Kannan Krishnan , Université de Montréal & Richard Carrier , Health Canada

1. 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

2. 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

3. Allocation factor: 20% default to DWCs Ingestion rate = 1.5 L/day (Health Canada) Maximum acceptable concentration (MAC) of DWCs MAC = Tolerable Daily Intake X Body Weight X Allocation Factor Volume ingested

4. 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)

5. Multisource exposures and risk assessment Air Water Food Consumer products Soil

6. MAC = TDI X BW X Allocation factor L L: Sufficient for multi-route exposures? DWCs & Multiroute Exposures

7. 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

8. CwaterFawValvt BW CwaterKpAt BW CwaterVwater BW + + Total Exposure from DWCs • 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 =

9. Total Exposure from DWCs Cwater[ Vwater + FawValvt +KpAt ] Total Exposure = BW

10. MAC = TDI x BW x Allocation factor L-Eq L-Eq = Loral + L-eqdermal + L-eqinhalation Multi-route exposure calculation

11. 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

12. Exposure to DWCs during showering and bathing • Dose metric? • Exposure condition? • Ethical, feasible..? • Animal models..?

13. Animal model Inhalation Multiroute Gavage Dermal

14. Toluene multiroute exposure: Additivity of internal dose (low dose) Gagné et al., The Toxicologist, 2008

15. Toluene multiroute exposure: Additivity of internal dose (high dose) Gagné et al., The Toxicologist, 2008

16. Chemical in air LUNG Dermal contact SKIN FAT RICHLY PERFUSED TISSUES Oral ingestion LIVER GI TRACT Metabolism PBPK modeling of multi-route exposure to DWCs

17. Level of sophistication.. Morbidity and Mortality Cellular Changes Perturbation Toxic Moiety- -Target Interaction Tissue Dose of Toxic Moiety Absorbed Dose Potential Dose

18. 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

19. 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)

20. TCE blood conc in adults and children after 10-min shower

21. Fraction of systemically available dose (Fs) and L-equivalent (L-eq) for TCE

22. + 1.5 L 2.4 L-eq L-eq for TCE

23. 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

24. Chloroform PBPK model simulations

25. Chloroform PBPK model simulations

26. L-eq for Chloroform

27. 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?

28. 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)

29. 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)

30. Tier I evaluation: inhalation exposure

31. YES NO Tier II STOP Determination of L-eq: L-eq = Fair-water X 236 Fair-water 0.001 0.002 0.004 0.008 L-eq 0.25 0.5 1 2 Two-tier approach: inhalation route • Inhalation route, tier I: • Inhalation route, tier II: Fair-water > 0.00063?

32. 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

33. 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)

34. 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??

35. Tier I evaluation: dermal route

36. Kp > 0.024 cm/h? YES NO Tier II STOP 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 Two-tier approach: dermal route • Dermal route, tier I: • Dermal route, tier II:

37. Kp relevant for DWCs ? (Bogen 1994)

38. Effective Kp (Cleek and Bunge 1993; Bogen 1994)

39. 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

40. Inhalation Air Skin contact Ingestion Soil Skin contact Inhalation Ingestion Water Skin contact Inhalation Food Ingestion Ingestion Consumer products Skin contact Inhalation Receptor person or population at point of exposure Environmental media Route of exposure Source of contamination Allocation factor L-Eq

41. Inhalation Air Skin contact Ingestion Soil Skin contact Inhalation Ingestion Ingestion Water Water Skin contact Skin contact Inhalation Inhalation Food Ingestion Ingestion Consumer products Skin contact Inhalation Receptor person or population at point of exposure Environmental media Route of exposure Source of contamination L-Eq

42. 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

43. END