PhysiologPhysiologically Bically Baasedsed ModelModelss of theof the Lung Lung

S. Moll

H. Meyer

S. Mielordt

Seminar Pharmakokinetik - Mathematische Modelle und ihre Anwendung - WS 03/04 FU Berlin

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OuOuttlineline

Pharmacokinetics vs. Toxicokinetics

Physiology matters: The Lung

Development of a Physiologically Based Toxicokinetic Model

Concrete example: Styrene and its metabolites

Simulation

Discussion

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ToxicokineticToxicokineticss

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

www.atsdr.cdc.gov/toxprofiles

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ToxicokineticToxicokinetics IIs II

The lung is the main source for the absorption of toxic compounds

Industrial chemicals

Exhaust gas

Military toxins

Insecticides

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Lung - EvolutionLung - Evolution

www.zum.de

Developed from intestinal protuberance

Evolved to maximize surface ( alveoles) and throughput

Limiting factor for peak power of a creature

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The Lung The Lung

www.hyg.uni-heidelberg.de www.kcl.ac.uk

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Lung – furtherLung – further

www.jamesline.comwww.hyg.uni-heidelberg.de

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Pre - PBPK - ModelingPre - PBPK - Modeling

www.ifado.de/chemicals/

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PBPK - ModelingPBPK - Modeling

www.ifado.de/chemicals/

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Modeling GoalsModeling Goals

Transferability of results from animals to human

Fewer details sometimes better

Causalities

by

Anatomy

Biochemistry, metabolism

Disease dependent changes

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Lung – Models 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)

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One Model for Everyone? One Model for Everyone?

One model sufficient?

- Gender

- Age

- Genetic variation

Toxicokinetics vs.Toxicodynamics

Intention is crucial for modeling!

Isopropanol metabolite in blood

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Styrene Styrene

Unsaturated aromatic hydrocarbon

Very lipophil

Noxious to microorganisms

Ubiquitous in Environment

Sweet smell

Used in plastic industry as a preproduct

www.biomess.de

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Styrene and its Metabolic DegradationStyrene and its Metabolic Degradation

Styrene (ST)Cytochrome

P-450

Styrene Oxide (SO)

PhenylethyleneGlycol

Epoxide Hydrolase

Furthermetabolism and

excretion

+ glutathione(GSH)

x-Phenyl-2-hydroxy-

ethylmercapturicacid

Only lung und liver

. . . . . .

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Styrene 7,8 oxideStyrene 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

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The Lung - The Lung - Model by Model by CsanCsanády et. al.ády et. al.

Gy.A. Csana´dy et al.

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Styrene Level ComparisonStyrene Level Comparison

ST

– Concentration m

g/l

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Styrene Levels in different TissuesStyrene Levels in different Tissues

ST

– Concentration m

g/l

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SO – Calculation in Lung Tissue SO – Calculation in Lung Tissue

 

Parameter Mouse Rat Human Units

Vmax 8.9e-4 9.3e-4 2.5e-6 mmol/h/l

Km 1.8e-2 1.4e-1 1.8e-2 mmol/l

Vmax/Km 490 66 1.4   

Michaelis-Menten properties of CYP 450 – ST interaction

SO = ([ST] * Vmax …) / ([ST] + Km …)

e-4

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SO – Level (Lung isolated) SO – Level (Lung isolated)

Linear

Logarithmic

SO

– C

on

cen

tratio

n m

g/l

SO

– C

on

cen

tratio

n m

g/l

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SO

– C

on

cen

tratio

n m

g/l

Hypothetical SO (Lung isolated) Hypothetical SO (Lung isolated)

Linear, with hypothetical safety factor

Logarithmic , with hypothetical safety factor

SO

– C

on

cen

tratio

n m

g/l

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Degradation of Styrene oxideDegradation of Styrene oxide

Gy.A. Csana´dy et al.

GSH depletion supported model assumption

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SO - Long-term BurdenSO - Long-term Burden

SO

– Concentration m

g/l

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ConclusionConclusion

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

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DiscussionDiscussion

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

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ReferencesReferences 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)

www.epa.gov/ttn/atw/hlthef/styrene.html

www.styreneforum.org

www.bzs.bund.de/bzsinfo/broschur/zsforschung/band_50.pdf

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SundownerSundowner

ntpaul.sprog.auc.dk