Transcript Approaches for Evaluating the Relevance of Multiroute Exposures in Establishing Guideline Values for Drinking Water Contaminants Kannan Krishnan and Richard Carrier

Approaches for Evaluating the
Relevance of Multiroute Exposures
in Establishing Guideline Values
for Drinking Water Contaminants
Kannan Krishnan, Université de Montréal
&
Richard Carrier, Health Canada
Outline
 DWC risk assessment: An introduction
 Concept of Litre-equivalents (L-eq)
 Estimating L-eq: Data and models
 Multi-route exposures and 2-tier
evaluation
 Concluding remarks
Maximum acceptable concentration
(MAC) of DWCs
Allocation factor: 20% default to DWCs
MAC = Tolerable Daily Intake X Body Weight X Allocation Factor
Volume ingested
Ingestion rate = 1.5 L/day
(Health Canada)
Guideline Values for DWCs
RfD (mg/kg/d) x BW (kg) x RSC
Consumption (L/d)
 RfD = Reference dose
 RSC = Relative source contribution
 BW = Body weight
 Consumption level (2 L/d) only reflects ingestion
Multisource exposures
and risk assessment
Air
Water
Food
Consumer
products
Soil
DWCs & Multiroute Exposures
MAC = TDI X BW X Allocation factor
L
L: Sufficient for multi-route exposures?
L-Equivalent
 Refers to the “ingestive equivalent” of dermal
exposures in terms of L (Bogen 1994; JEAEE
4: 457).
 Ratio of the daily dose (mg) received by the
dermal (or inhalation) route during domestic
water use to the dose (mg) received via the
consumption of drinking water
 Systemically-acting toxicants
Total Exposure from DWCs
Total Exposure = CwaterVwater + CwaterFawValvt + CwaterKpAt
BW
BW
BW








Cwater = Water concentration of DWC
Vwater = Volume of water ingested
BW = Body weight
Faw = Air to water ratio
Valv = Alveolar ventilation rate
T = Duration of exposure
Kp = Skin permeability coefficient
A = Area of skin exposed
Total Exposure from DWCs
Total Exposure = Cwater[ Vwater + FawValvt + KpAt ]
BW
Multi-route exposure calculation
MAC = TDI x BW x Allocation factor
L-Eq
L-Eq = Loral + L-eqdermal + L-eqinhalation
Multiroute Exposures during
Water use: Data-driven L-eq





Inhalation Exposure
Inhalation dose = 7.5 µ g
Oral dose (1.5 L) = 7.5 µ g
L-equivalent = 1.5 x (7.5/7.5) = 1.5 L
Total L-eq = 1.5 L + 1.5 L + 0 L = 3.0 L-eq
Exposure to DWCs during showering
and bathing
 Dose metric?
 Exposure condition?
 Ethical, feasible..?
 Animal models..?
Animal model
Inhalation
Gavage
Dermal
Multiroute
Toluene multiroute exposure:
Additivity of internal dose (low dose)
Concentration of toluene in blood
(mg/L)
10.00
multi
addition
1.00
0.10
0.01
0
1
2
3
4
5
6
7
T(h)
Gagné et al., The Toxicologist, 2008
Toluene multiroute exposure:
Concentration of toluene in blood
(mg/L)
Additivity of internal dose (high dose)
100.00
multi
addition
10.00
1.00
0.10
0
1
2
3
4
5
6
7
T(h)
Gagné et al., The Toxicologist, 2008
PBPK modeling of multi-route
exposure to DWCs
Chemical in air
LUNG
Dermal contact
SKIN
FAT
RICHLY PERFUSED
TISSUES
Oral ingestion
LIVER
GI
TRACT
Metabolism
Level of sophistication..
Morbidity and
Mortality
Cellular
Changes
Perturbation
Toxic Moiety-Target Interaction
Tissue Dose of
Toxic Moiety
Absorbed Dose
Potential Dose
Calculating L-equivalents for DWCs
 L-eq (inhalation) = Fa/w x Valv x t x Fabs
 L-eq (dermal) = Kp x A x t x Fabs x 10-3
 Fabs – Estimated from data or PK models
PBPK Modeling
to derive Fabs for TCE
 Physiological parameters
 Biochemical parameters
 Physiological parameters
 Route-specific absorption parameters


Skin permeability coefficient (0.12 cm/hr)
Air to water concentration ratio (0.71)
TCE blood conc in adults and children
after 10-min shower
Arterial blood conc. (mg/L)
1.0E-04
Adult
10 yrs
1.0E-05
14 yrs
6 yrs
1.0E-06
1.0E-07
1.0E-08
0
1
2
3
Time (hr)
4
5
Fraction of systemically available dose
(Fs) and L-equivalent (L-eq) for TCE
Age
group
Exposure
activity
Dermal
Fs
Inhalation
Fs
Dermal
L-eq
Inhalation
L-eq
Adult
Showering
0.63
0.64
0.30
0.55
Adult
Bathing
0.63
0.66
0.71
1.7
Child
(14yr)
Showering
0.48
0.61
0.20
0.51
Child
(14yr)
Bathing
0.48
0.61
0.61
1.53
Child
(10yr)
Showering
0.47
0.57
0.15
0.43
Child
(10yr)
Bathing
0.47
0.59
0.44
1.35
Child
(6yr)
Showering
0.43
0.51
0.10
0.40
Child
(6yr)
Bathing
0.41
0.52
0.28
1.17
L-eq for TCE
+
1.5 L
2.4 L-eq
Input Data for Chloroform
 Air-to-water transfer ratio

Field data for chloroform
 Dermal permeability constant

Literature data (Health Canada)
 Fabs

PBPK models for chloroform for all age groups
Chloroform PBPK model simulations
Chloroform inhalation and dermal exposure model simulations
Alveolar air concentration (ug/L)
100
10
1
0
10
20
30
Time (min)
40
50
60
Chloroform PBPK model simulations
1
Arterial blood concentration (ug/L)
adult
6 yrs
10 yrs
14 yrs
0.1
0.01
0.001
0
10
20
30
Time (min)
40
50
60
L-eq for Chloroform
Ingestion Inhalation Skin contact
Total
Adults
1.50
1.70
0.91
4.11 L
14-yr old
child
1.20
1.53
0.61
3.34 L
1.10
1.35
0.44
2.89 L
1.10
1.17
0.28
2.55 L
10-yr old
child
6-yr old
child
Two-tier approach (Multiroute exp.)
 Tier 1: Are the non-ingestion exposure routes
important?
 Tier 2: What value of L-eq to use for each
route?
Inhalation (L-eq) – Tier 1
Rationale and Basis
 Inhalation exposure would be important for a
DWC if this route contributes to at least 10%
of the DW consumption level
 L-eq,inhalation = Fair-water x Valv x t x Fabs
 10% is the screening level (0.15 L-eq)
Inhalation exposure (L-eq) – Tier 1
Development
 0.15 L = 675 L/hr x 0.5 hr x 0.7 x Fair-water
 Fair-water = 0.00063 (cut-off value for Tier I
screening)
Tier I evaluation: inhalation exposure
Fair-water
Tier 1
Result
Methanol
0.0001
No; stop
Methyl ethyl ketone
0.0014
Yes; tier 2
Chloroform
0.0076
Yes; tier 2
Trichloroethylene
0.0075
Yes; tier 2
Chemical
Two-tier approach: inhalation route
 Inhalation route, tier I:
Fair-water > 0.00063?
YES
NO
STOP
Tier II
 Inhalation route, tier II:
Determination of L-eq:
Fair-water
L-eq
L-eq = Fair-water X 236
0.001
0.002
0.004
0.008
0.25
0.5
1
2
Computing air concentration
associated with drinking water
 Air to water partition coefficient


Henry`s law constant
Kaw = H/RT
 Air to water transfer coefficient


Relative to radon transfer
Diffusion constants
 Amount by volume

Based on first principles
Cair
Cwater
Dermal exposure (L-eq) – Tier 1
Rationale and Basis
 Dermal exposure would be important for a
DWC if this route contributes to at least 10%
of the DW consumption level (i.e., 0.15 L)

L-eq,dermal = Kp x A X t x Fabs x 0.001

10% is the cut-off (L-eq of 0.15)
Dermal exposure (L-eq) – Tier 1
Development
 0.15 L = Kp cm/hr x 18 000 cm2 x 1 x 0.5 hr x
0.001 L/cm3 x 0.7
 CUTOFF Kp = 0.024 cm/hr
 Effective Kp??
Tier I evaluation: dermal route
Chemical
Kp
Tier 1
Result
Dibromoacetic acid
0.00223
No
Dichloroacetonitrile
0.0163
No
Trichloroethylene
0.12
Yes
Chloroform
0.16
Yes
Two-tier approach: dermal route
 Dermal route, tier I:
Kp > 0.024 cm/h?
YES
NO
STOP
Tier II
 Dermal route, tier II:
Determination of L-eq:
L-eq = 6.3 X Kp
Kp
0.04
0.08
0.16
0.24
0.32
0.4
L-eq
0.25
0.5
1
1.5
2
2.5
Kp relevant for DWCs ?
(Bogen 1994)
Log10 K p  0.812  (0.01014  MW )  (0.616  log 10 K ow )
Effective Kp (Cleek and Bunge 1993; Bogen 1994)
K
if
eff
p
 K p (10
0.00305MW
2hr / 3t )
t  k , where   L (6 Dm )
2
m
1
Multiroute exposure vs RSCs
 Shouldn’t we increase the RSCs?
 No – do one or the other (RSC or L-eq)
 Recalculating RSCs (for oral route) is not
necessary unless there is a way of revising
the RSC for inhalation and dermal routes
Source of
contamination
Environmental
media
Route of
exposure
Inhalation
Air
Skin contact
Ingestion
Soil
Skin contact
Inhalation
Ingestion
Water
Skin contact
Inhalation
Food
Ingestion
Ingestion
Consume
r products
Skin contact
Inhalation
Receptor person or
population at point of
exposure
Source of
contamination
Environmental
media
Route of
exposure
Inhalation
Air
Skin contact
Ingestion
Soil
Skin contact
Inhalation
Ingestion
Ingestion
Water
Water
contact
SkinSkin
contact
Inhalation
Inhalation
Food
Ingestion
Ingestion
Consume
r products
Skin contact
Inhalation
Receptor person or
population at point of
exposure
Conclusions
 Inhalation and dermal routes of exposures are not
negligible for DWCs (Kp > 0.024 cm/hr; Ta:w
0.00063)
>
 Chemical-specific data or models are useful for
estimating L-eq
 2-tier screening approaches might help identify those
DWCs for which detailed modeling is required
 Should not alter both RSCs and L-eq in case of
multiroute exposures