Physiologically Based Models of the Lung S. Moll H. Meyer S. Mielordt Seminar Pharmakokinetik - Mathematische Modelle und ihre Anwendung - WS 03/04 FU Berlin

2 Outline Pharmacokinetics vs. Toxicokinetics Physiology matters: The Lung Development of a Physiologically Based Toxicokinetic Model Concrete example: Styrene and its metabolites Simulation Discussion

3 Toxicokinetics The study of the absorption, distribution and elimination of toxic compounds in the living organism Analogous to Pharmacokinetics, but undesired uptake of chemicals by Lung Skin Gastrointestinal tract

4 Toxicokinetics II The lung is the main source for the absorption of toxic compounds Industrial chemicals Exhaust gas Military toxins Insecticides

5 Lung - Evolution Developed from intestinal protuberance Evolved to maximize surface (  alveoles) and throughput Limiting factor for peak power of a creature

6 The Lung

7 Lung – further

8 Pre - PBPK - Modeling

9 PBPK - Modeling

10 Modeling Goals Transferability of results from animals to human Fewer details sometimes better Causalities by Anatomy Biochemistry, metabolism Disease dependent changes

11 Lung – Models Which facts are important to include? What can be left out? Degrees of Freedom (e.g.: physiological accuracy, # compartments, wash-in wash-out, metabolism, tissue layers between blood and air,...) Possible one, two, three compartments (e.g.: upper respiratory tract, bronchia, alveoles)

12 One Model for Everyone? One model sufficient? - Gender - Age - Genetic variation Toxicokinetics vs.Toxicodynamics  Intention is crucial for modeling! Isopropanol metabolite in blood

13 Styrene Unsaturated aromatic hydrocarbon Very lipophil Noxious to microorganisms Ubiquitous in Environment Sweet smell Used in plastic industry as a preproduct

14 Styrene and its Metabolic Degradation Styrene (ST) Cytochrome P-450 Styrene Oxide (SO) Phenylethylene Glycol Epoxide Hydrolase Further metabolism and excretion + glutathione (GSH) x-Phenyl- 2-hydroxy- ethylmercapturic acid Only lung und liver...

15 Styrene 7,8 oxide DNA strand breaks occur after SO exposure SO-DNA adducts have been found in mice and in cultured mammalian cells SO causes leukemia and lymphoma in humans Lung and stomach cancer in animals

16 The Lung - Model by Csanády et. al. Gy.A. Csana´dy et al.

17 Styrene Level Comparison ST – Concentration mg/l

18 Styrene Levels in different Tissues ST – Concentration mg/l

19 SO – Calculation in Lung Tissue ParameterMouseRatHumanUnits Vmax8.9e-49.3e-42.5e-6mmol/h/l Km1.8e-21.4e-11.8e-2mmol/l Vmax/Km Michaelis-Menten properties of CYP 450 – ST interaction SO = ([ST] * Vmax …) / ([ST] + Km …) e-4

20 SO – Level (Lung isolated) Linear Logarithmic S O – Concentration mg/l

21 S O – Concentration mg/l Hypothetical SO (Lung isolated) Linear, with hypothetical safety factor Logarithmic, with hypothetical safety factor S O – Concentration mg/l

22 Degradation of Styrene oxide Gy.A. Csana´dy et al.  GSH depletion supported model assumption

23 SO - Long-term Burden S O – Concentration mg/l

24 Conclusion Use species specific differential PBPK instead of estimated safety factors Metabolizing lung is important for risk evaluation of air toxics Description of biological mechanisms... - is foundation of model construction - allows transfer of results from animal experiments to human

25 Discussion What kind of facts can be shown by the modeling? Transfer of animal data to human possible? Model complexity vs. precision Parameter estimation verification Fitting of Data - Cross Validation

26 References  A toxicokinetic model for styrene and its metabolite styrene-7,8- oxide in mouse, rat and human with special emphasis on the lung (Gy.A. Csanády, W. Kessler, H.D. Hoffmann, J.G. Filser)  Evaluation of the Potential Impact of Age and Gender-Specific Lung Morphology and Ventilation Rate on the Dosimeter of Vapors (Ramesh Sarangapani et.al.)  PKQuest: A general physiologically based pharmacokinetic model. Introduction and application to propranolol (David G. Levitt)  PBPK-Toolkit (Wolfram Liebermeister)   

27 Sundowner ntpaul.sprog.auc.dk