Showing papers on "Physiologically based pharmacokinetic modelling published in 1995"
TL;DR: The MOE approach is recommended as an alternative to the LMS approach for chemicals with a carcinogenic mode of action which entails increased cell proliferation, leading to the expectation of a highly nonlinear cancer dose-response.
103 citations
TL;DR: Results indicate that the CCA is a potentially useful concept for studying the action of compounds with reactive metabolites.
88 citations
TL;DR: The burgeoning use of PBPK models in toxicology research and chemical risk assessment today is primarily related to their ability to make more accurate predictions of target tissue dose for different exposure situations in different animal species, including humans.
86 citations
TL;DR: The simulations with the human TOL/XYL mixture PBPK model indicate that an eight hour co-exposure to concentrations that remain within the current threshold limit values of TOL and XYL would not result in significant pharmacokinetic interferences, thus implying that data on biological monitoring of worker exposure to these solvents would be unaffected during co-Exposures.
Abstract: A physiologically-based pharmacokinetic (PBPK) model for a mixture of toluene (TOL) and xylene (XYL), developed and validated in the rat, was used to predict the uptake and disposition kinetics of TOL/XYL mixture in humans. This was accomplished by substituting the rat physiological parameters and the blood:air partition coefficient with those of humans, scaling the maximal velocity for hepatic metabolism on the basis of body weight0.75, and keeping all other model parameters species-invariant. The human TOL/XYL mixture PBPK model, developed based on the quantitative biochemical mechanism of interaction elucidated in the rat (i.e., competitive metabolic inhibition), simulated adequately the kinetics of TOL and XYL during combined exposures in humans. The simulations with this PBPK model indicate that an eight hour co-exposure to concentrations that remain within the current threshold limit values of TOL (50 ppm) and XYL (100 ppm) would not result in significant pharmacokinetic interferences, thus implying that data on biological monitoring of worker exposure to these solvents would be unaffected during co-exposures.
72 citations
Book•
08 Oct 1995
TL;DR: A concise guide to mathematical modeling and analysis of pharmacokinetic data is given in this paper, which contains valuable methods for maximizing the information obtained from given data, and is an ideal resource for scientists, scholars, and advanced students.
Abstract: A concise guide to mathematical modeling and analysis of pharmacokinetic data, this book contains valuable methods for maximizing the information obtained from given data. It is an ideal resource for scientists, scholars, and advanced students.
70 citations
TL;DR: It is contention that PBPK modeling should be viewed as one of many modeling tools for drug development, and guidelines on when P BPK modeling techniques could be applied in an industrial setting to satisfy the needs of regulatory customers are provided.
Abstract: Since the pioneering work of Haggard and Teorell in the first half of the 20th century, and of Bischoff and Dedrick in the late 1960s, physiologically based pharmacokinetic (PBPK) modeling has gone through cycles of general acceptance, and of healthy skepticism. Recently, however, the trend in the pharmaceuticals industry has been away from PBPK models. This is understandable when one considers the time and effort necessary to develop, test, and implement a typical PBPK model, and the fact that in the present-day environment for drug development, efficacy and safety must be demonstrated and drugs brought to market more rapidly. Although there are many modeling tools available to the pharmacokineticist today, many of which are preferable to PBPK modeling in most circumstances, there are several situations in which PBPK modeling provides distinct benefits that outweigh the drawbacks of increased time and effort for implementation. In this Commentary, we draw on our experience with this modeling technique in an industry setting to provide guidelines on when PBPK modeling techniques could be applied in an industrial setting to satisfy the needs of regulatory customers. We hope these guidelines will assist researchers in deciding when to apply PBPK modeling techniques. It is our contention that PBPK modeling should be viewed as one of many modeling tools for drug development.
66 citations
TL;DR: A physiologically based pharmacokinetic model for methyl mercury in the pregnant rat and fetus has been developed and will allow the development of target organ (brain) dose-response relationships from studies of developmental toxicity in the rat which can be extrapolated to human physiology and used to develop exposure guidelines and standards that are protective against the MeHg exposure to the fetus.
56 citations
TL;DR: PBPK modeling helps to identify the factors that are most important in determining the health risks associated with exposure to a chemical, and provides a means for estimating the impact of those factors both on the average risk to a population and on the specific risk to an individual.
52 citations
TL;DR: Methods for assessing the impact of uncertainty in the parameter values on prediction of tissue dose are proposed, along with methods for identifying those parameters to which predictions of tissue doses are most sensitive.
Abstract: Physiologically based pharmacokinetic (PBPK) models are now commonly used to predict the dose of toxic metabolites of chemical substances reaching target tissues. A typical PBPK model can involve 20 or more physiological, physiochemical, and biochemical parameters, each of which is estimated with some degree of error. In this article, methods for assessing the impact of uncertainty in the parameter values on prediction of tissue dose are proposed, along with methods for identifying those parameters to which predictions of tissue doses are most sensitive. Many of the model parameters are related to body weight, which is assumed to vary in accordance with a doubly truncated normal distribution. The application of the proposed methods is illustrated using a PBPK model for benzene.
50 citations
TL;DR: This review paper gives an overview of the building blocks of physiologically based pharmacokinetic (PBPK) models and their implementation using computer facilities and two common assumptions are revisited: the flow-limited assumption and the metabolic clearance using Michaelis-Menten kinetics assumption.
50 citations
TL;DR: The research effort is devoted to the challenges and potential applications of physiologically based pharmacokinetic/pharmacodynamic modeling in the risk assessment of chemical mixtures, and 3 specific research projects are described.
TL;DR: It will be possible to eliminate an uncertainty factor of 10 for interspecies extrapolations in the 2-methoxyethanol risk assessment if the PBPK model described here is used.
TL;DR: A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of its primary metabolite and proximate toxicant 2-methoxyacetic acid in the pregnant CD-1 mouse to facilitate more realistic human risk assessments for the developmental toxicity of 2-ME and related compounds.
TL;DR: One of the specific research projects is described: PB-PK/PD modeling of toxicologic interactions between Kepone and carbon tetrachloride and the coupling of Monte Carlo simulation for the prediction of acute toxicity.
TL;DR: A sex-specific, physiologically based pharmacokinetic model has been developed to describe the absorption, distribution, and elimination of fluorides in rats and humans and provides a basis for across-species extrapolation of the effective fluoride dose at the target tissue, bone in the assessment of risk from different exposure conditions.
TL;DR: A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations.
Abstract: A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10-6 lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10-6 risk.
TL;DR: The results suggest that the default assumption of using rat tissue:air PCs in human PBPK models may be acceptable for certain tissues (liver, adipose tissues), but questionable for others (e.g., muscle).
Abstract: The objective of this study was to develop an approach for incorporating tissue composition data into physiologically based pharmacokinetic (PBPK) models in order to facilitate "built-in" calculation of tissue: air partition coefficients (PCs) of volatile organic chemicals. The approach involved characterizing tissue compartments within PBPK models as a mixture of neutral lipids, phospholipids, and water (instead of using the conventional description of them as "empty" boxes). This approach enabled automated calculation of the tissue solubility of chemicals from n-octanol and water solubility data, since these data approximate those of solubility in tissue lipids and water. Tissue solubility was divided by the saturable vapor concentration at 37 degrees C to estimate the tissue: air PCs within PBPK models, according to the method of Poulin and Krishnan (1995c). The highest and lowest lipid and water levels for human muscle, liver, and adipose tissues were obtained from the literature and incorporated within the tissue composition-based PBPK model to calculate the tissue: air PCs of dichloromethane (DCM) and simulate the pharmacokinetics of DCM in humans. The PC values predicted for human tissues were comparable to those estimated using rat tissues in cases where the relative levels of lipids and water were comparable in both species. These results suggest that the default assumption of using rat tissue: air PCs in human PBPK models may be acceptable for certain tissues (liver, adipose tissues), but questionable for others (e.g., muscle). The PBPK modeling exercise indicated that the interindividual differences in tissue dose arising from variations of tissue: air PCs may not be reflected sufficiently by venous blood concentrations. Overall, the present approach of incorporating tissue composition data into PBPK models would not only enhance the biological basis of these models but also provide a means of evaluating the impact of interindividual and interspecies differences in tissue composition on the tissue dose surrogates used in PBPK-based risk assessments.
TL;DR: Salient applications of PBPK/PD modeling to health risk assessments and characterization of hazardous substances are illustrated with examples.
TL;DR: A computer program is described that allowed us to link a physiologically based pharmacokinetic (PBPK) model for lactational transfer of PCE in the lactating mother with the estimate of extra cancer risk for breast-fed infants, according to the U.S. Environmental Protection Agency (EPA) methodology.
TL;DR: 'Predictive and Alternative Toxicology' in terms of tissue dosimetry at the pharmacokinetic and pharmacodynamic levels is achievable with simple and complex but chemically defined mixtures.
TL;DR: The use of Physiologically-based pharmacokinetic (PB-PK) models for risk assessment with drugs and xenobiotics has been studied for almost 70 years in the literature.
TL;DR: A basic PBPK model for the dosimetry of organic acids in discrete areas of the brain was constructed using 2,4-D as a model compound and could be a useful tool for evaluating the safety of this class oforganic acids.
TL;DR: The rationale for research to reduce extrapolation-related uncertainties is surveyed, focusing specifically on the need to develop mechanistically based methods and models, including test methods to identify and characterize health effects, integrated human exposure models, physiologically based pharmacokinetic (PBPK) models and biologically based dose-response (BBDR) models.
TL;DR: As default positions are replaced by biological data the risk assessments become less uncertain when extrapolating between species, and combining information on tissue dosimetry and response data can also provide an estimate of variability within populations, which is impossible with present default type methodology.
TL;DR: Experimental evidence is provided of the utility of the PBPK model for PCE in interspecies, route-to-route, and dose extrapolations in venous blood of unanesthetized male Sprague-Dawley rats and beagle dogs.
Abstract: The ability of a physiologically based pharmacokinetic (PBPK) model to predict the uptake and elimination of perchloroethylene (PCE) in venous blood was evaluated by comparison of model simulations with experimental data for two species, two routes of exposure, and three dosage levels. Unanesthetized male Sprague-Dawley rats and beagle dogs were administered 1, 3, or 10 mg PCE/kg body weight in polyethylene glycol 400 as a single bolus, either by gavage or by intraarterial (ia) injection. Serial blood samples were obtained from a jugular vein cannula for up to 96 h following dosing. The PCE concentrations were analyzed by headspace gas chromatography. For each dose and route of administration, terminal elimination half-lives in rats were shorter than in dogs, and areas under the blood concentration-time curve were smaller in rats than in dogs. Over a 10-fold range of doses, PCE blood levels in the rat were well predicted by the PBPK model following ia administration, and slightly underpredicted following oral administration. The PCE concentrations in dog blood were generally overpredicted, except for fairly precise predictions for the 3 mg/kg oral dose. These studies provide experimental evidence of the utility of the PBPK model for PCE in interspecies, route-to-route, and dose extrapolations.
TL;DR: PBPK models have been successfully used to predict the dose and time-dependent chemical disposition and protein induction properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a wide variety of experimental data sets with rodents.
TL;DR: This paper shows that, for a class of dynamical models widely used in biologically-based risk assessments, it is unnecessary to estimate the values of the individual parameters, and proves that this is the case for the class of linear, constant-coefficient, globally stable compartmental flow systems used in many classical pharmacokinetic and low-dose PBPK models.
Abstract: It is sometimes argued that the use of increasingly complex "biologically-based" risk assessment (BBRA) models to capture increasing mechanistic understanding of carcinogenic processes may run into a practical barrier that cannot be overcome in the near term: the need for unrealistically large amounts of data about pharmacokinetic and pharmacodynamic parameters. This paper shows that, for a class of dynamical models widely used in biologically-based risk assessments, it is unnecessary to estimate the values of the individual parameters. Instead, the input-output properties of such a model--specifically, the ratio of the area-under-curve (AUC) for any selected output to the AUC of the input--is determined by a single aggregate "reduced" constant, which can be estimated from measured input and output quantities. Uncertainties about the many individual parameter values of the model, and even uncertainties about its internal structure, are irrelevant for purposes of quantifying and extrapolating its input-output (e.g., dose-response) behavior. We prove that this is the case for the class of linear, constant-coefficient, globally stable compartmental flow systems used in many classical pharmacokinetic and low-dose PBPK models. Examples are cited that suggest that the value of the reduced parameter representing such a system's aggregate behavior may be relatively insensitive to changes in (and hence to uncertainties about) the values of individual parameters. The theory is illustrated with a model of pharmacokinetics and metabolism of cyclophosphamide (CP), a drug widely used in cancer chemotherapy and as an immunosuppressive agent.
TL;DR: Although there are a variety of potential technical problems associated with the use of these models for hazard identification and risk assessment, PBPK/PD modeling represents an important technical advance in risk assessment methodology that should continue to be developed and applied.
TL;DR: The proceedings in this volume suggest several important future research needs to validate modeling in toxicology and to include applied mathematics of toxicology, including both SAR and PBPK modeling, inoxicology curricula.
01 Apr 1995
TL;DR: The physiologically based pharmacokinetic (PBPK) model was used to describe mathematically the disposition and metabolism of the chemicals employing chemical-specific parameters and apparent whole-body metabolic constants calculated from these expenments.
Abstract: : The purpose of this study was to measure the tissue to air partition coefficients and to describe the uptake and distribution kinetics of iodohalogenated compounds iodotrifluoromethane (CF3I), perfluorohexyl iodide (C6F13I) and l-iodoheptafluoropropane (C3F7l) via closed chamber recirculating gas uptake methods. Inhalation pharmacokinetics for all chemicals were determined experimentally in Fischer-344 (F-344) male rats. A physiologically based pharmacokinetic (PBPK) model was used to describe mathematically the disposition and metabolism of the chemicals employing chemical-specific parameters and apparent whole-body metabolic constants calculated from these expenments