Applications of global sensitivity analysis to the optimization of a dermal PBPK model of bromochloromethane. (English) Zbl 1486.92070

Summary: Physiologically based pharmacokinetic (PBPK) models can be used to develop frameworks for risk assessment and predictive toxicology testing routines. However, the predictive power of these models is only as good as the confidence in the parameters within the model itself. Sensitivity analysis, or the study of the effect of propagated error on the predictive power of the model, can be used to determine which model parameters are most likely to affect change in the model. This is important when considering optimization routines, as optimizing non-sensitive parameters may lead to biologically incorrect parameter estimates. This study explores the sensitivity of physiological, metabolic, and chemical-specific parameters for a published dermal exposure PBPK model of bromochloromethane.


92C45 Kinetics in biochemical problems (pharmacokinetics, enzyme kinetics, etc.)
34C60 Qualitative investigation and simulation of ordinary differential equation models


SAFE Toolbox
Full Text: DOI


[1] F. Campolongo and A. Saltelli, Sensitivity analysis of an environmental model: an application of different analysis methods, Reliability Engineering & System Safety, 57.1 (1997), 49-69.
[2] F. Campolongo, J. Cariboni, and A. Saltelli, An effective screening design for sensitivity analysis of large models, Environmental modeling and software, 22.10 (2007), 1509-1518.
[3] W. A. Chiu, M. S. Okino, and M. V. Evans, Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and bayesian approach, Toxicology and Applied Pharmacology, 241.1 (2009), 36-60.
[4] W. S. Cuello, T. A. T. Janes, J. M. Jessee, M. A. Venecek, M. E. Sawyer, C. R. Eklund, and M. V. Evans, Physiologically based pharmacokinetic (PBPK) modeling of metabolic pathways of bromochloromethane in rats, Journal of Toxicology, 2012.
[5] M. D. Delp, M. V. Evans, and C. Duan, Effects of aging on cardiac output, regional blood flow, and body composition in Fischer-344 rats, Journal of Applied Physiology, 85.5 (1998), 1813-1822.
[6] N.-H. Hsieh, B. Reisfeld, F. Y. Bois, and W. A. Chiu, Applying a global sensitivity analysis workflow to improve the computational efficiencies in physiologically-based pharmacokinetic modeling, Frontiers in Pharmacology, 9 (2018), 588, ISSN 1663-9812.
[7] International Agency for Research on Cancer and others, Chlorinated drinking-water; chlorination by-products; some other halogenated compounds; cobalt and cobalt compounds, IARC monographs on the evaluation of carcinogenic risks to humans, 52 (1991).
[8] G. W. Jepson and J. N. McDougal, Physiologically based modeling of nonsteady state dermal absorption of halogenated methanes from an aqueous solution, Toxicology and Applied Pharmacology, 144.2 (1997), 315-324.
[9] K. McNally, R. Cotton, and G. Loizou, A workflow for global sensitivity analysis of PBPK models, Frontiers in Pharmacology, 2 (2011), ISSN 1663-9812.
[10] IM. D. Morris, Factorial sampling plans for preliminary computational experiments, Technometrics, 33.2 (1991), 161-174.
[11] F. Pianosi, F. Sarrazin, and T. Wagener, A Matlab toolbox for global sensitivity analysis, Environmental Modeling and Software, 70 (2015), 80-85.
[12] G. Sin and K. V. Gernaey, Improving the Morris method for sensitivity analysis by scaling the elementary effects, In Computer Aided Chemical Engineering, Elsevier, 26 (2009), 925-930.
[13] C. M. Thompson, B. Sonawane, H. A. Barton, R. S. DeWoskin, J. C. Lipscomb, P. Schlosser, W. A. Chiu, and K. Krishnan, Approaches for applications of physiologically based pharmacokinetic models in risk assessment, Journal of Toxicology and Environmental Health, Part B, 11. (2008), 519-547.
[14] United States Environmental Protection Agency, Health and environmental effects document for bromochloromethane, Tech. Rep. EPA/600/8-91/016 (NTSI PB91213702), Washington, DC, 1990.
[15] United States Environmental Protection Agency, Bromochloromethane testing rationale, Tech. Rep. CAS 74-97-5 (NTSI 201-16826A), Washington, DC, 2009.
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. In some cases that data have been complemented/enhanced by data from zbMATH Open. This attempts to reflect the references listed in the original paper as accurately as possible without claiming completeness or a perfect matching.