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.