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 = C water V water BW C water F aw V alv t BW + C water K p At BW + C water = Water concentration of DWC V water = Volume of water ingested BW = Body weight F aw = Air to water ratio V alv = Alveolar ventilation rate T = Duration of exposure K p = Skin permeability coefficient A = Area of skin exposed

C water [ V water + F aw V alv t + K p At ] Total Exposure = BW Total Exposure from DWCs

Multi-route exposure calculation MAC = TDI x BW x Allocation factor L-Eq L-Eq = L oral + L-eq dermal + L-eq inhalation

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 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) Gagné et al., The Toxicologist, 2008

Toluene multiroute exposure: Additivity of internal dose (high dose) 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 of Toxic Moiety Toxic Moiety- -Target Interaction Perturbation Cellular Changes Morbidity and Mortality Level of sophistication..

Calculating L-equivalents for DWCs L-eq (inhalation) = F a/w x V alv x t x F abs L-eq (dermal) = Kp x A x t x F abs x F abs – Estimated from data or PK models

PBPK Modeling to derive F abs 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

Fraction of systemically available dose (Fs) and L-equivalent (L-eq) for TCE Age group Exposure activity Dermal F s Inhalation F s Dermal L-eq Inhalation L-eq Adult Showering Adult Bathing Child (14yr) Showering Child (14yr) Bathing Child (10yr) Showering Child (10yr) Bathing Child (6yr) Showering Child (6yr) Bathing

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) F abs PBPK models for chloroform for all age groups

Chloroform PBPK model simulations

L-eq for Chloroform IngestionInhalationSkin contact Total Adults L 14-yr old child L 10-yr old child L 6-yr old child 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 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 = F air-water x V alv x t x F abs 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 F air-water F air-water = (cut-off value for Tier I screening)

Tier I evaluation: inhalation exposure ChemicalF air-water Tier 1 Result Methanol0.0001No; stop Methyl ethyl ketone0.0014Yes; tier 2 Chloroform0.0076Yes; tier 2 Trichloroethylene0.0075Yes; tier 2

Two-tier approach: inhalation route Inhalation route, tier I: Inhalation route, tier II: F air-water > ? Determination of L-eq: L-eq = F air-water X 236 F air-water L-eq YES Tier II NO STOP

Computing air concentration associated with drinking water Air to water partition coefficient Henry`s law constant K aw = H/RT Air to water transfer coefficient Relative to radon transfer Diffusion constants Amount by volume Based on first principles C water C air

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 F abs x % is the cut-off (L-eq of 0.15)

Dermal exposure (L-eq) – Tier 1 Development 0.15 L = Kp cm/hr x cm 2 x 1 x 0.5 hr x L/cm 3 x 0.7 CUTOFF Kp = cm/hr Effective Kp??

Tier I evaluation: dermal route ChemicalKpKp Tier 1 Result Dibromoacetic acid No Dichloroacetonitrile0.0163No Trichloroethylene0.12Yes Chloroform0.16Yes

Two-tier approach: dermal route Dermal route, tier I: Dermal route, tier II: YES Tier II NO STOP Kp > cm/h? Determination of L-eq: L-eq = 6.3 X Kp Kp L-eq

K p relevant for DWCs ? (Bogen 1994)

Effective Kp (Cleek and Bunge 1993; Bogen 1994)

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 Skin contact Inhalation Source of contamination Environmental media Route of exposure Receptor person or population at point of exposure AirSoilWaterFood Consume r products L-Eq Allocation factor

Inhalation Skin contact Ingestion Skin contact Inhalation Ingestion Skin contact Inhalation Ingestion Skin contact Inhalation Source of contamination Environmental media Route of exposure AirSoilWaterFood Consume r 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 (K p > cm/hr; T a:w > ) 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