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X2012 F.Jongeneelen

IndusTox Consult
IndusTox Consult

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.

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A generic, cross-chemical predictive PBTK-model running in MS-Excel Frans Jongeneelen & Wil ten Berge X2012, Edinburgh (UK), 2-5 July 2012
Physiologically Based ToxicoKinetic (PBTK) modeling in chemical risk assessment Domain of PBTK modeling Schematic from: Georgopoulos 2
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 袖mol/l 2,00E-04 VenBl C1 袖mol/l 1,50E-04 VenBl C2 袖mol/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 3
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 4
Routing of chemicals and metabolites Absorption: 3 routes 1. Inhalation 2. Oral uptake 3. Dermal uptake Partitioning in the body 損 Algorithm for estimate of blood:air partitioning 損 Algorithms for estimates of tissue:blood partitioning in 11 compartments Metabolism 損 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
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 6
Examples of simulations compared with observations Example 1: metabolites in urine of men and women after exposure to Methyl Tert-Butyl Ether (MTBE) 7
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? 8
Simulation example 1 Metabolism of MTBE MTBE TBA MPD HIBA parent compound 1st- 2nd- 3rd-metabolite 9
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 10
Simulation example 1 MTBE Modeling: entering model parameters Tert-ButylAlcohol (TBA) Methylpropanediol (MPD) 11
Simulation example 1 Modeling: entering exposure scenario and selection of exposed subject Airborne exposure scenario Select subject 12
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 (袖mol/L) 200 C1 = TBA (袖mol/L) 150 C2 = MPD (袖mol/L) C3 = HIBA (袖mol/L) 100 50 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Hours 13
Simulation example 1 Observed and predicted concentrations in urine of men and women in rest 14
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 15
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 16
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 17
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 18
Acknowledgement Funding from CEFIC-LRI Thank you 19

More Related Content

X2012 F.Jongeneelen

  • 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 2
  • 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 袖mol/l 2,00E-04 VenBl C1 袖mol/l 1,50E-04 VenBl C2 袖mol/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 3
  • 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 4
  • 5. Routing of chemicals and metabolites Absorption: 3 routes 1. Inhalation 2. Oral uptake 3. Dermal uptake Partitioning in the body 損 Algorithm for estimate of blood:air partitioning 損 Algorithms for estimates of tissue:blood partitioning in 11 compartments Metabolism 損 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 6
  • 7. Examples of simulations compared with observations Example 1: metabolites in urine of men and women after exposure to Methyl Tert-Butyl Ether (MTBE) 7
  • 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? 8
  • 9. Simulation example 1 Metabolism of MTBE MTBE TBA MPD HIBA parent compound 1st- 2nd- 3rd-metabolite 9
  • 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 10
  • 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 12
  • 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 (袖mol/L) 200 C1 = TBA (袖mol/L) 150 C2 = MPD (袖mol/L) C3 = HIBA (袖mol/L) 100 50 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Hours 13
  • 14. Simulation example 1 Observed and predicted concentrations in urine of men and women in rest 14
  • 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 15
  • 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 16
  • 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 17
  • 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 18