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Addressing Early Life Sensitivity Using Physiologically Based Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation
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  • Journal title : Toxicological Research
  • Volume 32, Issue 1,  2016, pp.15-20
  • Publisher : The Korean Society of Toxicology
  • DOI : 10.5487/TR.2016.32.1.015
 Title & Authors
Addressing Early Life Sensitivity Using Physiologically Based Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation
Yoon, Miyoung; Clewell, Harvey J. III;
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Physiologically based pharmacokinetic (PBPK) modeling can provide an effective way to utilize in vitro and in silico based information in modern risk assessment for children and other potentially sensitive populations. In this review, we describe the process of in vitro to in vivo extrapolation (IVIVE) to develop PBPK models for a chemical in different ages in order to predict the target tissue exposure at the age of concern in humans. We present our on-going studies on pyrethroids as a proof of concept to guide the readers through the IVIVE steps using the metabolism data collected either from age-specific liver donors or expressed enzymes in conjunction with enzyme ontogeny information to provide age-appropriate metabolism parameters in the PBPK model in the rat and human, respectively. The approach we present here is readily applicable to not just to other pyrethroids, but also to other environmental chemicals and drugs. Establishment of an in vitro and in silico-based evaluation strategy in conjunction with relevant exposure information in humans is of great importance in risk assessment for potentially vulnerable populations like early ages where the necessary information for decision making is limited.
Early life sensitivity;PBPK;IVIVE;Ontogeny;
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Shedding New Lights with the Breakthrough Ideas to Understand Current Trends in Modern Toxicology, Toxicological Research, 2016, 32, 1, 1  crossref(new windwow)
Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine, Journal of Pharmacokinetics and Pharmacodynamics, 2016, 43, 5, 481  crossref(new windwow)
Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays, Archives of Toxicology, 2017, 1432-0738  crossref(new windwow)
Andersen, M.E. and Krewski, D. (2010) The vision of toxicity testing in the 21st century: moving from discussion to action. Toxicol. Sci., 117, 17-24. crossref(new window)

Judson, R.S., Kavlock, R.J., Setzer, R.W., Hubal, E.A., Martin, M.T., Knudsen, T.B., Houck, K.A., Thomas, R.S., Wetmore, B.A. and Dix, D.J. (2011) Estimating toxicity-related biological pathway altering doses for high-throughput chemical risk assessment. Chem. Res. Toxicol., 24, 451-462. crossref(new window)

Knudsen, T.B., Houck, K.A., Sipes, N.S., Singh, A.V., Judson, R.S., Martin, M.T., Weissman, A., Kleinstreuer, N.C., Mortensen, H.M., Reif, D.M., Rabinowitz, J.R., Setzer, R.W., Richard, A.M., Dix, D.J. and Kavlock, R.J. (2011) Activity profiles of 309 ToxCast chemicals evaluated across 292 biochemical targets. Toxicology, 282, 1-15. crossref(new window)

Ankley, G.T., Bennett, R.S., Erickson, R.J., Hoff, D.J., Hornung, M.W., Johnson, R.D., Mount, D.R., Nichols, J.W., Russom, C.L., Schmieder, P.K., Serrrano, J.A., Tietge, J.E. and Villeneuve, D.L. (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ. Toxicol. Chem., 29, 730-741. crossref(new window)

Clewell, H.J., Tan, Y.M., Campbell, J.L. and Andersen, M.E. (2008) Quantitative interpretation of human biomonitoring data. Toxicol. Appl. Pharmacol., 231, 122-133. crossref(new window)

Yoon, M., Cambell, J.L., Andersen, M.E. and Clewell, H.J. (2012) Quantitative in vitro to in vivo extrapolation of cellbased toxicity assay results. Crit. Rev. Toxicol., 42, 633-652. crossref(new window)

Clewell, H.J., Gentry, P.R., Covington, T.R., Sarangapani, R. and Teeguarden, J.G. (2004) Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Toxicol. Sci., 79, 381-393. crossref(new window)

Saghir, S.A., Khan, S.A. and McCoy, A.T. (2012) Ontogeny of mammalian metabolizing enzymes in humans and animals used in toxicological studies. Crit. Rev. Toxicol., 42, 323-357. crossref(new window)

Clewell, H.J., Teequarden, J., McBonald, T., Sarangapani, R., Lawrence, G., Covington, T., Gentry R. and Shipp, A. (2002) Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Crit. Rev. Toxicol., 32, 329-389. crossref(new window)

Clewell, H.J., Reddy, M.B., Lave, T. and Andersen, M.E. (2007) Physiologically Based Pharmacokinetic Modeling. Preclinical Development Handbook, John Wiley and Sons, Inc. pp. 1167-1227.

Phillips, M.B., Yoon, M.Y., Young, B. and Tan, Y.M. (2014) Analysis of biomarker utility using a PBPK/PD model for carbaryl. Front. Pharmacol., 5, 246.

Price, P.S., Schnelle, K.D., Cleveland, C.B., Bartels, M.J., Hinderliter, P.M., Timchalk, C. and Poet, T.S. (2011) Application of a source-to-outcome model for the assessment of health impacts from dietary exposures to insecticide residues. Regul. Toxicol. Pharmacol., 61, 23-31. crossref(new window)

Brown, R.P., Delp, M.D., Lindstedt, S.L., Rhomberg, L.R. and Beliles, R.P. (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health, 13, 407-484. crossref(new window)

Wu, H., Yoon, M.Y., Verner, M.A., Xue, J., Luo, M., Andersen, M.E., Longnecker, M.P. and Clewell, H.J. (2015) Can the observed association between serum perfluoroalkyl sub stances and delayed menarche be explained on the basis of puberty-related changes in physiology and pharmacokinetics? Environ. Int., 82, 61-68. crossref(new window)

Price, P.S., Conolly, R.B., Chaisson, C.F., Gross, E.A., Young, J.S., Mathis, E.T. and Tedder, D.R. (2003) Modeling interindividual variation in physiological factors used in PBPK models of humans. Crit. Rev. Toxicol., 33, 469-503. crossref(new window)

Houston, J.B. and Galetin, A. (2008) Methods for predicting in vivo pharmacokinetics using data from in vitro assays. Curr. Drug Metab., 9, 940-951. crossref(new window)

Jamei, M., Marciniak, S., Edwards, D., Wragg, K., Feng, K., Barnett, A. and Rostami-Hodjegan, A. (2013) The simcyp population based simulator: architecture, implementation, and quality assurance. Silico Pharmacol., 1, 9. crossref(new window)

Jamei, M., Marciniak, S., Feng, K., Barnett, A., Tucker, G. and Rostami-Hodjegan, A. (2009) The Simcyp population-based ADME simulator. Expert Opin. Drug Metab. Toxicol., 5, 211-223. crossref(new window)

Rostami-Hodjegan, A. and Tucker, G.T. (2007) Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat. Rev. Drug Discovery, 6, 140-148. crossref(new window)

Clewell, H.J. and Andersen, M.E. (1996) Use of physiologically based pharmacokinetic modeling to investigate individual versus population risk. Toxicology, 111, 315-329. crossref(new window)

Clewell, H.J. (1993) Coupling of computer modeling with in vitro methodologies to reduce animal usage in toxicity testing. Toxicol. Lett., 68, 101-117. crossref(new window)

Hinderliter, P.M., Price, P.S., Bartels, M.J., Timchalk, C. and Poet, T.S. (2011) Development of a source-to-outcome model for dietary exposures to insecticide residues: an example using chlorpyrifos. Regul. Toxicol. Pharmacol., 61, 82-92. crossref(new window)

Kedderis, G.L. (2007) In vitro to in vivo extrapolation of metabolic rate constants for physiologically based pharmacokinetic models. Toxicokinet. Risk Assess., 185-210.

Yoon, M., Kedderis, G.L., Yan, G.Z. and Glewell, H.J. (2015) Use of in vitro data in developing a physiologically based pharmacokinetic model: Carbaryl as a case study. Toxicology, 332, 52-66. crossref(new window)

Groothuis, F.A., Heringa, M.B., Nicol, B., Hermens, J.L., Blaauboer, B.J. and Kramer, N.I. (2015) Dose metric considerations in in vitro assays to improve quantitative in vitro?in vivo dose extrapolations. Toxicology, 332, 30-40. crossref(new window)

Johnson, T.N., Rostami-Hodjegan, A. and Tucker, G.T. (2006) Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin. pharmacokinet., 45, 931-956. crossref(new window)

Nong, A., McCarver, D.G., Hines, R.N. and Krishnan, K. (2006) Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. Toxicol. Appl. Pharmacol., 214, 78-87. crossref(new window)

Wetmore, B.A., Allen, B., Clewell, H.J., Parker, T., Wambaugh, J.F., Almond, L.M. and Thomas, R.S. (2014) Incorporating population variability and susceptible subpopulations into dosimetry for high-throughput toxicity testing. Toxicol. Sci., 142, 210-224. crossref(new window)

Hines, R.N. (2008) The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol. Ther., 118, 250-267. crossref(new window)

Rowland, M., Peck, C. and Tucker, G. (2011) Physiologicallybased pharmacokinetics in drug development and regulatory science. Annu. Rev. Pharmacol. Toxicol., 51, 45-73. crossref(new window)

Sheets, L.P., Doherty, J.D., Law, M.W., Reiter, L.W. and Crofton, K.M. (1994) Age-dependent differences in the susceptibility of rats to deltamethrin. Toxicol. Appl. Pharmacol., 126, 186-190. crossref(new window)

Anand, S.S., Kim, K.B., Padilla, S., Muralidhara, S., Kim, H.J., Fisher, J.W. and Bruckner, J.V. (2006) Ontogeny of hepatic and plasma metabolism of deltamethrin in vitro: role in age-dependent acute neurotoxicity. Drug Metab. Dispos., 34, 389-397.

Kim, K.B., Anand, S.S., Kim, H.J., White, C.A., Fisher, J.W., Tornero-Velez, R. and Bruckner, J.V. (2010) Age-, dose-and time-ependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicol. Sci., 115, 354-368. crossref(new window)

Crow, J.A., Borazjani, A., Potter, P.M. and Ross, M.K. (2007) Hydrolysis of pyrethroids by human and rat tissues: examination of intestinal, liver and serum carboxylesterases. Toxicol. Appl. Pharmacol., 221, 1-12. crossref(new window)

Godin, S.J., Scollon, E.J., Hughes, M.F., Potter, P.M., DeVito, M.J. and Ross, M.K. (2006) Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: differential oxidative and hydrolytic metabolism by humans and rats. Drug Metab. Dispos., 34, 1764-1771. crossref(new window)

Hideo, K. (2012) Biotransformation and enzymes responsible for metabolism of pyrethroids in mammals, in parameters for pesticide QSAR and PBPK/PD models for human risk assessment. Am. Chem. Soc., 41-52.

Ross, M.K., Borazjani, A., Edwards, C.C. and Potter, P.M. (2006) Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases. Biochem. Pharmacol., 71, 657-669. crossref(new window)

Hines, R.N. (2007) Ontogeny of human hepatic cytochromes P450. J. Biochem. Mol. Toxicol., 21, 169-175. crossref(new window)

Yang, D., Pearce, R.E., Wang, X., Gaedigk, R., Wan, Y.J. and Yan, B. (2009) Human carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem. Pharmacol., 77, 238-247. crossref(new window)

Clewell, H.J. and Yoon, M. (2015) Predicting pyrethroids target tissue exposure across ages: application of in vitro-in vivo extrapolation and physiologically based pharmacokinetic modeling. EPA-HQ-OPP-2015-0130.

Mirfazaelian, A., Kim, K.B., Anand, S.S., Kim, H.J., Tornero-Velez, R., Bruckner, J.V. and Fisher, J.W. (2006) Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat. Toxicol. Sci., 93, 432-442. crossref(new window)

Tornero-Velez, R., Mirfazaelian, A., Kim, K.B., Anand, S.S., Kim, H.J., Haines, W.T., Bruckner, J.V. and Fisher, J.W. (2010) Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model. Toxicol. Appl Pharmacol., 244, 208-217. crossref(new window)

Lake, B.G. (2015) Studies on the in vitro metabolism of deltamethrin by rat and human tissue preparations. EPA-HQOPP-2015-0130.

Pope, C.N., Karanth, S., Liu, J. and Yan, B. (2005) Comparative carboxylesterase activities in infant and adult liver and their in vitro sensitivity to chlorpyrifos oxon. Regul. Toxicol. Pharmacol., 42, 64-69. crossref(new window)