemical. PK data was acquired by performing gas uptake PK studies with male F344 rats in a closed chamber. Chamber air samples were analyzed every 10-20 min by gas chromatography/flame ionization detection and all nontarget chemicals were co-integrated. A four-compartment PBPK model with metabolic interactions was constructed using the BTEX, n-hexane, and lumped chemical data. Target chemical kinetic parameters were refined by studies with either the single chemical alone or with all five chemicals together. o-Xylene, at high concentrations, decreased alveolar ventilation, consistent with respiratory irritation. A six-chemical interaction model with the lumped chemical group was used to estimate lumped chemical partitioning and metabolic parameters for a winter blend of gasoline with methyl t-butyl ether and a summer blend without any oxygenate. Computer simulation results from this model matched well with experimental data from single chemical, five-chemical mixture, and the two blends of gasoline. The PBPK model analysis indicated that metabolism of individual components was inhibited up to 27% during the 6-h gas uptake experiments of gasoline exposures.

Animals↗
PubMed2001

Analysis of methylmercury disposition in humans utilizing a PBPK model and animal pharmacokinetic data.

Physiologically based pharmacokinetic (PBPK) models are excellent tools to aid in the extrapolation of animal data to humans. When the fate of the chemical is the same among species being compared, animal data can appropriately be considered as a model for human exposure. For methylmercury exposure, sufficient data exist to allow comparison of numerous mammalian species to humans. PBPK model validation entails obtaining blood and tissue concentrations of the parent chemical and metabolite(s) at various times following a known exposure. From ethical and practical considerations, human tissue concentrations following a known exposure to an environmental toxicant are scarce. While animal-to-human extrapolation demands that sufficient human data exist to validate the model, the validation requirements are less stringent if multiple animal models are utilized within a single model template. A versatile PBPK model was used to analyze the distribution and elimination of methylmercury and its metabolite, inorganic mercury. Uniquely, the model is formed in a generic way from a single basic template during the initial program compilation. Basic parameters are defined for diffferent PBPK models for mammalian species that span a relatively large range of sizes. In this article, the analyses include 12 species (mouse, hamster, rat, guinea pig, cat, rabbit, monkey, sheep, pig, goat, cow, and human). Allometric (weight-based) correlations of tissue binding coefficients, metabolism rate constants, and elimination parameters for both methylmercury and inorganic mercury are presented for species for which sufficient data are available. The resulting human model, in accord with the animal models, predicts relatively high inorganic mercury levels in the kidneys long after the disappearance of methylmercury from the blood.

Animals↗
PubMed2004

Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: implications for assessing children's risks from environmental agents.

Children's risks can differ from those in adults for numerous reasons, one being differences in the pharmacokinetic handling of chemicals. Immature metabolism and a variety of other factors in neonates can affect chemical disposition and clearance. These factors can be incorporated into physiologically based pharmacokinetic (PBPK) models that simulate the fate of environmental toxicants in both children and adults. PBPK models are most informative when supported by empirical data, but typically pediatric pharmacokinetic data for toxicants are not available. In contrast, pharmacokinetic data in children are readily available for therapeutic drugs. The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults. Model development involved scale-up of in vitro metabolic parameters to whole liver and adjusting metabolic function for the ontological pattern of CYP1A2 and other CYPs. Model runs were able to simulate the large differences in half-life and clearance between neonates and adults. Further, the models were able to reproduce the faster metabolic clearance of theophylline relative to caffeine in neonates. This differential between xanthines was found to be due primarily to an extra metabolic pathway available to theophylline, back-methylation to caffeine, that is not available to caffeine itself. This pathway is not observed in adults exemplifying the importance of secondary or novel routes of metabolism in the immature liver. Greater CYP2E1 metabolism of theophylline relative to caffeine in neonates also occurs. Neonatal PBPK models developed for these drugs may be adapted to other CYP1A2 substrates (e.g., arylamine toxicants). A stepwise approach for modeling environmental toxicants in children is proposed.

Adult↗
PubMed2026

Decoding Nonlinearities in AAV-Based Gene Therapy Using PBPK Modelling.

The objective of this research was to develop a physiologically based pharmacokinetic (PBPK) model for AAV-based gene therapy, which can capture the nonlinearity observed in both viral vector and transgene product pharmacokinetics (PK) across a wide range of doses, while accounting for the effect of immunogenicity. To develop the PBPK model, previously published PK data generated in mice using AAV8 vector containing the transgene for a non-binding monoclonal antibody was used. Immunocompetent mice were administered with AAV at a wide range of doses (1E8, 1E9, 5E9, 1E10, 2E10, 1E11, 2E11, 1E12, and 1E13vg per mouse), and the PK of transgene and transgene product (i.e., antibody) in plasma and/or tissue was collected. The nonlinearity in transgene product concentrations was characterized using a saturable production process and a concentration-dependent antibody elimination rate was used to characterize the effect of anti-drug antibody (ADA) on transgene product. The model successfully described the PK of both the vector and the transgene product across all dose levels and accurately captured the sigmoidal dose-exposure-response relationship for AAV. Notably, the model described a dose-dependent ADA response, with the high dose group exhibiting an earlier onset and faster rate of transgene product elimination. Lower dose group showed delayed onset and minimal ADA-mediated elimination of transgene product. Overall, the PBPK model presented here effectively characterizes vector and transgene product kinetics in mice and demonstrates utility in preclinical-to-clinical translation and dose optimization of AAV-based gene therapies.

Animals↗
PubMed1997

Trichloroethylene cancer risk: simplified calculation of PBPK-based MCLs for cytotoxic end points.

Cancer risk assessments for trichloroethylene (TCE) based on linear extrapolation from bioassay results are questionable in light of new data on TCE's likely mechanism of action involving induced cytotoxicity, for which a threshold-type dose-response model may be more appropriate. Previous studies have shown that if a genotoxic mechanism for TCE is assumed, algebraic methods can considerably simplify the use of physiologically based pharmacokinetic (PBPK) models to estimate virtually safe environmental concentrations for humans based on rodent cancer-bioassay data. We show here how such methods can be extended to the case in which TCE is assumed to induce cancer via cytotoxicity, to estimate environmentally safe concentrations based on rodent toxicity data. These methods can be substituted for the numerical methods typically used to calculate PBPK-effective doses when these are defined as peak concentrations. We selected liver and kidney as plausible target tissues, based on an analysis of rodent TCE-bioassay data and on a review of related data bearing on mechanism. Tumor patterns in rodent bioassays are shown to be consistent with our estimates of PBPK-based, effective cytotoxic doses to mice and rats used in these studies. When used with a margin of exposure of 1000, our method yielded maximum concentration levels for TCE of 16 ppb (87 micrograms/m3) for TCE in air respired 24 hr/day, 700 ppb (3.8 mg/m3) for TCE in air respired for relatively brief daily periods (e.g., 0.5 hr while showering/bathing), and 210 micrograms/liter for TCE in drinking water assuming a daily 2-liter ingestion. Cytotoxic effective doses were also estimated for occupational respiratory exposures. These estimates indicate that the current OSHA permissible exposure limit for TCE would produce metabolite concentrations that exceed an acute no observed adverse effect level for hepatotoxicity in mice. On this basis, the OSHA TCE limit is not expected to be protective.

Animals↗
PubMed2005

Determination of age and gender differences in biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice and rats to improve PBPK modeling.

2-Butoxyethanol (BE) is the most widely used glycol ether solvent. BEs major metabolite, butoxyacetic acid (BAA), causes hemolysis with significant species differences in sensitivity. Several PBPK models have been developed over the past two decades to describe the disposition of BE and BAA in male rats and humans to refine health risk assessments. More recent efforts by Lee et al. [Lee, K.M., Dill, J.A., Chou, B.J., Roycroft, J.H., 1998. Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. Toxicol. Appl. Pharmacol. 153, 211-226] to describe the kinetics of BE and BAA in the National Toxicology Program (NTP) chronic inhalation studies required the use of several assumptions to extrapolate model parameters from earlier PBPK models developed for young male rats to include female F344 and both sexes of B6C3F1 mice and the effects of aging. To replace these assumptions, studies were conducted to determine the impact of age, gender and species on the metabolism of BE, and the tissue partitioning, renal acid transport and plasma protein binding of BAA. In the current study, the Lee et al. PBPK model was updated and expanded to include the further metabolism of BAA and the salivary excretion of BE and BAA which may contribute to the forestomach irritation observed in mice in the NTP study. The revised model predicted that peak blood concentrations of BAA achieved following 6 h inhalation exposures are greatest in young adult female rats at concentrations up to 300 ppm. This is not the case predicted for old (> or =18 months) animals, where peak blood concentrations of BAA in male and female mice were similar to or greater than female rats. The revised model serves as a quantitative tool for integrating an extensive pharmacokinetic and mechanistic database into a format that can readily be used to compare internal dosimetry across dose, route of exposure and species.

Administration, Inhalation↗
PubMed1997

Physiological "constants" for PBPK models for pregnancy.

Physiologically based pharmacokinetic (PBPK) models for pregnancy are inherently more complex than conventional PBPK models due to the growth of the maternal and embryo/fetal tissues. Physiological parameters such as compartmental volumes or flow rates are relatively constant at any particular time during gestation when an acute experiment might be conducted, but vary greatly throughout the course of gestation (e.g., contrast relative fetal weight during the first month of gestation with the ninth month). Maternal physiological parameters change during gestation, depending upon the particular system; for example, cardiac output increases by approximately 50% during human gestation; plasma protein concentration decreases during pregnancy; overall metabolism remains fairly constant. Maternal compartmental volumes may change by 10-30%; embryo/fetal volume increases over a billionfold from conception to birth. Data describing these physiological changes in the human are available from the literature. Human embryo/fetal growth can be well described using the Gompertz equation. By contrast, very little of these same types of data is available for the laboratory animal. In the rodent there is a dearth of information during organogenesis as to embryo weights, and even less organ or tissue weight or volume data during embryonic or fetal periods. Allometric modeling offers a reasonable choice to extrapolate (approximately) from humans to animals; validation, however, is confined to comparisons with limited data during the late embryonic and fetal periods of development (after gestation d 11 in the rat and mouse). Embryonic weight measurements are limited by the small size of the embryo and the current state of technology. However, the application of the laser scanning confocal microscope (LSCM) to optically section intact embryos offers the capability of precise structural measurements and computer-generated three-dimensional reconstruction of early embryos. Application of these PBPK models of pregnancy in laboratory animal models at teratogenically sensitive periods of development provides exposure values at specific target tissues. These exposures provide fundamentally important data to help design and interpret molecular probe investigations into mechanisms of teratogenesis.

Animals↗