ToxSci Advance Access published online on May 4, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm100
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Characterizing Uncertainty and Variability in Physiologically-based Pharmacokinetic (PBPK) Models: State of the Science and Needs for Research and Implementation
* US EPA, ORD, National Center for Computational Toxicology, RTP, NC, 27711, USA, barton.hugh{at}epa.gov
US EPA, ORD, National Center for Environmental Assessment, Washington, DC 20460, USA, Chiu.Weihsueh{at}epa.gov
US EPA, ORD, National Center for Computational Toxicology, RTP, NC, 27711, USA, setzer.woodrow{at}epa.gov
The Hamner Institutes For Health Sciences, Research Triangle Park, NC, 27709, USA, MAndersen{at}thehamner.org
¶ Miami University, Oxford, Ohio 45056, USA, baileraj{at}muohio.edu
|| Institut National de L'Environnement Industriel et des Risques, Unité de Toxicologie Expérimentale, 60550 Vernuil-En-Halatte, France, frederic.bois{at}ineris.fr
lll US EPA, ORD, National Center for Environmental Assessment, RTP, NC, 27711, USA, dewoskin.rob{at}epa.gov
llll Summit Toxicology, Lyons, CO 80540, USA, shays{at}summittoxicology.com
# Karolinska Institute, Stockholm, Sweden, gunnar.johanson{at}ki.se
** EC/R Incorporated, 6330 Quadrangle Drive, Suite 325, Chapel Hill, NC 27517, USA, jones.nancy{at}ecrweb.com
Health and Safety Laboratory, Buxton S17 9JN, UK, george.loizou{at}hsl.gov.uk
a US EPA, ORD, National Health and Environmental Effects Laboratory, RTP, NC 27711, USA, macphail.robert{at}epa.gov
b National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA, portier@niehs.nih.gov
c Health and Safety Laboratory, Buxton S17 9JN, UK , Martin.Spendiff{at}hsl.gov.uk
d The Hamner Institutes For Health Sciences, Research Triangle Park, NC, 27709, USA, ctan{at}thehamner.org
1 To whom correspondence should be addressed at Hugh A. Barton, Ph.D., ORD National Center for Computational Toxicology, U.S. EPA B205-01, 109 TW Alexander Drive, Research Triangle Park, NC 27711, 919-541-1995 Phone, 919-541-1194 Fax, barton.hugh{at}epa.gov
Received March 1, 2007; revision received April 20, 2007; accepted April 24, 2007
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Abstract |
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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 non-default 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 non-deterministic (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 Oct 31-Nov 2, 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 non-deterministic/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 non-deterministic/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 multi-disciplinary 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.
Key Words: Physiologically-based pharmacokinetic modeling; uncertainty; population variability; nonlinear modeling; risk assessment; Bayesian models.
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