Showing papers on "Physiologically based pharmacokinetic modelling published in 1991"

Development and utilization of physiologically based pharmacokinetic models for toxicological applications.

Abstract: Recent advances in physiologically based pharmacokinetic (PB-PK) modeling have introduced novel approaches for evaluating toxicological problems. Because PB-PK models are amenable to extrapolation of tissue dosimetry, they are increasingly being applied to chemical risk assessment. This paper reviews the development of PB-PK modeling for toxicological applications. It briefly compares and contrasts the fundamental differences between conventional compartmental analysis and PB-PK modeling. The theory and principles, data requirements and the methodologies to obtain them, and the steps to construct PB-PK models are described. A comprehensive listing of PB-PK models for environmental chemicals developed to date is referenced. Salient applications of PB-PK modeling to toxicological problems are illustrated with examples. Finally, the uncertainties and limitations in PB-PK modeling are also discussed. 84 refs.

Modeling benzene pharmacokinetics across three sets of animal data: parametric sensitivity and risk implications.

Abstract: Typically, the uncertainty affecting the parameters of physiologically based pharmacokinetic (PBPK) models is ignored because it is not currently practical to adjust their values using classical parameter estimation techniques. This issue of parametric variability in a physiological model of benzene pharmacokinetics is addressed in this paper. Monte Carlo simulations were used to study the effects on the model output arising from variability in its parameters. The output was classified into two categories, depending on whether the output of the model on a particular run was judged to be generally consistent with published experimental data. Statistical techniques were used to examine sensitivity and interaction in the parameter space. The model was evaluated against the data from three different experiments in order to test for the structural adequacy of the model and the consistency of the experimental results. The regions of the parameter space associated with various inhalation and gavage experiments are distinct, and the model as presently structured cannot adequately represent the outcomes of all experiments. Our results suggest that further effort is required to discern between the structural adequacy of the model and the consistency of the experimental results. The impact of our results on the risk assessment process for benzene is also examined.

Physiologically Based Pharmacokinetic Models: Applications in Carcinogenic Risk Assessment

Abstract: Pharmacokinetics is the study of the absorption, distribution, metabolism and elimination of chemicals in biological systems. As such, it provides a means of resolving some of the ambiguities in exposure assessment and of evaluating the scientific assumptions upon which risk assessment is based.

Physiologically-based pharmacokinetic models in risk and exposure assessment.

Abstract: Pharmacokinetic non-linearities occur between different doses and between different species. Physiologically based pharmacokinetic models are accurate tools for taking these non-linearities into account. Dichloromethane and perchloroethylene are two examples discussed in this paper. For dichloromethane the pharmacokinetic non-linearity factor results in a greater delivered dose than would be predicted from linear relationships as the dose increases. For perchloroethylene the opposite holds true. In addition a brief illustration of the use of pharmacokinetic models as tools for interpreting biomarker data is provided.

Effects ofconsumption ofethanol on thebiological monitoring ofexposuretoorganicsolvent vapours: asimulation study withtrichloroethylen e

Abstract: Thisstudyillustrates possible influences of consumptionofethanolon thepharmacokinetic behaviour ofinhaled trichloroethylene (TRI)inrelation tobiological monitoring ofexposure. The results wereobtained for a standardmale workerof 70kg by physiologically based pharmacokinetic modelling. Depending onthepatternofconsumptionofethanol, enzymeinhibition or induction was assumedto prevailinthis worker.The inhibition andinduction were modelledbyassuming competitive metabolic interaction betweenTRI and ethanoland increased maximum velocity (Vmax)ofTRI metabolismrespectively. Ingestionof moderateamountsofethanol before thestart ofworkoratlunchtime,butnotattheendof work,causedpronounced increases inblood TRIconcentrations anddecreases intheurinaryexcretion ratesofTRI metabolites, this effect lasting until thenextday.Theeffects were smaller thehigher theexposure concentration ofTRI.Induction ofTRI metabolism, supposedlyby consumptionof ethanolthe previous evening, causedonlysmallchangesin thepharmacokinetic profile at50ppm, but appreciable changes at500ppm.