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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 assessment




Prof. Dimosthenis A. Sarigiannis
Director of Environmental Engineering Laboratory
Department of Chemical Engineering, Aristotle University of Thessaloniki - 54124, Greece
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
INTERA platform: main components
                                       visual representation
7th 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                               blood

Source conditions: e.g.
oEmission strength
oTime pattern
                                               Housing conditions: e.g.                        Individual conditions: e.g.                                Inter-individual response to
oChemical/physical properties
                                               Dimensions and layout                           Time activity patterns in house                            xenobiotics
of pollutant
                                               Ventilation characteristics                     Source use pattern
                                               Sources location
The BTEX case study
      7th International Conference on the Science of Exposure Assessment (X2012)           Edinburgh, Scotland     2 – 5 July 2012   4




Chemical name                CAS No                 Formula                        MW                log Kow
Benzene                      71-43-2                C6H6                           78.11             2.13

Toluene                      108-88-3               C7H8 or C6H5CH3                92.14             2.65

Ethylbenzene                 100-41-4               C8H10                          106.17            3.13

Xylenes                      1330-20-7              C6H4C2 H6                      106.16             3.12 -3.15

How 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 a
multi-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)
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
        parameters




Personal exposure ET is given as a function of the
concentrations C in the locations encountered,
the time spent in these locations and the type of
performed activity, which in turn affects the
breathing rate
       ET           f n Cn inhn
                n
where inh is the inhalation correction coefficient
for each type of microenvironment encountered in
the calculations
PBPK model for benzene and the metabolites
7th International Conference on the Science of Exposure Assessment (X2012)   Edinburgh, Scotland   2 – 5 July 2012   6
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]             model
Benzene 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
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)
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/shops
Concentration (μg/m3)




                          40
                                                     Train/bus/car/taxi
                                                     Outdoor
                          30

                          20

                          10

                            0
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/kindergartens
Concentration (μg/m3)




                                                  Offices/public buildings
                         150                      Bars/cafes/restaurants/shops
                                                  Train/bus/car/taxi
                                                  Outdoor
                         100



                          50



                            0
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 buildings
Concentration (μg/m3)




                          30               Bars/cafes/restaurants/shops
                                           Train/bus/car/taxi
                          25
                                           Outdoor
                          20

                          15

                          10

                            5

                            0
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/kindergartens
Concentration (μg/m3)




                          80              Offices/public buildings
                                          Bars/cafes/restaurants/shops
                          60              Train/bus/car/taxi
                                          Outdoor
                          40


                          20


                            0
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                         Ethylbenzene
Intake (μg/kg_bw/d)




                                                    Xylenes
                          5

                          4

                          3

                          2

                          1

                          0
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     14
Probability 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 density
Probability 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
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
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
                                                                                                                                                            0.07
Benzene 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
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    17
Probability density




                      0.00           0.02                  0.03                  0.05              0.07             0.08
                                                      Internal exposure (μg/L)
                                                                                                                  Exposure scenario assessed:
                                                                                                                  Belgium, Adult male
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
Conclusions
 7th International Conference on the Science of Exposure Assessment (X2012)   Edinburgh, Scotland   2 – 5 July 2012   19




There are significant data gaps with regard to the indoor concentrations data on BTEX
across EU.

Exposure to TEX is significantly below the existing Exposure Limit values, thus the
importance of BTEX exposure arises due to the prolonged exposure to benzene.

Internal exposure to benzene toxic metabolites is higher to children, due to the
relatively higher bodyweight normalized daily dose

BTEX PBPK/D model was validated against independent biomonitoring data set. Results
showed that the PBPK/D model provides accurate predictions of both the interaction
mechanism among the constituents of the mixture and of the benzene metabolic chain.

At the levels of environmental concentrations met in EU indoor locations, no mixture
interaction at the metabolism level is manifested; thus, co-exposure to BTEX does not
pose any reason for additional concern. The BTEX mixture effect can be addressed by
additivity.

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Btex

  • 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 assessment Prof. Dimosthenis A. Sarigiannis Director of Environmental Engineering Laboratory Department 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 representation 7th 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 blood Source conditions: e.g. oEmission strength oTime pattern Housing conditions: e.g. Individual conditions: e.g. Inter-individual response to oChemical/physical properties Dimensions and layout Time activity patterns in house xenobiotics of 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 4 Chemical name CAS No Formula MW log Kow Benzene 71-43-2 C6H6 78.11 2.13 Toluene 108-88-3 C7H8 or C6H5CH3 92.14 2.65 Ethylbenzene 100-41-4 C8H10 106.17 3.13 Xylenes 1330-20-7 C6H4C2 H6 106.16 3.12 -3.15 How 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 a multi-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 parameters Personal exposure ET is given as a function of the concentrations C in the locations encountered, the time spent in these locations and the type of performed activity, which in turn affects the breathing rate ET f n Cn inhn n where inh is the inhalation correction coefficient for each type of microenvironment encountered in the calculations
  • 6. PBPK model for benzene and the metabolites 7th 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] model Benzene 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/shops Concentration (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/kindergartens Concentration (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 buildings Concentration (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/kindergartens Concentration (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 Ethylbenzene Intake (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 14 Probability 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 density Probability 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 0.07 Benzene 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 17 Probability 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 19 There are significant data gaps with regard to the indoor concentrations data on BTEX across EU. Exposure to TEX is significantly below the existing Exposure Limit values, thus the importance of BTEX exposure arises due to the prolonged exposure to benzene. Internal exposure to benzene toxic metabolites is higher to children, due to the relatively higher bodyweight normalized daily dose BTEX PBPK/D model was validated against independent biomonitoring data set. Results showed that the PBPK/D model provides accurate predictions of both the interaction mechanism among the constituents of the mixture and of the benzene metabolic chain. At the levels of environmental concentrations met in EU indoor locations, no mixture interaction at the metabolism level is manifested; thus, co-exposure to BTEX does not pose any reason for additional concern. The BTEX mixture effect can be addressed by additivity.