1. 1 Problem Formulation to Dose-Response: Advances via the ARA Beyond Science and Decisions Workshops Presented by: M.E. (Bette) Meek bmeek@uottawa.ca

2. NAS Committee:Advancing Risk Assessment - Background “Chemical Risk assessment at a crossroads” Facing substantial challenges, e.g., – long delays in completing complex risk assessments, some of which take decades – lack of data – the need to address the many unevaluated chemicals in the marketplace Recommendations for practical improvements to the U.S. Environmental Protection Agency (EPA) – Shorter (2-5 y) and – longer (10-20 y) term 2

3. Figure S-1 A framework for risk based decision making that maximizes the utility of risk assessment Purpose oriented “Fit for Purpose” Broader range of options and array of impacts Individual, population 3

4. Unified Approach to “Default” Dose Response Assessment; Use of “Defaults” “A consistent approach to risk assessment for cancer and non- cancer effects is scientifically feasible and needs to be implemented” Predicated principally on the basis of perceived need to quantify risks for risk-risk and risk-benefit comparisons “EPA should develop clear, general standards for the level of evidence needed to justify the use of agent-specific data and not resort to default” 4

5. Figure 5.8 New unified process for selecting approach and methods for dose-response assessment for cancer and noncancer. 5

6. Challenge: Extending these considerations to address value of information and purpose specific assessment strategies including mode of action (MOA) understanding that: – More efficient assessment as a basis to address the many unevaluated chemicals in the marketplace requires: Moving to more predictive, mode of action based approaches & tiered assessment strategies Recognizing the importance of interdisciplinary collaboration/communication/engagement – E.g., significant contributions of EPA and the international community in considering adequacy of data in moving from default to more progressive MOA based approaches 6

7. The Need to Move On Revised NAS 4-Step Paradigm Hazard Characterization Risk Assessment & Characterization Exposure Assessment & Characterization Dose Response Assessment & Characterization Weight of Evidence D-R/Temporal Relationships Consistency, Specificity Biological Plausibility Uncertainty Weight of Evidence D-R/Temporal Relationships Consistency, Specificity Biological Plausibility Uncertainty Problem Formulation Hazard Characterization (early focus not only on effect but how the effect is induced - mode of action) 7

8. Yes, no further action required No, continue with iterative refinement as needed (i.e. more complex exposure & hazard models) Is the margin of exposure adequate? Tiered Exposure Assessments Tiered Hazard Assessments Increasing refinement of hazard Increasing refinement of exposure Tier 0 Simple semi- quantitative estimates of exposure Tier 1 Generic exposure scenarios using conservative point estimates Tier 2 Tier 3 Probabilistic exposure estimates Refined exposure assessment, increased use of actual measured data Tier 0 Default dose addition for all components Tier 2 More refined potency (RFP) and grouping based on MOA Tier 3 PBPK or BBDR; probabilistic estimates of risk Tier 1 Refined potency based on individual POD, refinement of POD 8 Nature of exposure? Is exposure likely? Co-exposure within a relevant timeframe? Rationale for considering compounds in an assessment group? Problem Formulation for Grouping Assessment Uncertainty, Sensitivity

9. IPCS/ILSI MOA/HR (WOE) Framework Implications of Kinetic & Dynamic Data for Dose– Response Q1. Is the weight of evidence sufficient to establish the MoA in animals? Q2. Fundamental qualitative differences in key events? Q3. Fundamental quantitative differences in key events? “Key Events” established based on “Hill Criteria” Comparison of “Key Events” & relevant biology between animals & humans 9 Postulated MOAs D-R/Temporal Relationships Consistency, Specificity Biological Plausibility Confidence?

10. Engaging the Risk Assessment Community Evolution of MOA/HR Analysis U.S. EPA ’99/’05 cancer guidelines IPCS framework for WOE for MOA in animals –Sonich Mullin et al., 2001 ILSI RSI development of HR component and case studies –Meek et al., 2003; Cohen et al., 2004; Seed et al., 2005 IPCS revision of frameworks and addition of case studies –Boobis et al., 2006; Boobis et al., 2008 ILSI RSI Key Events Dose Response Framework –Boobis et al., 2010 ECETOC Workshop - mapping MOAs & key events to chemical categories –Carmichael et al. (2011) OECD Workshop (2010) – QSAR/MOA –Extending MOA/HR framework concepts as the coordinating construct between: The ecological & health risk communities The QSAR modelling and risk assessment communities IPCS coordinating steering group on mode of action (constituted in October, 2010) –Revision of the MOA/HR framework – evolving methodologies –Database on MOAs/key events/”codification” of Bradford Hill criteria Training workshops (2006 to present at locations in Canada, the U.S., Europe & the Asian region) –ILSI RSI/Health Canada/U.S. EPA/IPCS/University of Ottawa 10

11. Objectives – ARA Project Engagement/Evolution Sharing and additionally evolving a broad range of “fit for purpose” risk assessment tools Coordinating & Extending specific recommendations in the NAS Report on Science & Decisions: Advancing Risk Assessment – Considering a broad range of (internationally available) tools & their potential evolution to address critical areas identified in the report Considering Dose Response tailored to Need – Appropriate consideration of Mode Of Action (MOA) and Value of Information – Evolving consideration of human variability & biologically based methodology for determining probability of response – Tiered, “Purpose Oriented” Assessment, in appropriate context – Through consideration of case studies 11

12. Roles/Responsibilities The Alliance for Risk Assessment Steering Committee (ARA SC) – representatives from state, tribal, and federal government, academia, and environmental NGOs – selected members of the Expert Panel after a review of publically solicited nominations Dose Response Advisory Committee (DRAC) – sponsors including state, federal, industry, and NGO representatives – Developed workshop structure & charge questions, presenters, consulting with ARA Steering Committee Science Panel – input on the utility of the case study methods to address specific problem formulations, and identify areas for additional development 12

13. Process/Output - 3 Workshops March 2010 Pre workshop: Broad solicitation and brainstorming regarding illustrative case studies Initial vetting and review of proposals for case studies October 2010 Review of case studies Recommendation for draft methods framework for “fit for purpose” dose-response analysis, reflecting: different conceptual models, data availability & risk management needs May 2011 Additional case studies and identified issues : – Problem formulation, Mode of action. Endogenous & background exposures 13

14. Process/Output/Learnings Recommendations: additional dissemination of dose-response analysis techniques for a wide range of problem formulations or decision contexts Development of templates for transparency in selecting dose- response approaches, relevant to use in specified risk management Additional case studies on: – combined exposures, – value of information – in vitro to in vivo extrapolation – an entire purpose driven risk assessment, from problem formulation to conclusion 14

15. Process/Output (Cont’d) Ongoing: manuscript in preparation Framework to be “evergreen” with a Standing Panel to review case studies/issue papers Learnings: Need to have assessors considering context to address appropriate focus & complexity (problem formulation for assessment) Evolving Framework & 24 case studies Engagement Model 15

16. Figure S-1 A framework for risk based decision making that maximizes the utility of risk assessment Purpose oriented “Fit for Purpose” Broader range of options and array of impacts Individual, population 16

17. Organizational Framework 17

18. Figure 5.8 New unified process for selecting approach and methods for dose-response assessment for cancer and noncancer. 18

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21. Case Study – Combined Exposures Screening Assessment for Noncancer Effects of THMs using Biomonitoring Data (Aylward et al.) Context: Tier 2 exposure, Tier 1 hazard of the WHO Combined Exposures Framework Use of internal dose measures for both: – Exposure metrics – NHANES blood THM data – Dose-response – Biomonitoring Equivalents (BEs) 21 Rat Dose NOAEL/LOAEL Tolerable Human Dose – RfD BE RfD Human Blood Level Screening tool! Hays et al. 2008; Reg. Tox. Pharm. 51 (3 Suppl. 1):S4.

22. Yes, no further action required No, continue with iterative refinement as needed (i.e. more complex exposure & hazard models) Is the margin of exposure adequate? Tiered Exposure Assessments Tiered Hazard Assessments Increasing refinement of hazard Increasing refinement of exposure Tier 0 Simple semi- quantitative estimates of exposure Tier 1 Generic exposure scenarios using conservative point estimates Tier 2 Tier 3 Probabilistic exposure estimates Refined exposure assessment, increased use of actual measured data Tier 0 Default dose addition for all components Tier 2 More refined potency (RFP) and grouping based on MOA Tier 3 PBPK or BBDR; probabilistic estimates of risk Tier 1 Refined potency based on individual POD, refinement of POD 22 Nature of exposure? Is exposure likely? Co-exposure within a relevant timeframe? Rationale for considering compounds in an assessment group? Problem Formulation for Grouping Assessment Uncertainty

23. Two Risk Assessment Approaches Investigated Hazard quotient/Hazard index approach – Does not provide estimates of risk, just assessment of above/below RfD Low dose risk extrapolation – Two approaches 23

24. Application of a Source-to-Outcome Model to Quantitatively Assess Variability in Dose and Sensitivity in Humans (Chlorpyrifos; Price et al.) Tier 3 analysis (probabilistic exposure estimates, PBPK & reliance on MOA-related precursor) – reserved for cases where there is a small margin between exposure and effect; combined effects Relevant to substances that act by a similar mode of action (i.e., AChE inhibition) Addresses more generic issues raised by the NAS committee 24

25. Yes, no further action required No, continue with iterative refinement as needed (i.e. more complex exposure & hazard models) Is the margin of exposure adequate? Tiered Exposure Assessments Tiered Hazard Assessments Increasing refinement of hazard Increasing refinement of exposure Tier 0 Simple semi- quantitative estimates of exposure Tier 1 Generic exposure scenarios using conservative point estimates Tier 2 Tier 3 Probabilistic exposure estimates Refined exposure assessment, increased use of actual measured data Tier 0 Default dose addition for all components Tier 2 More refined potency (RFP) and grouping based on MOA Tier 3 PBPK or BBDR; probabilistic estimates of risk Tier 1 Refined potency based on individual POD, refinement of POD 25 Nature of exposure? Is exposure likely? Co-exposure within a relevant timeframe? Rationale for considering compounds in an assessment group? Problem Formulation for Grouping Assessment Uncertainty

26. Description of modeling

27. Relevance to Advancements in Risk Assessment MOA Based: Assessed variability in both – exposure (variation of residue levels across foods and variation in individual’s dietary consumptions) and – response (variation in physiology and metabolism) Evaluated response to the range of actual human exposures Assessed human sensitivity in multiple age groups (infants, children, adults) Modeling was made more predictive by focusing on early “key event” - namely cholinesterase inhibition (ChEI)

28. Forward Looking Assessment Public problem formulation with proposal for “fit for purpose” assessment –Assimilated Overview of Data –Proposed Focus –Efficiency –Proposed Process Tiered assessment options drawing on predictive tools in early tiers –Importance of mechanistic underpinning What’s the engagement strategy? 28

29. Collaborators 29

30. Barbara Harper, Confederated Tribes of the Umatilla Indian Reservation William Hayes, State of Indiana Bette Meek, University of Ottawa Anita Meyer, United States Army Corps of Engineers Edward Ohanian, U. S. Federal Government Ruthann Rudel, Silent Spring Phil Wexler, National Library of Medicine -----recused----- Michael Dourson, Toxicology Excellence for Risk Assessment Michael Honeycutt, Texas Commission on Environmental Quality ARA Steering Committee 30

31. Dose-Response Advisory Committee Rick Becker, ACC Michael Dourson, TERA Julie Fitzpatrick, EPA Roberta Grant, TCEQ Lynne Haber, TERA Michael Honeycutt, TCEQ Lynn H. Pottenger, Dow Chemical Jennifer Seed, EPA 31

32. 32 Michael Bolger, U.S. FDA James S. Bus, Dow Chemical John Christopher, CH2M/Hill Rory Conolly, U.S. EPA Michael Dourson, TERA *Adam M. Finkel, UMDNJ William Hayes, Indiana DEM (Workshop II only) R. Jeffrey Lewis, ExxonMobil Biomedical Randy Manning, Georgia DNR (Workshop III only) Bette Meek, U of Ottawa (Chairperson) Paul Moyer, Minnesota DH (Workshop II only) *Greg Paoli, Risk Sciences International Rita Schoeny, U.S. EPA *On NAS Science and Decisions panel Expert Panel

33. More Information? ARA Dose Response Framework – (working beta) http://www.allianceforrisk.org/workshop/framework/ problemformulation.html http://www.allianceforrisk.org/workshop/framework/ problemformulation.html Evolution of the ILSI/IPCS Frameworks – Mode of Action Meek & Klaunig (2010) Chemico-Biological Interactions 184:279–285 Carmichael et al. (2011) Crit Rev Toxicol. 2011 Mar;41(3):175-86 Crit Rev Toxicol. Guidance for CSAF http://www.who.int/ipcs/methods/harmonization/areas/unc ertainty/en/index.htmlhttp://www.who.int/ipcs/methods/harmonization/areas/unc ertainty/en/index.html Combined Exposures Meek et al. (2011) Reg Tox Pharm 60: S1-S14 33