This document discusses tiered aggregate exposure assessment, using bisphenol A (BPA) as a case study. It describes conducting aggregate exposure assessments at different tiers of complexity, from initial screening assessments to more refined assessments that consider multiple exposure pathways and variability. For BPA, the assessments compare total exposure from various scenarios to the EFSA tolerable daily intake value, and examine the contribution of different exposure routes. PBPK modeling is also discussed as a method to estimate internal dose from exposure for BPA.

1. 1
TIERED AGGREGATE EXPOSURE ASSESSMENT: THE
CASE OF BISPHENOL A
D.A. Sarigiannis1,2, S.P. Karakitsios1,2, A. Gotti1
1Environmental Engineering Laboratory (EnvE-Lab), Department of Chemical Engineering, Aristotle University of Thessaloniki GR-54124, Thessaloniki, Greece
2Natural Resources and Renewable Energy Laboratory, CPERI, Centre for Research and Technology - Hellas, GR-57001, Thermi-Thessaloniki, Greece
Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 1

2. 2
What is “aggregate
exposure”?
Aggregate exposure is defined as the quantitative exposure assessment to a
single agent from all potential exposure pathways and routes
Do we always need to conduct an aggregate exposure assessment? And if yes, at
what level of complexity?
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3. 3
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An exposure scenario is the set of
conditions that describe how the
substance is manufactured or used
during its life-cycle and how the
manufacturer or importer controls, or
recommends others to control,
exposures of humans and the environment
Exposure scenarios shall be developed for:
i) the manufacturing process and
ii) for identified uses including own uses by the M/I, and uses further
down the chemical supply chain and consumer uses,
iii) life cycle stages resulting from manufacture and identified uses
(article service life and waste life stages)
Why we need to carry out
exposure assessment?
REACH regulation
ECHA guidance documents

4. 4
Why we need to refine
exposure assessment?
Increasingbenefit→
Increasingcost→
Social Benefit
Social cost
Optimal
cost-benefit
Acceptable risk
Exposure reduction →
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5. 5
Decision Strategy for Tiered Approach
to Aggregated Exposure Assessment
Aggregation “within” scenario Aggregation “across” scenario
Define Exposure
scenario (single
source)
Ignoring the
magnitude of
exposure is there
a basis for
aggregation
across routes?
Screening
magnitude of
exposure, is one
route dominant
and other routes
negligible?
YES
SEA
within
Exposure
scenario
(Tier 1)
AEA
within
Exposure
scenario
(Tier 1)
SEA
within
Exposure
scenario
(Tier 2)
AEA
within
Exposure
scenario
(Tier 2)
NO
NO
TIER 0
TIER 1
TIER 2
Define Set of
Relevant
Exposure
scenario (multiple
sources and
pathways)
Ignoring the
magnitude of
exposure is there
a basis for
aggregation
across scenarios
Screening the
magnitude of
exposure, is one
exposure scenario
dominant?
YES
No AEA
across
Exposure
scenario
AEA
across
Exposure
scenario
(Tier 1)
AEA
across
Exposure
scenario
(Tier 2)
NO
NO
TIER 0
TIER 1
TIER 2
Develop a set for
plausible scenario
combinations
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Methodological concept of the
TAGS approach and computational platform
Food
contamination
Drinking water
contamination
Water
contamination
Consumer products
Indoor air
Outdoor air
Environmental - contamination
Bioaccumulation
Active smoking
Oral exposure
Dermal exposure
Non-dietary
oral exposure
Direct skin application
Agriculture
In house building
materials, objects and
activities
Inhalation exposure
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
LungsArterial
blood
Venous
blood
Arterial
blood
Venous
blood
Multimedia environmental modeling Exposure modeling Internal dose modeling

7. 7
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_
_ _ _ _ _
_
_ _
_ _
_ _
_
chem gas
chem gas ind out chem gas chem gas out
chem PM
chem gas p chem gas
p PM
chem dust dust
d chem gas chem PM
dust
dC
V E Q C C V
dt
C
k C V r C V
K C
C m
r C C V
K
_ _
_
_
_ _
chem PM chem PM
p chem gas
p PM
chem PM
ind out PM PM out
PM
dC C
V r C V
dt K C
C
Q C C V
C
_ _ _
_ _
_
chem dust chem dust dust
d chem gas chem PM
dust
dC C m
V r C C V
dt K
Gas phase mass equilibrium
Particles phase mass equilibrium
Dust phase mass equilibrium
Multimedia/microenvironmental
models

8. 8
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9. 9
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GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
metabolite
formation
Arterial
blood
Venous
blood
Arterial
blood
Venous
blood
( ) lim Pr
ij
i i j ij ij ij ij ij
dC
V Q CA CV Metab E Absorp Binding
dt
PBPK models serve three main purposes:
- internal dose – Biologically Effective Dose (BED) assessment
for refined exposure characterization (I)
- the capability to derive an exposure conversion factor
(ECF)/advanced exposure reconstruction for biomonitoring
data assimilation (II)
- the capability to derive Biomonitoring Equivalents (BEs) - link
to BED for direct comparison to legislative/toxicological
thresholds (III)
Physiology Based PharmacoKinetic (PBPK) models are
modeling tools that describe the mechanisms of
absorption, distribution, metabolism and elimination (ADME)
of chemicals in the body resulting from acute and/or chronic
exposure regimes
Internal dosimetry models

10. 10
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Multiple
model runs Model to estimate exposure
( , , )EXPOSURE f A B C
Parameter A Parameter B Parameter C
Probability
distribution based on
accumulated output
results
Probability
Exposure
Model prediction
Distribution of input values for parameters A, B and C
Uncertainty and variability
implementation

11. 11
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Testing the TAGS methodology –
The Bisphenol A (BPA) case study
Application Tonnes/year Information Source
BPA production 1150000 PlasticsEurope (1) Figures for BPA production and polycarbonate use are
estimated volumes
Figures for other use categories are calculated from
estimated percentage increase/decrease since 2003
figures as provided by relevant industry group.
Information sources:
PlasticsEurope (1) Polycarbonate / Bisphenol A Group
PlasticsEurope (2) Epoxy Resins Committee
Cefic (1) Unsaturated Polyester Resin Committee
Cefic (2) ESPA European Stabiliser Producers Association
Cefic(3) European Council for Plasticisers and Intermediates
ETPA European Thermal Paper Association
ECVM European Council of Vinyl Manufacturers
EuPC European Plastics Converters
BPA uses
Polycarbonate 865000 PlasticsEurope (1)
Epoxy resins 191520 PlasticsEurope (2)
– can coatings 2755 PlasticsEurope (2)
– ethoxylated BPA 2260 PlasticsEurope (2)
Phenoplast cast resin processing 8800
Unsaturated polyesters 3600 Cefic (1)
Thermal paper 1890 ETPA
PVC – polymerisation 0 ECVM
- stabiliser packages 450 ECVM, Cefic (2), (3), EuPC
- phthalate plasticisers 900 ECVM, Cefic (2), (3), EuPC
- direct stabilisation 450 ECVM, Cefic (2), (3), EuPC
Others 7245
Net exports 65000 PlasticsEurope (1)
Total consumption 1149870

12. 12
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Testing the TAGS methodology –
The Bisphenol A (BPA) case study
o Comparison of aggregated dose to EFSA TDI (50 μg/kg-bw/day)
o Identification of the exposure scenarios across the several population groups (data from scientific
literature, RAR reports based on contamination and biomonitoring data) using worst case estimates
o Aggregation across (if eligible) scenarios and within scenarios
o Identification of the exposure scenarios across the several population groups (data from scientific
literature, RAR reports from several regulatory bodies)
o Aggregation across scenarios (if eligible……) and within scenarios at (a) external exposure (b) at internal
dose levels
o Comparison of internal dose derived by the several exposure scenarios to (a) EFSA TDI (50 μg/kg-bw/day)
and (b) the equivalent internal dose
Tier 1
Tier 2
o Environmental contamination through Emission Release Categories based on process categories (tonnage
fractions)
o Environmental contamination through actual releases for each process category

13. 13
0.00
0.20
0.40
0.60
0.80
1.00
1.20
RCR
RCR - Inhalation
RCR - Dermal
RCR - Oral
1Considering that Infant formula is diluted with water in a proportion 1:3.5, instead of 1:7 which is the intended use
2Premature infants are fed enterically and parenterically. In the first case they are also exposed to the amount of BPA from infant formula
2
1
Tier 1 assessment
(routes contribution)
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14. 14
TIER 2a outcome
(routes contribution based on
average values)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
RCR
RCR - Inhalation
RCR - Dermal
RCR - Oral
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15. 15
TIER 2a outcome
(variability assessment)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
RCR
95%
Maximum
Minimum
5%
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16. 16
Mother –Fetus interaction
Breast feeding link
b d
V a T c T e
Organ volumes (V) and blood flows (Q) were taken
from the ICRP (2002) report and the obtained data
were fitted to time (T) in order to exclude
continuous time depended non lineal polynomial
formulas in the form of:
0.75
_
_ _
_
tissue child
tissue child tissue adult
tissue adult
V
PS PS
V
The permeability parameters PS were scaled
according to the formula:
ADME processes
( ) lim Pr
ij
i i j ij ij ij ij ij
dC
V Q CA CV Metab E Absorp Binding
dt
_
_ _ _ _ _
uterus_M uterus M
uterus M art M d uter pla placenta uterus M
uterus
Q C
F C K C C
t P
_ _ _ _
_ _ _
placenta placenta
d uter pla placenta uterus M placenta_B art B
placenta
placenta
d pla amniot placenta amniot m placenta placenta
amniot
Q C
K C C F C
t P
P
K C C K C
P
_ _
_ _ _int_
_
breast breast
cell breast breast excr
breast
dC C
V PS fu C L
dt K
_
_ _ /
_
breast
excr milk milk blood
breast
C
L Q P
K
_ _
_ /
_ _
ow tissue tissue
milk blood
ow blood blood
K Fl Fw
P
K Fl Fw
_ _ _ _ _
_ _ _ _ _
placentaamniot
d pla amniot placenta amniot e gut B gut B
amniot
e bile B liver B a amniot B amniot
PQ
K C C K C
t P
K C K C
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
BPA - Glu &
BPA – Sulf
formation
Placenta
Placenta
Arterial blood Arterial blood Venous blood
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Gonads
Lungs
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Gonads
Lungs
BPA - Glu &
BPA – Sulf
formation
Arterial blood Arterial blood Venous blood
/
ow tissue tissue
tissue blood
ow blood blood
K Fl Fw
P
K Fl Fw
The blood/tissue partition coefficients are
contaminant specific and are estimated by the
tissue lipids content and the octanol/water partition
coefficient of the contaminant by the following
formula
Sarigiannis, D.A., Karakitsios, S.P. A dynamic physiology based
pharmacokinetic model for assessing lifelong internal dose. In AIChE
2012, Pittsburgh, PA.
Additional considerations
 Very strong plasma proteins binding
 Reduced clearance during early
developmental stages (ontogeny of related
enzymes)
 Route specific bioavailability differences
The Bisphenol-A
two-generation PBPK model
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17. 17
BPA pharmacokinetic
considerations
- BPA-GLU de-conjugates to BPA in the placenta, increasing
the actual dose during pregnancy
- BPA-GLU de-conjugates to BPA in the stomach, increasing
the actual dose during breast feeding, thus, the sum of BPA
and BPA-GLU needs to be taken into account as BPA dose
during breast feeding
- Very strong plasma protein and RBC binding
- Strong inter individual variability regarding glucuronidation
capacity (significantly lower clearance for neonates/infants)
- First-pass metabolism decisive for clearance – wide
bioavailability differences are expected from routes beyond
oral (up to six times higher internal dose concentrations for
inhalation compared to oral)
0.144 0.152 0.160 0.167 0.175 0.183
Free plasma BPA (μg/L)
Adult EFSA TDI dose
(50 μg/kg-bw/d) biomonitoring
equivalent
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18. 18
TIER 2b outcome
(routes contribution based on
average values)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RCR
RCR - Inhalation
RCR - Dermal
RCR - Oral
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19. 19
0.0
0.5
1.0
1.5
2.0
2.5
RCR
95%
Maximum
Minimum
5%
TIER 2b outcome
(variability assessment)
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20. 20
The optimum combination of human protection against exposure to chemicals from multiple
sources is ensured by a well constructed and targeted Tiered approach
Linking Emissions, Concentrations, Exposure and Internal dose within a “continuous”
mathematical frame allows the exploration of alternative scenarios and the explicit incorporation
of uncertainty and variability in the overall assessment
Tier 2b assessment always gives higher 95th percentiles and maximum values compared to Tier
2, due to the incorporation of inter-individual differences in the metabolism
A cost-efficient methodology for assessing aggregate exposure is needed
Conclusions
Tier 2b assessment is recommended when Tier 2a RCR is above 0.1 and large bioavailability
differences are expected (ontogeny of the related enzymes employed for the metabolism, route
depended differences). In any case, the overall actual increasing RCR factor will be less than the
default UF uncertainty factor for inter-individual differences which is equal to 10, resulting to
most cost-efficient risk management and identification of the actual problematic scenarios.
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21. 21
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Conclusions –
The role of chemical engineer
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
metabolite
formation
Arterial
blood
Venous
blood
Arterial
blood
Venous
blood
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
GI tract – portal vein
Liver
Heart
Brain
Muscles
Skin
Kidneys
Adipose
Bones
Breast
Uterus - gonads
Lungs
metabolite
formation
Arterial
blood
Venous
blood
Arterial
blood
Venous
blood
Animal PBPK model
(supplementary) Human PBPK model
MOA ?
Environmental fate
Hazardassessment
Exposure assessment
QSARs
Riskcharacterization
Physico-chemical
properties
Food
chain
Consumer
products
Biomonitoringdata
BPAD → Human BED → Human BE
Predictive
toxicology
in vitro/alternative
omics
New chemical:
• Uses
• Structure/physico-chemical
properties

22. 22
Thank you for your kind
attention
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Acknowledgments:
The current study was carried out under the project B5: Realistic estimation
of exposure to substances from multiple sources (TAGS), granted by the
European Chemical Industry Council (CEFIC)