Characterizing uncertainty and variability in physiologically based pharmacokinetic models: state of the science and needs for research and implementation.
Physiologically based pharmacokinetic (PBPK) models are used in mode-of-action based risk and safety assessments to estimate internal dosimetry in animals and humans. When used in risk assessment, these models can provide a basis for extrapolating between species, doses, and exposure routes or for justifying nondefault values for uncertainty factors. Characterization of uncertainty and variability is increasingly recognized as important for risk assessment; this represents a continuing challenge for both PBPK modelers and users. Current practices show significant progress in specifying deterministic biological models and nondeterministic (often statistical) models, estimating parameters using diverse data sets from multiple sources, using them to make predictions, and characterizing uncertainty and variability of model parameters and predictions. The International Workshop on Uncertainty and Variability in PBPK Models, held 31 Oct-2 Nov 2006, identified the state-of-the-science, needed changes in practice and implementation, and research priorities. For the short term, these include (1) multidisciplinary teams to integrate deterministic and nondeterministic/statistical models; (2) broader use of sensitivity analyses, including for structural and global (rather than local) parameter changes; and (3) enhanced transparency and reproducibility through improved documentation of model structure(s), parameter values, sensitivity and other analyses, and supporting, discrepant, or excluded data. Longer-term needs include (1) theoretical and practical methodological improvements for nondeterministic/statistical modeling; (2) better methods for evaluating alternative model structures; (3) peer-reviewed databases of parameters and covariates, and their distributions; (4) expanded coverage of PBPK models across chemicals with different properties; and (5) training and reference materials, such as cases studies, bibliographies/glossaries, model repositories, and enhanced software. The multidisciplinary dialogue initiated by this Workshop will foster the collaboration, research, data collection, and training necessary to make characterizing uncertainty and variability a standard practice in PBPK modeling and risk assessment.
Barton
Hugh A
HA
US EPA, ORD, National Center for Computational Toxicology, Research Triangle Park, North Carolina 27711, USA. barton.hugh@epa.gov
Chiu
Weihsueh A
WA
Setzer
R Woodrow
RW
Andersen
Melvin E
ME
Bailer
A John
AJ
Bois
Frédéric Y
FY
Dewoskin
Robert S
RS
Hays
Sean
S
Johanson
Gunnar
G
Jones
Nancy
N
Loizou
George
G
Macphail
Robert C
RC
Portier
Christopher J
CJ
Spendiff
Martin
M
Tan
Yu-Mei
YM
D000818:Animals; D002138:Calibration; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D018570:Risk Assessment