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PBPK models in risk assessment--A focus on chloroprene.
Chem Biol Interact. 2007 Mar 20; 166(1-3):352-9.CB

Abstract

Mathematical models are increasingly being used to simulate events in the exposure-response continuum, and to support quantitative predictions of risks to human health. Physiologically based pharmacokinetic (PBPK) models address that portion of the continuum from an external chemical exposure to an internal dose at a target site. Essential data needed to develop a PBPK model include values of key physiological parameters (e.g., tissue volumes, blood flow rates) and chemical specific parameters (rate of chemical absorption, distribution, metabolism, and elimination) for the species of interest. PBPK models are commonly used to: (1) predict concentrations of an internal dose over time at a target site following external exposure via different routes and/or durations; (2) predict human internal concentration at a target site based on animal data by accounting for toxicokinetic and physiological differences; and (3) estimate variability in the internal dose within a human population resulting from differences in individual pharmacokinetics. Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, P.M. Hinderliter, Kinetic modeling of beta-chloroprene metabolism. I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans, Toxicol. Sci. 79 (1) (2004) 18-27; M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28-37] developed a PBPK model for chloroprene (2-chloro-1,3-butadiene; CD) that simulates chloroprene disposition in rats, mice, hamsters, or humans following an inhalation exposure. Values for the CD-PBPK model metabolic parameters were obtained from in vitro studies, and model simulations compared to data from in vivo gas uptake studies in rats, hamsters, and mice. The model estimate for total amount of metabolite in lung correlated better with rodent tumor incidence than did the external dose. Based on this PBPK model analytical approach, Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28-37; M.W. Himmelstein, R. Leonard, R. Valentine, Kinetic modeling of beta-chloroprene metabolism: default and physiologically-based modeling approaches for cancer dose response, in: IISRP Symposium on Evaluation of Butadiene & Chloroprene Health Effects, September 21, 2005, TBD--reference in this proceedings issue of Chemical-Biological Interactions] propose that observed species differences in the lung tumor dose-response result from differences in CD metabolic rates. The CD-PBPK model has not yet been submitted to EPA for use in developing the IRIS assessment for chloroprene, but is sufficiently developed to be considered. The process that EPA uses to evaluate PBPK models is discussed, as well as potential applications for the CD-PBPK model in an IRIS assessment.

Authors+Show Affiliations

US EPA/NCEA (National Center for Environmental Assessment), Mail Drop B243-01, Research Triangle Park, NC 27711, USA. dewoskin.rob@epa.gov

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17324392

Citation

DeWoskin, Robert S.. "PBPK Models in Risk assessment--A Focus On Chloroprene." Chemico-biological Interactions, vol. 166, no. 1-3, 2007, pp. 352-9.
DeWoskin RS. PBPK models in risk assessment--A focus on chloroprene. Chem Biol Interact. 2007;166(1-3):352-9.
DeWoskin, R. S. (2007). PBPK models in risk assessment--A focus on chloroprene. Chemico-biological Interactions, 166(1-3), 352-9.
DeWoskin RS. PBPK Models in Risk assessment--A Focus On Chloroprene. Chem Biol Interact. 2007 Mar 20;166(1-3):352-9. PubMed PMID: 17324392.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PBPK models in risk assessment--A focus on chloroprene. A1 - DeWoskin,Robert S, Y1 - 2007/02/08/ PY - 2006/03/15/received PY - 2007/01/24/revised PY - 2007/01/25/accepted PY - 2007/2/28/pubmed PY - 2007/5/24/medline PY - 2007/2/28/entrez SP - 352 EP - 9 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 166 IS - 1-3 N2 - Mathematical models are increasingly being used to simulate events in the exposure-response continuum, and to support quantitative predictions of risks to human health. Physiologically based pharmacokinetic (PBPK) models address that portion of the continuum from an external chemical exposure to an internal dose at a target site. Essential data needed to develop a PBPK model include values of key physiological parameters (e.g., tissue volumes, blood flow rates) and chemical specific parameters (rate of chemical absorption, distribution, metabolism, and elimination) for the species of interest. PBPK models are commonly used to: (1) predict concentrations of an internal dose over time at a target site following external exposure via different routes and/or durations; (2) predict human internal concentration at a target site based on animal data by accounting for toxicokinetic and physiological differences; and (3) estimate variability in the internal dose within a human population resulting from differences in individual pharmacokinetics. Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, P.M. Hinderliter, Kinetic modeling of beta-chloroprene metabolism. I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans, Toxicol. Sci. 79 (1) (2004) 18-27; M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28-37] developed a PBPK model for chloroprene (2-chloro-1,3-butadiene; CD) that simulates chloroprene disposition in rats, mice, hamsters, or humans following an inhalation exposure. Values for the CD-PBPK model metabolic parameters were obtained from in vitro studies, and model simulations compared to data from in vivo gas uptake studies in rats, hamsters, and mice. The model estimate for total amount of metabolite in lung correlated better with rodent tumor incidence than did the external dose. Based on this PBPK model analytical approach, Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28-37; M.W. Himmelstein, R. Leonard, R. Valentine, Kinetic modeling of beta-chloroprene metabolism: default and physiologically-based modeling approaches for cancer dose response, in: IISRP Symposium on Evaluation of Butadiene & Chloroprene Health Effects, September 21, 2005, TBD--reference in this proceedings issue of Chemical-Biological Interactions] propose that observed species differences in the lung tumor dose-response result from differences in CD metabolic rates. The CD-PBPK model has not yet been submitted to EPA for use in developing the IRIS assessment for chloroprene, but is sufficiently developed to be considered. The process that EPA uses to evaluate PBPK models is discussed, as well as potential applications for the CD-PBPK model in an IRIS assessment. SN - 0009-2797 UR - https://www.unboundmedicine.com/medline/citation/17324392/PBPK_models_in_risk_assessment__A_focus_on_chloroprene_ DB - PRIME DP - Unbound Medicine ER -
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