Abstract
This chapter presents the human model implemented in MERLIN-Expo. This model is a physiologically based pharmacokinetic (PBPK) model that describes the relationship between an external dose and an internal dosimetry using parameters related to the anatomy and physiology of individuals and the physico-chemical properties of the contaminants. The goal of the PBPK model is to simulate the toxicokinetics of contaminants in humans, e.g. the amounts or concentrations of contaminants in different organs/tissues, under various exposure conditions. The generic PBPK model is based on a detailed compartmentalisation of the human body and parameterised with relationships describing the time evolution of the physiology and anatomy of the individuals. In this chapter, we present the detailed description of the human model and the conditions to apply it in MERLIN-Expo. Finally, the model predictability is evaluated by a direct comparison between computational predictions and experimental data on small case studies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Andersen ME (1991) Physiological modelling of organic compounds. Ann Occup Hyg 35(3):309–321
Brochot C, Smith TJ, Bois FY (2007) Development of a physiologically based toxicokinetic model for butadiene and four major metabolites in humans: global sensitivity analysis for experimental design issues. Chem Biol Interact 167(3):168–183
Nestorov I (2003) Whole body pharmacokinetic models. Clin Pharmacokinet 42(10):883–908
Reddy MB, Yang RSH, Clewell III HJ, et al (2005) Physiologically based pharmacokinetic modelling: science and applications. Wiley, Hoboken
Teorell T (1937) Kinetics of distribution of substances administered to the body. Arch Int Pharmacodyn Ther 57:205–240
Beaudouin R, Micallef S, Brochot C (2010) A stochastic whole-body physiologically based pharmacokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan. Regul Toxicol Pharmacol 57(1):103–116
Clewell HJ, Gentry PR, Covington TR, et al (2004) Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Toxicol Sci 79(2):381–393
Edginton AN, Schmitt W, Willmann S (2006) Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet 45(10):1013–1034
Kerger BD, Leung HW, Scott P, et al (2006) Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. Environ Health Perspect 114(10):1596–1602
Haddad S, Restieri C, Krishnan K (2001) Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. J Toxicol Environ Health A 64(6):453–464
Price K, Haddad S, Krishnan K (2003) Physiological modeling of age-specific changes in the pharmacokinetics of organic chemicals in children. J Toxicol Environ Health A 66(5):417–433
Yang F, Tong XP, McCarver DG, et al (2006) Population-based analysis of methadone distribution and metabolism using an age-dependent physiologically based pharmacokinetic model. J Pharmacokinet Pharmacodyn 33(4):485–518
Environmental Protection Agency (US EPA) (2006) Approaches for the application of physiologically based pharmacokinetic (PBPK) models and supporting data in risk assessment (final report). Environmental Protection Agency (US EPA), Washington, DC
International Programme on Chemical Safety (IPCS) (2010) Characterization and application of physiologically based pharmacokinetic models in risk assessment. World Health Organization, Geneva
Peters SA (2012) Physiologically-based pharmacokinetic (PBPK) modeling and simulations: principles, methods, and applications in the pharmaceutical industry. Wiley, Hoboken
Andersen ME (2003) Toxicokinetic modeling and its applications in chemical risk assessment. Toxicol Lett 138(1–2):9–27
Clewell HJ, Tan YM, Campbell JL, et al (2008) Quantitative interpretation of human biomonitoring data. Toxicol Appl Pharmacol 231(1):122–133
Ulaszewska MM, Ciffroy P, Tahraoui F, et al (2012) Interpreting PCB levels in breast milk using a physiologically based pharmacokinetic model to reconstruct the dynamic exposure of Italian women. J Exposure Sci Environ Epidemiol 22(6):601–609
Zeman FA, Boudet C, Tack K, et al (2013) Exposure assessment of phthalates in French pregnant women: results of the ELFE pilot study. Int J Hyg Environ Health 216(3):271–279
Gerlowski LE, Jain RK (1983) Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci 72:1103–1127
Sharma M, Maheshwari M, Morisawa S (2005) Dietary and inhalation intake of lead and estimation of blood lead levels in adults and children in Kanpur, India. Risk Anal 25(6):1573–1588
Pelkonen O, Turpeinen M (2007) In vitro-in vivo extrapolation of hepatic clearance: biological tools, scaling factors, model assumptions and correct concentrations. Xenobiotica 37(10–11):1066–1089
Barter ZE, Bayliss MK, Beaune PH, et al (2007) Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: Reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Curr Drug Metab 8(1):33–45
National Health and Nutrition Examination Survey (1995) Third national health and nutrition examination survey, 1988–1991. Selected laboratory and mobile examination center data. version 1, September 1995
Altman PL, Dittmer DS (1962) Growth, including reproduction and morphological development. Federation of American Societies for Experimental Biology, Washington, DC
International Commission on Radiological Protection (2002) Basic anatomical and physiological data for use in radiological protection: reference values. Valentin J, Stockholm
Lexell J, Taylor CC, Sjostrom M (1988) What is the cause of the aging atrophy – total number, size and proportion of different fiber types studied in Whole vastus lateralis muscle from 15-year-old to 83-year-old men. J Neurol Sci 84(2–3):275–294
Luisada AA, Bhat PK, Knighten V (1980) Changes of cardiac-output caused by aging – an impedance cardiographic study. Angiology 31(2):75–81
Johnson TN, Rostami-Hodjegan A, Tucker GT (2006) Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet 45(9):931–956
Vinegar A, Jepson GW, Overton JH (1998) PBPK modeling of short-term (0 to 5 min) human inhalation exposures to halogenated hydrocarbons. Inhal Toxicol 10(5):411–429
Darwich AS, Neuhoff S, Jamei M, et al (2010) Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the “advanced dissolution, absorption, metabolism (ADAM)” model. Curr Drug Metab 11(9):716–729
Yu LX, Lipka E, Crison JR, et al (1996) Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Adv Drug Deliv Rev 19(3):359–376
Bois FY, Jamei M, Clewell HJ (2010) PBPK modelling of inter-individual variability in the pharmacokinetics of environmental chemicals. Toxicology 278(3):256–267
Kalow W (2001) Chapter 1: genetic factors that cause variability in human drug metabolism. In: Pacifici GM, Pelkonen O (eds) Interindividual variability in human drug metabolism. Taylor & Francis, London, pp. 1–14
Zeise L, Bois FY, Chiu WA, et al (2013) Addressing human variability in next-generation human health risk assessments of environmental chemicals. Environ Health Perspect 121(1):23–31
Johns DO, Owens EO, Thompson CM, et al (2010) Physiological parameters and databases for PBPK modeling. In: Kannan K, Andersen ME (eds) Quantitative modeling in toxicology. Wiley, Chichester, pp. 107–134
Price PS, Conolly RB, Chaisson CF, et al (2003) Modeling interindividual variation in physiological factors used in PBPK models of humans. Crit Rev Toxicol 33(5):469–503
Dorne JL, Walton K, Renwick AG (2003) Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment. Food Chem Toxicol 41(2):201–224
Mezzetti M, Ibrahim JG, Bois FY, et al (2003) A Bayesian compartmental model for the evaluation of 1,3-butadiene metabolism. J R Stat Soc Ser C Appl Stat 52:291–305
Poulin P, Krishnan K (1996) A tissue composition-based algorithm for predicting tissue: air partition coefficients of organic chemicals. Toxicol Appl Pharmacol 140(2):521–522
Plowchalk DR, Andersen ME, deBethizy JD (1992) A physiologically based pharmacokinetic model for nicotine disposition in the Sprague-Dawley rat. Toxicol Appl Pharmacol 116(2):177–188
Shin BS, Hong SH, Bulitta JB, et al (2009) Physiologically based pharmacokinetics of zearalenone. J Toxicol Environ Health A 72(21–22):1395–1405
Bjorkman S, Fyge A, Qi Z (1996) Determination of the steady state tissue distribution of midazolam in the rat. J Pharm Sci 85(8):887–889
Ichimura F, Yokogawa K, Yamana T, et al (1983) Physiological pharmacokinetic model for pentazocine. 1. Tissue distribution and elimination in the rat. Int J Pharm 15(3):321–333
Bjorkman S, Stanski DR, Verotta D, et al (1990) Comparative tissue concentration profiles of fentanyl and alfentanil in humans predicted from tissue/blood partition data obtained in rats. Anesthesiology 72(5):865–873
Ebling WF, Wada DR, Stanski DR (1994) From piecewise to full physiologic pharmacokinetic modeling: applied to thiopental disposition in the rat. J Pharmacokinet Biopharm 22(4):259–292
Csanady GA, Oberste-Frielinghaus HR, Semder B, et al (2002) Distribution and unspecific protein binding of the xenoestrogens bisphenol A and daidzein. Arch Toxicol 76(5–6):299–305
Gearhart JM, Mahle DA, Greene RJ, et al (1993) Variability of physiologically based pharmacokinetic (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE). Toxicol Lett 68(1–2):131–144
Van der Molen GW, Kooijman SALM, Slob W (1996) A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD. Fundam Appl Toxicol 31:83–94
Maruyama W, Yoshida K, Tanaka T, et al (2003) Simulation of dioxin accumulation in human tissues and analysis of reproductive risk. Chemosphere 53(4):301–313
Environment Agency (2000) Report of survey on the exposure of dioxins in human (in Japanese)
Iida T, Hirakawa H, Matsueda T, et al (1999) Recent trend of polychlorinated dibenzo-p-dioxins and their related compounds in the blood and sebum of Yusho and Yu-Cheng patients. Chemosphere 38(5):981–993
Milbrath MO, Wenger Y, Chang CW, et al (2009) Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding. Environ Health Perspect 117(3):417–425
Toyoda M, Uchibe H, Yanagi T, et al (1999) Dietary daily intake of PCDDs, PCDFs and coplanar PCBs by total diet study in Japan. J Food Hyg Soc Jpn 40(1):98–110
Houde M, De Silva AO, Muir DC, et al (2011) Monitoring of perfluorinated compounds in aquatic biota: an updated review. Environ Sci Technol 45(19):7962–7973
Noorlander CW, van Leeuwen SPJ, Biesebeek JDT, et al (2011) Levels of perfluorinated compounds in food and dietary intake of PFOS and PFOA in The Netherlands. J Agric Food Chem 59(13):7496–7505
Cornelis C, D’Hollander W, Roosens L, et al (2012) First assessment of population exposure to perfluorinated compounds in Flanders, Belgium. Chemosphere 86(3):308–314
Perez F, Nadal M, Navarro-Ortega A, et al (2013) Accumulation of perfluoroalkyl substances in human tissues. Environ Int 59:354–362
Domingo JL, Ericson-Jogsten I, Perello G, et al (2012) Human exposure to perfluorinated compounds in Catalonia, Spain: contribution of drinking water and fish and shellfish. J Agric Food Chem 60(17):4408–4415
Haug LS, Huber S, Becher G, et al (2011) Characterisation of human exposure pathways to perfluorinated compounds–comparing exposure estimates with biomarkers of exposure. Environ Int 37(4):687–693
Shoeib M, Harner T, Webster GM, et al (2011) Indoor sources of poly- and perfluorinated compounds (PFCS) in Vancouver, Canada: implications for human exposure. Environ Sci Technol 45(19):7999–8005
Olsen GW, Burris JM, Ehresman DJ, et al (2007) Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect 115(9):1298–1305
Emmett EA, Shofer FS, Zhang H, et al (2006) Community exposure to perfluorooctanoate: relationships between serum concentrations and exposure sources. J Occup Environ Med 48(8):759–770
Ericson I, Gomez M, Nadal M, et al (2007) Perfluorinated chemicals in blood of residents in Catalonia (Spain) in relation to age and gender: a pilot study. Environ Int 33(5):616–623
Domingo JL, Jogsten IE, Eriksson U, et al (2012) Human dietary exposure to perfluoroalkyl substances in Catalonia, Spain. Temporal trend. Food Chem 135(3):1575–1582
Ericson I, Nadal M, van Bavel B, et al (2008) Levels of perfluorochemicals in water samples from Catalonia, Spain: is drinking water a significant contribution to human exposure? Environ Sci Pollut R 15(7):614–619
EFSA (2011) European Food Safety Authority database in exposure assessment
Loccisano AE, Campbell Jr JL, Andersen ME, et al (2011) Evaluation and prediction of pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model. Regul Toxicol Pharmacol 59(1):157–175
Azar A, Snee RD, Habibi K (1975) An epidemiologic approach to community air lead exposure using personal air samplers. Environ Qual Saf Suppl 2:254–290
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Brochot, C., Quindroit, P. (2018). Modelling the Fate of Chemicals in Humans Using a Lifetime Physiologically Based Pharmacokinetic (PBPK) Model in MERLIN-Expo. In: Ciffroy, P., Tediosi, A., Capri, E. (eds) Modelling the Fate of Chemicals in the Environment and the Human Body. The Handbook of Environmental Chemistry, vol 57. Springer, Cham. https://doi.org/10.1007/978-3-319-59502-3_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-59502-3_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-59500-9
Online ISBN: 978-3-319-59502-3
eBook Packages: Earth and Environmental ScienceEarth and Environmental Science (R0)