To establish safe exposure guidelines and limits, EPA often relies on mathematical models to inform extrapolations from experiments to real-world scenarios. The accuracy of these extrapolations and the risk assessments they inform continues to be improved by the development of models that are based on specific knowledge about what happens when an individual is exposed to a toxin.
In particular, physiologically-based pharmacokinetic (PBPK) models are based on knowledge of how a toxin enters the body, the path a toxin takes as it moves through the body, how it is broken down, and how it exits. PBPK models also take into account the interaction of multiple biochemical and physiological processes and allow scientists to take into account differences between individuals that may be based on age, genetics, lifestyle factors such as smoking or alcohol consumption, or health conditions such as diabetes or obesity.
In December 2008, EPA released the Physiological Parameters Database for Older Adults (Beta 1.1), developed under contractual agreement, containing values of human physiological parameters specific to older adults obtained from published scientific literature. EPA is currently involved in several efforts to compile these data into electronic formats, such as relational databases, in order to provide a resource for facilitating and improving PBPK model development. One such database is already publically available with parameters specific to neonatal rodents (Database of Physiological Parameters for Early Life Rats and Mice).
In August 2006, EPA's National Center for Environmental Assessment published the report Approaches for the Application of Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment. This report is a definitive desk reference and learning tool for risk assessors and risk managers who are interested in evaluating and using PBPK models in their work.
The March 2006 report, Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Inter-individual Differences in Physiology and Biochemistry Pertinent to Risk, also published by EPA's National Center for Environmental Assessment, provides guidance on using PBPK models to account for differences in individuals' response to toxins. This report contains tutorial materials and contains case studies of two chemicals that are important water contaminants, trichloroethylene and chloroform.
Kedderis, G. L. AND J. Lipscomb. Application of in Vitro Biotransformation Data and Pharmacokinetic Modeling to Risk Assessment. TOXICOLOGY AND INDUSTRIAL HEALTH. Princeton Scientific Publishers, Princeton, NJ, 17(5-10): 315-321, (2001).
U.S. EPA. Approaches for the Application of Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment (Final Report). U.S. Environmental Protection Agency, Washington, D.C., EPA/600/R-05/043F.
U.S. EPA. Considerations for Developing a Dosimetry-Based Cumulative Risk Assessment Approach for Mixtures of Environmental Contaminants (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-07/064, 2009.
CALDWELL, J. C., M. V. EVANS, AND K. Krishnan. Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms [journal Article]. , Journal of Toxicology. Hindawi Publishing Corporation, New York, NY, 2012:10, (2012).
Lipscomb, J. AND G. L. Kedderis. Incorporating Human Interindividual Biotransformation Variance in Health Risk Assessment. , The Science of The Total Environment (2002).
CHIU, W. AND P. WHITE. Steady-State Solutions to PBPK Models and Their Applications to Risk Assessment I: Route-to-Route Extrapolation of Volatile Chemicals Authors' Response to Letter By Dr. Kenneth Bogen. RISK ANALYSIS. Blackwell Publishing, Malden, MA, 26(3):769-780, (2006).
CALDWELL, J. C., K. Krishnan, AND M. V. Evans. State of the Science: Biologically Based Modeling in Risk Assessment [editorial]. , Journal of Toxicology. Hindawi Publishing Corporation, New York, NY, 2012:2, (2012).
CHIU, W. Uncertainties in Trichloroethylene Pharmacokinetic Models. , INSIDE EPA. Inside Washington Publishers, Washington, DC, 13(20), (2006).
U.S. EPA. Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk (Final Report). U.S. Environmental Protection Agency, Washington, D.C., EPA/600/R-06/014A.
U.S. EPA. Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-08/090.