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  • 1. 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 1 Mechanistic risk assessment of indoor air pollutants - BTEX Europe-wide assessmentProf. Dimosthenis A. SarigiannisDirector of Environmental Engineering LaboratoryDepartment of Chemical Engineering, Aristotle University of Thessaloniki - 54124, Greece
  • 2. INTERA platform: main characteristics 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 2• Flexibility and ease of use: according to data availability, the user can start from different starting points along the source to dose continuum.• Exposure assessment is carried out dynamically in the time.• All routes of exposure are considered.• Exposure determinants are stored and automatically retrieved from internal Library and/or from KMS according Geographical Location, Gender and Age class.• Main parameters affecting exposure results can be defined as PDF  MC probabilistic simulation.• Generic PBPK model accounting for assessment of internal doses in tissues of parent compound and up to three its metabolites.• Physiological parameters are automatically scaled on Bodyweight (blood flow, organ volumes, clearance rate, alveolar ventilation).• Results are visualized through a GIS mapping tool and a chart generation tool linked to the computational platform allowing comparison of different scenario’s and identifying influence of exposure determinants on exposure
  • 3. INTERA platform: main components visual representation7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 3 Probabilistic framework across the full chain GI tract – portal vein GI tract – portal vein Outdoor Liver Liver contribution Oral exposure Vapour Heart Heart Particulates SOURCE Brain Brain Pollutant Droplets Muscles Muscles Skin Skin Other pollutant Dermal exposure Kidneys Kidneys Other Indoor processes indoor oDispersion Adipose Adipose sources oSorption oDeposition oChemical reactions Bones Bones oResuspension oDilution/ventilation Breast Breast Uterus - gonads Uterus - gonads Inhalation exposure Arterial Lungs Venous Arterial Lungs Venous blood blood blood bloodSource conditions: e.g.oEmission strengthoTime pattern Housing conditions: e.g. Individual conditions: e.g. Inter-individual response tooChemical/physical properties Dimensions and layout Time activity patterns in house xenobioticsof pollutant Ventilation characteristics Source use pattern Sources location
  • 4. The BTEX case study 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 4Chemical name CAS No Formula MW log KowBenzene 71-43-2 C6H6 78.11 2.13Toluene 108-88-3 C7H8 or C6H5CH3 92.14 2.65Ethylbenzene 100-41-4 C8H10 106.17 3.13Xylenes 1330-20-7 C6H4C2 H6 106.16 3.12 -3.15How are people exposed to BTEX?Exposure in the indoor environment is dominated by inhalation (ECB RAR’s).As BTEX is not is not one chemical, but a quaternary mixture of chemicals, exposure to BTEX involves amulti-chemical approach which has to take into account possible interactions between the four substances.BTEX health effects• neurological impairment• benzene (and more precise its toxic metabolites) can additionally cause hematological effects including acute myelogenous leukemia (AML)
  • 5. Case study work flow 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 5 Data acquisition Exposure is the input for the BTEX PBPK • BTEX concentrations for several model, taking into account the mixture types of locations interaction occurring at the level of BTEX • Activity pattern data metabolism (competitive inhibition) • Physiological and biochemical parametersPersonal exposure ET is given as a function of theconcentrations C in the locations encountered,the time spent in these locations and the type ofperformed activity, which in turn affects thebreathing rate ET f n Cn inhn nwhere inh is the inhalation correction coefficientfor each type of microenvironment encountered inthe calculations
  • 6. PBPK model for benzene and the metabolites7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 6
  • 7. Validation of the PBPK model 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 7 Benzene in blood (exposure 10 ppm for 4 h) 10000 Benzene exposure: 92 Urinary concentration* Urinary concentration from PBPK/PD Metabolite ppm Median [min – max] modelBenzene in blood (nmol/l) 1000 PH 196 [27.1 - 374] 342.5 100 CAT 40.3 [3.79 - 85.1] 71.9 HQ 22.1 [3.3 - 50.6] 11.5 S-PMA 7.69 [0.123 - 27.5] 6.2 10 MA 41.2 [7.25 - 133] 32.6 Benzene exposure: 13.6 Urinary concentration* Urinary concentration from PBPK/PD 1 Metabolite 0 5 10 15 20 25 30 35 ppm Median [min – max] model time (hours) PH 18.2 [3.87 - 175] 86.2 PBPK/PD results Average 3 subjects CAT 3.09 [0.673 - 23.8] 30.4 Benzene in exhaled air (exposure 10 ppm for 4 h) HQ 3.97 [0.524 - 36.2] 4.5 1000 S-PMA 0.175 [0.050 - 5.89] 1.6 MA 7.14 [1.14 - 77.8] 8.8 Benzene in exhaled air (umol/m3) 100 Benzene exposure: 1.18 Urinary concentration** Urinary concentration from PBPK/PD Metabolite ppm Median [min – max] model 10 PH 14.9 [ 1.5 - 389.6] 85.3 CAT 2.3 [ 0.4 - 48.2] 27.4 HQ 1.9 [ 0.3 - 47.0] 4.0 1 S-PMA 0.06 [ 0.00036 - 7.04] 0.6 MA 1.7 [0.1 - 60.5] 5.8 0.1 0 5 10 15 20 25 30 35 * Data from Waidyanatha et al. (2004) time (hours) ** Data from Kim et al. (2006) PBPK/PD results Average 3 subjects
  • 8. Validation of the PBPK model 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 8 Toluene concentration in Venous Blood Ethylbenzene concentration in Venous Blood 10.000 10.000 1.000 1.000(mg/Liter) (mg/Liter) 0.100 0.100 0.010 0.010 0.001 0.001 0 2 4 6 8 10 12 0 2 4 6 8 10 12 time (hours) time (hours) TOL 17 ppm + XYL 33 ppm + EBZ 33 ppm TOL 17 ppm Exp. data (TEX) Exp.data (T) TOL 17 ppm + XYL 33 ppm + EBZ 33 ppm EBZ 33 ppm Exp. data (TEX) Exp. data (E) m-Xylene concentration in Venous Blood 10.000 Comparison of the PBPK/PD model results relevant to blood concentration of toluene (a), m-xylene (b) and ethylbenzene (c) predicted by the individual chemical (solid lines) or a 1.000 ternary chemical PBPK model (dashed lines) with corresponding experimental data (symbols) obtained in (mg/Liter) 0.100 humans exposed for 7 hr to 17, 33, and 33 ppm, respectively, of these solvents alone (square points) or in combination 0.010 (diamond points) 0.001 0 2 4 6 8 10 12 time (hours) TOL 17 ppm + XYL 33 ppm + EBZ 33 ppm XYL 33 ppm Exp data (TEX) Exp data (X)
  • 9. Average benzene concentrations in several EU locations 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 9 70 60 Homes Schools/kindergartens 50 Offices/public buildings Bars/cafes/restaurants/shopsConcentration (μg/m3) 40 Train/bus/car/taxi Outdoor 30 20 10 0
  • 10. Average toluene concentrations in several EU locations 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 10 250 200 Homes Schools/kindergartensConcentration (μg/m3) Offices/public buildings 150 Bars/cafes/restaurants/shops Train/bus/car/taxi Outdoor 100 50 0
  • 11. Average ethylbenzene concentrations in several EU locations 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 11 45 40 Homes 35 Schools/kindergartens Offices/public buildingsConcentration (μg/m3) 30 Bars/cafes/restaurants/shops Train/bus/car/taxi 25 Outdoor 20 15 10 5 0
  • 12. Average xylenes concentrations in several EU locations 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 12 120 m,p,o-Xylenes 100 Homes Schools/kindergartensConcentration (μg/m3) 80 Offices/public buildings Bars/cafes/restaurants/shops 60 Train/bus/car/taxi Outdoor 40 20 0
  • 13. Average BTEX intake across EU 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 13 8 7 Benzene Toluene 6 EthylbenzeneIntake (μg/kg_bw/d) Xylenes 5 4 3 2 1 0
  • 14. Intake probability distribution (MC analysis incorporating exposure and biokinetic variability) 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 14Probability density Toluene Probability density Benzene 0 2 3 4 6 7 8 9 11 12 13 0 1 3 4 5 7 Daily intake (μg/kg_bw/d) Daily intake (μg/kg_bw/d) Ethylbenzene Xylenes Probability densityProbability density 0.05 0.09 0.13 0.18 0.22 0.26 0.2 0.4 0.6 0.9 1.1 1.4 1.6 1.9 2.1 2.3 2.6 Daily intake (μg/kg_bw/d) Daily intake (μg/kg_bw/d) Exposure scenario assessed: Belgium, Adult male
  • 15. Intake probability distribution (MC analysis incorporating exposure and biokinetic variability)7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 15
  • 16. Benzene external and internal exposure diurnal variability 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 16 Benzene exposure Benzene exposure (inhalation rate correction) 30 Benzene blood 0.09 Toxic metabolites in bone marrow 0.08 25 0.07Benzene exposure (μg/m3) Internal exposure (μg/L) 20 0.06 0.05 15 0.04 10 0.03 0.02 5 0.01 0 0 0 24 48 72 96 120 144 168 Time (h) Exposure scenario assessed: Belgium, Adult male
  • 17. Internal exposure to benzene toxic metabolites in bone marrow (MC analysis incorporating exposure and biokinetic variability) 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 17Probability density 0.00 0.02 0.03 0.05 0.07 0.08 Internal exposure (μg/L) Exposure scenario assessed: Belgium, Adult male
  • 18. Internal exposure to benzene toxic metabolites in bone marrow (MC analysis incorporating exposure and biokinetic variability)7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 18
  • 19. Conclusions 7th International Conference on the Science of Exposure Assessment (X2012) Edinburgh, Scotland 2 – 5 July 2012 19There are significant data gaps with regard to the indoor concentrations data on BTEXacross EU.Exposure to TEX is significantly below the existing Exposure Limit values, thus theimportance of BTEX exposure arises due to the prolonged exposure to benzene.Internal exposure to benzene toxic metabolites is higher to children, due to therelatively higher bodyweight normalized daily doseBTEX PBPK/D model was validated against independent biomonitoring data set. Resultsshowed that the PBPK/D model provides accurate predictions of both the interactionmechanism among the constituents of the mixture and of the benzene metabolic chain.At the levels of environmental concentrations met in EU indoor locations, no mixtureinteraction at the metabolism level is manifested; thus, co-exposure to BTEX does notpose any reason for additional concern. The BTEX mixture effect can be addressed byadditivity.

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