This document describes a generic physiologically based toxicokinetic (PBTK) model contained in a Microsoft Excel file called IndusChemFate. The model can predict the absorption, distribution, metabolism and excretion of chemicals in the human body based on their physical-chemical properties and exposure scenarios entered by the user. Two examples are given where the model predictions match observed data on metabolite concentrations in urine after inhalation of Methyl Tert-Butyl Ether and ethanol levels in blood after dermal exposure. The document recommends applications of the model in biomonitoring interpretation, first-tier chemical risk assessment, and education.

1. A generic, cross-chemical predictive
PBTK-model running in MS-Excel
Frans Jongeneelen & Wil ten Berge
X2012, Edinburgh (UK), 2-5 July 2012

2. Physiologically Based ToxicoKinetic (PBTK)
modeling in chemical risk assessment
Domain of PBTK modeling
Schematic from: Georgopoulos
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3. Exposure scenario
 Three routes of uptake:
Overview Inhalation - concentration
Dermal – dose rate
PBTK-model Oral - dose
 Duration of exposure
IndusChemFate  Personal Protective Equipment
 Species / subgroup
 Physical activity level (rest/ light)
1. Enter parameters
Compound parameters
 Physical-chemical properties:
 Density
 Molecular weight
 Vapour pressure
 Log(Kow) at pH 5.5 and 7.4
 Water Solubility
 Biochemical parameters :
PBTK-model
 Metabolism (kM and Vmax)
 Renal tubulair resorption 4,50E-04
Pyrene and metabolites (Venous Blood)
 Enterohepatic circulation ratio 4,00E-04
3,50E-04
3,00E-04
2,50E-04
VenBl C0 µmol/l
2,00E-04
VenBl C1 µmol/l
1,50E-04 VenBl C2 µmol/l
2. Run model and get result 1,00E-04
5,00E-05
0,00E+00
0,000 10,000 20,000 30,000 40,000
Hours
50,000 60,000 70,000 80,000
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4. Physiology of the PBTK-model
Parent compound
Inhalation
Exhalation
Lungs
Cyclus of 1st metabolite
Heart
Exhalation
Brain
Dermal Evaporation Lungs
load
Heart
Dermis Brain
V A
E R
Adipose
N T
O E Dermis
Muscle R V A
U R
E Adipose
S I N T
Bone A E
O
L U Muscle R
Bone marrow S I
Oral Bone A
intake L
Bone marrow
Stomach +
intestine Stomach + To 2nd
B B intestine metabolite
L L B B
O
Liver O L L cyclus
O Liver O
O O
Kidney O O
D D D Kidney D
Excretion of Excretion of
parent compound 1st metabolite
in urine in urine
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5. 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 pathways
1. 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

6. 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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7. Examples of simulations compared
with observations
Example 1: metabolites in urine of men and women
after exposure to Methyl Tert-Butyl Ether (MTBE)
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8. Simulation example 1
Inhalation study of Methyl Tert-Butyl Ether
(MTBE) in men & women (Dekant et al, 2001)
• 3 male and 3 female volunteers were exposed in an
exposure 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 gender
differences?
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9. Simulation example 1
Metabolism of MTBE
MTBE  TBA  MPD  HIBA
parent compound  1st-  2nd-  3rd-metabolite
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10. Simulation example 1
Modeling: parameterisation of MTBE and
metabolites
1) Physical-chemical properties
MTBE + 3 metabolites
2) Biochemical parameters of MTBE
MTBE + 3 metabolites
3) Exposure scenario
Inhalation MTBE: 4 h of 140 mg/m3
Exposed subject: male or female in rest
Follow up time: 72 h
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11. Simulation
example 1 MTBE
Modeling:
entering
model
parameters
Tert-ButylAlcohol (TBA)
Methylpropanediol (MPD) 11

12. Simulation example 1
Modeling: entering exposure scenario
and selection of exposed subject
Airborne
exposure
scenario
Select subject
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13. Simulation example 1
Modeling: predicted concentration of MTBE
and metabolites in urine of men in rest
MTBE and metabolites in urine
450
400
350
300
250 C0 = MTBE (µmol/L)
200 C1 = TBA (µmol/L)
150 C2 = MPD (µmol/L)
C3 = HIBA (µmol/L)
100
50
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Hours
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14. Simulation example 1
Observed and predicted concentrations in urine
of men and women in rest
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15. Simulation example 2: Dermal uptake of
ethanol at hygienic hand + arm disinfection
Compound Exposure Exposure scenario Measured Reference
route parameter
Ethanol Dermal Disinfection of hands + Ethanol in Kramer et
arms to elbow with 95% blood al, 2007
ethanol
10 Rubs with 20 ml in 80
min
Six male volunteers
In open room of 37 m3
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16. Simulation example 2
Observed and predicted concentrations of ethanol in
blood after disinfection of hands and arms
Simulated dermal uptake + inhalation of 300 mg/m3!
Simulated : dermal uptake only
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17. 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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18. 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
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19. Acknowledgement
Funding from CEFIC-LRI
Thank you
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