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

MAC = Tolerable Daily Intake X Body Weight X Allocation Factor

Volume ingested

Allocation factor: 20% default to DWCs

Ingestion rate = 1.5 L/day

(Health Canada)

Guideline Values for DWCs

RfD = Reference dose RSC = Relative source contribution BW = Body weight Consumption level (2 L/d) only reflects ingestion

RfD (mg/kg/d) x BW (kg) x RSC Consumption (L/d)

Multisource exposures and risk assessment

Air

Food

Water

Soil

Consumer products

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

BW CwaterFawValvt

BW +

CwaterKpAtBW

+

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

Cwater[ Vwater + FawValvt + KpAt ]Total Exposure = BW

Total Exposure from DWCs

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

Multiroute

Dermal

Inhalation

Gavage

Toluene multiroute exposure: Additivity of internal dose (low dose)

0.01

0.10

1.00

10.00

0 1 2 3 4 5 6 7

T(h)

Co

nc

en

tra

tio

n o

f to

lue

ne

in

blo

od

(m

g/L

)

multi

addition

Gagné et al., The Toxicologist, 2008

Toluene multiroute exposure: Additivity of internal dose (high dose)

0.10

1.00

10.00

100.00

0 1 2 3 4 5 6 7

T(h)

Con

cent

ratio

n of

tolu

ene

in b

lood

(m

g/L)

multi

addition

Gagné et al., The Toxicologist, 2008

PBPK modeling of multi-route exposure to DWCs

GI TRACT

Chemical in air

LUNG

FAT

RICHLY PERFUSED TISSUES

LIVER

Metabolism

SKIN

Dermal contact

Oral ingestion

Potential Dose

Absorbed Dose

Tissue Dose ofToxic Moiety

Toxic Moiety--Target Interaction

Perturbation

CellularChanges

Morbidity and Mortality

Level of sophistication..

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

1.0E-08

1.0E-07

1.0E-06

1.0E-05

1.0E-04

0 1 2 3 4 5

Time (hr)

Art

eri

al

blo

od

co

nc.

(m

g/L

) Adult

10 yrs

14 yrs

6 yrs

Fraction of systemically available dose (Fs) and L-equivalent (L-eq) for TCEAge

groupExposure

activity

Dermal

Fs

Inhalation Fs

Dermal

L-eqInhalation

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

1

10

100

0 10 20 30 40 50 60

Time (min)

Alv

eola

r air c

oncentr

atio

n (

ug/L

)

Chloroform PBPK model simulations

0.001

0.01

0.1

1

0 10 20 30 40 50 60

Time (min)

Art

eria

l blo

od c

once

ntra

tion

(ug/

L)

adult

6 yrs

10 yrs

14 yrs

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

10-yr old child

1.10 1.35 0.44 2.89 L

6-yr old child

1.10 1.17 0.28 2.55 L

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 1Rationale 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 1Development

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

Chemical Fair-waterTier 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

Two-tier approach: inhalation route

Inhalation route, tier I:

Inhalation route, tier II:

Fair-water > 0.00063?

Determination of L-eq: L-eq = Fair-water X 236

Fair-water

L-eq

0.001 0.002 0.004 0.008

0.25 0.5 1 2

YES

Tier II

NO

STOP

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

Cwater

Cair

Dermal exposure (L-eq) – Tier 1Rationale 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 1Development

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 KpTier 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:

Dermal route, tier II:

YES

Tier II

NO

STOP

Kp > 0.024 cm/h?

Determination of L-eq: L-eq = 6.3 X Kp

Kp

L-eq

0.04 0.08 0.16 0.24 0.32 0.4

0.25 0.5 1 1.5 2 2.5

Kp relevant for DWCs ? (Bogen 1994)

)log616.0()01014.0(812.0 1010 owp KMWKLog

Effective Kp (Cleek and Bunge 1993; Bogen 1994)

)3/210( 00305.0 thrKK MWp

effp

12 )6(, DmLwherektif m

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

Inhalation

Skin contact

Ingestion

Skin contact

Inhalation

Ingestion

Skin contact

Inhalation

Ingestion

Ingestion

Skin contact

Inhalation

Source of contamination

Environmental media

Route of exposure

Receptor person or population at point of

exposure

Air

Soil

Water

Food

Consumer products

L-Eq

Allocation factor

Inhalation

Skin contact

Ingestion

Skin contact

Inhalation

Ingestion

Skin contact

Inhalation

Ingestion

Ingestion

Skin contact

Inhalation

Source of contamination

Environmental media

Route of exposure

Air

Soil

Water

Food

Consumer products

Water

Ingestion

Skin contact

Inhalation

Receptor person or population at point of

exposure

L-Eq

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