x2012 f.jongeneelen
TRANSCRIPT
Frans Jongeneelen & Wil ten Berge
X2012, Edinburgh (UK), 2-5 July 2012
A generic, cross-chemical predictive PBTK-model running in MS-Excel
Physiologically Based ToxicoKinetic (PBTK) modeling in chemical risk assessment
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Schematic from: Georgopoulos
Domain of PBTK modeling
Overview PBTK-model IndusChemFate
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Exposure scenario Three routes of uptake:
Inhalation - concentrationDermal – dose rateOral - dose
Duration of exposure Personal Protective Equipment Species / subgroup Physical activity level (rest/ light)
PBTK-model
Compound parameters Physical-chemical properties:
DensityMolecular weight Vapour pressure Log(Kow) at pH 5.5 and 7.4Water Solubility
Biochemical parameters :Metabolism (kM and Vmax) Renal tubulair resorption Enterohepatic circulation ratio
0,00E+00
5,00E-05
1,00E-04
1,50E-04
2,00E-04
2,50E-04
3,00E-04
3,50E-04
4,00E-04
4,50E-04
0,000 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000
Hours
Pyrene and metabolites (Venous Blood)
VenBl C0 µmol/l
VenBl C1 µmol/l
VenBl C2 µmol/l
1. Enter parameters
2. Run model and get result
Physiology of the PBTK-model
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Lungs
Excretion of parent compound in urine
InhalationExhalation
V
E
N
O
U
S
B
L
O
O
D
A
R
T
E
R
I
A
L
B
L
O
O
D
Oral
intake
Dermal
load
Heart
Brain
Dermis
Adipose
Muscle
Bone
Stomach +
intestine
Liver
Kidney
Evaporation
Parent compound
Cyclus of 1st metabolite
To 2nd
metabolite
cyclus
Bone marrow
Lungs
Excretion of 1st metabolitein urine
Exhalation
VENOUS
BLOOD
ARTERIAL
BLOOD
Heart
Brain
Dermis
Adipose
Muscle
Bone
Stomach +
intestine
Liver
Kidney
Bone marrow
Routing of chemicals and metabolites• Absorption: 3 routes
1. Inhalation
2. Oral uptake
3. Dermal uptake
• Partitioning in the body» Algorithm for estimate of blood:air partitioning
» Algorithms for estimates of tissue:blood partitioning in 11 compartments
• Metabolism» Saturable metabolism according to Michaelis-Menten kinetics
• Excretion: 2 pathways1. Renal excretion: algorithm related to log (kow)
2. Exhaled air: related to blood:air partitioning coefficient
• Set of differential equations predict change of amount over time 5
The PBTK-model is easy-to-use
• Well-known software platform MS Excel
• The file IndusChemFate.xls contains 4 sheets:
1. Tutorial with instructions in short
2. Worksheet– For parameter entry
– For listing of numerical output
3. Datasheet with physical-chemical and biochemical properties of chemicals
4. Sheet with output in graphs
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Examples of simulations compared with observations
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Example 1: metabolites in urine of men and women
after exposure to Methyl Tert-Butyl Ether (MTBE)
Simulation example 1
Inhalation study of Methyl Tert-Butyl Ether (MTBE) in men & women (Dekant et al, 2001)
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• 3 male and 3 female volunteers were exposed in anexposure chamber during 4h to 140 mg/m3
• Three metabolites were measured in urine• Metabolite 1 = tert-butanol = TBA• Metabolite 2 = 2-methyl-1,2-propanediol = MPD• Metabolite 3 = 2-hydroxy isobutyrate = HIBA
• No differences were found between men and women
Question: Does modeling confirm the absence of genderdifferences?
Simulation example 1
Metabolism of MTBE
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MTBE TBA MPD HIBAparent compound 1st- 2nd- 3rd-metabolite
Simulation example 1
Modeling: parameterisation of MTBE and metabolites
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1) Physical-chemical properties MTBE + 3 metabolites
2) Biochemical parameters of MTBEMTBE + 3 metabolites
3) Exposure scenarioInhalation MTBE: 4 h of 140 mg/m3
Exposed subject: male or female in rest
Follow up time: 72 h
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Simulation example 1
Modeling: entering model parameters
MTBE
Tert-ButylAlcohol (TBA)
Methylpropanediol (MPD)
Simulation example 1
Modeling: entering exposure scenario and selection of exposed subject
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Airborne
exposure
scenario
Select subject
Simulation example 1
Modeling: predicted concentration of MTBE and metabolites in urine of men in rest
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0
50
100
150
200
250
300
350
400
450
0 6 12 18 24 30 36 42 48 54 60 66 72
Hours
MTBE and metabolites in urine
C0 = MTBE (µmol/L)
C1 = TBA (µmol/L)
C2 = MPD (µmol/L)
C3 = HIBA (µmol/L)
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Simulation example 1
Observed and predicted concentrations in urine of men and women in rest
Simulation example 2: Dermal uptake of ethanol at hygienic hand + arm disinfection
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Compound Exposureroute
Exposure scenario Measuredparameter
Reference
Ethanol Dermal Disinfection of hands + arms to elbow with 95% ethanol
10 Rubs with 20 ml in 80 min
Six male volunteers
In open room of 37 m3
Ethanol in blood
Kramer et al, 2007
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Simulated dermal uptake + inhalation of 300 mg/m3!
Simulated : dermal uptake only
Simulation example 2Observed and predicted concentrations of ethanol in blood after disinfection of hands and arms
Suggested application domain of the PBTK-model IndusChemFate
Biomonitoring provides a glimse of the personal dose. The PBTK-model can be of help for interpretation of results
Bridge the gap between external and internal exposure monitoring
1st tier assessment of the fate of data-poor chemicals in body
Educational tool to understand toxicokinetics of chemicals in human body in relation to physical-chemical properties
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Where to get more info?
• Download EXCEL-application file and user manual:
– Website CEFIC LRI, web page IndusChemFate
http://www.cefic-lri.org/lri-toolbox/induschemfate
• Two papers (Ann Occup Hyg, 2011; Int Arch Occup Environ Hlth, 2012)
• Ask us to do a live-demonstration
Acknowledgement
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Funding from CEFIC-LRI
Thank you