Sensitivity of Physiologically Based Pharmacokinetic Models to Variation in Model Parameters: Methylene Chloride
- 1 August 1994
- journal article
- Published by Wiley in Risk Analysis
- Vol. 14 (4), 521-531
- https://doi.org/10.1111/j.1539-6924.1994.tb00268.x
Abstract
The parameters in a physiologically based pharmacokinetic (PBPK) model of methylene chloride were varied systematically, and the resulting variation in a number of model outputs was determined as a function of time for mice and humans at several exposure concentrations. The importance of the various parameters in the model was highly dependent on the conditions (concentration, species) for which the simulation was performed and the model output (dose surrogate) being considered. Model structure also had a significant impact on the results. For sensitivity analysis, particular attention must be paid to conservation equations to ensure that the variational calculations do not alter mass balance, introducing extraneous effects into the model. All of the normalized sensitivity coefficients calculated in this study ranged between -1.12 and 1, and most were much less than 1 in absolute value, indicating that individual input errors are not greatly amplified in the outputs. In addition to ranking parameters in terms of their impact on model predictions, time-dependent sensitivity analysis can also be used as an aid in the design of experiments to estimate parameters by predicting the experimental conditions and sampling points which will maximize parameter identifiability.Keywords
This publication has 6 references indexed in Scilit:
- Sensitivity analysis for physiologically based pharmacokinetic modelsJournal of Pharmacokinetics and Biopharmaceutics, 1991
- Precision and sensitivity of pharmacokinetic models for cancer risk assessment: Tetrachloroethylene in mice, rats, and humansToxicology and Applied Pharmacology, 1990
- Evaluation of uncertainty in input parameters to pharmacokinetic models and the resulting uncertainty in outputToxicology Letters, 1989
- Variability of safe dose estimates when using complicated models of the carcinogenic process A case study: Methylene chlorideFundamental and Applied Toxicology, 1989
- Physiologically based pharmacokinetics and the risk assessment process for methylene chlorideToxicology and Applied Pharmacology, 1987
- Risk Assessment Extrapolations and Physiological ModelingToxicology and Industrial Health, 1985