physiologically based models of the lung s. moll h. meyer s. mielordt seminar pharmakokinetik -...
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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