Developing Risk Assessment Beyond Science and Decisions

1. Developing Risk AssessmentBeyond Science and Decisions  M.E. (Bette) Meek McLaughlin Centre University of Ottawa bmeek@uottawa.ca 1

2. Outline The NAS Report Science & Decisions: Advancing Risk Assessment Coordinating & Extending the Recommendations Potential Contribution of Other Initiatives National & International Dose Response tailored to Need Problem Formulation/Dose Response Analysis Focus of the Workshop 2

4. 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 4

5. NAS Committee:Advancing Risk Assessment - Focus Improving the technical analysis that supports risk assessment Chapters 4 to 7 Improving the utility of risk assessment Chapters 3 and 8 5

6. NAS Committee:Advancing Risk Assessment Design of risk assessment Uncertainty and variability Selection and use of defaults A unified default approach to dose-response Combined Exposures risk assessment Improving the utility of risk assessment Problem formulation/Issue Identification Stakeholder involvement Capacity building 6

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8. Phase I Problem Formulation Begins with a �signal� of potential harm Positive bioassay or epidemiological study; industrial contamination What options are there to reduce the hazards or exposures? How can risk assessment be used to evaluate the merits of the various options? 8

9. Phase II Planning, Risk Assessment & Confirmation of Utility Level & complexity consistent with the goals of decision-making Including uncertainty & variability analysis Assessment Meet the need, discriminate among options, adequate process? 9

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12. Implications of Regulatory Developments to Consider All Chemicals Need for increased efficiency in risk assessment Processing much larger numbers of substances More/better predictive tools & more efficient toxicity testing Drawing on new technologies such as the genomics Requires a fundamental paradigm shift 12

14. Phase III Risk Management Based on consideration of a broader range of options and array of impacts, beyond individual effects to include individual health status and ecosystem protection 14

15. NAS Committee:Advancing Risk Assessment Design of risk assessment Uncertainty and variability Selection and use of defaults A unified default approach to dose-response Combined Exposures risk assessment Improving the utility of risk assessment Problem formulation/Issue Identification Stakeholder involvement Capacity building 15

16. Selection and Use of Defaults �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� This is helpful to increase transparency as a basis to separate science judgment from science policy However: It sets up �default� as representing something other than: what we use when we don�t have predictive data about how chemicals induce their effects Recognizing that the scientific basis of defaults is nebulous, at best, 16

17. Default Methodology in Risk Assessment Curve fitting from high dose studies for adverse late (apical) endpoints (hazard identification) Linear extrapolation to estimate risk, or: �Safe Dose� N/LO(A)EL or BMC/D Uncertainty Factors Interspecies differences/ human variability (x10) 17

18. Default as the �Gold Standard� Adherence to default is likely: One of, and arguably, the single most important determinant of lack of progress in regulatory risk assessment to address: Susceptible subpopulations Harmonization across endpoints Combined exposures, Accuracy, & Predictive capacity 18

19. Changing the �Default Mindset� Rather than challenging the risk assessment community to justify moving from default, emphasis should necessarily be on data first Reverse the onus We need also to increase understanding of the erroneous premise that default is always protective Depends on mode of action (kinetic/dynamic data) 19

20. NAS Committee:Advancing Risk Assessment Design of risk assessment Uncertainty and variability Selection and use of defaults A unified default approach to dose-response Combined Exposures risk assessment Improving the utility of risk assessment Problem formulation/Issue Identification Stakeholder involvement Capacity building 20

21. Unified Approach to Default Dose Response Assessment �A consistent approach to risk assessment for cancer and non-cancer effects is scientifically feasible and needs to be implemented� �Because the RfD and RfC do not quantify risks for different magnitudes of exposure�their use in risk-risk and risk-benefit comparisons and risk management decision-making is limited� This seemed to prevail over discussions related to modes of action, background exposures & susceptibility 21

22. The �Recommendation� EPA implement a phased-in approach to consider chemicals under a unified dose-response assessment framework that includes a systematic evaluation of background exposures and disease processes, possible vulnerable populations, and modes of action that may affect human dose-response relationships = mode of action 22

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24. 24 Default Curve fitting at high dose for point of departure for late (apical) endpoints Linear extrapolation or N/LO(A)EL or BMC/D UF Interspecies differences/human variability (x10) Earlier endpoints in the most relevant species, considering kinetic and dynamic data, to address extrapolations

25. Mode of Action (MoA) information is core to evolution of the risk assessment paradigm

26. Exposure-Response Continuum(Source to Outcome Pathway)

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29. Default to Biologically Based Default Biologically Based Key Events

30. NAS Committee:Advancing Risk Assessment Design of risk assessment Uncertainty and variability Selection and use of defaults A unified default approach to dose-response Combined Exposures risk assessment Improving the utility of risk assessment Problem formulation/Issue Identification Stakeholder involvement Capacity building 30

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32. The Need for Efficiency:Evolving Legislative Mandates Canada �Categorization� (i.e., systematic priority setting) for 23, 000 chemicals by Sept., 2006 under the Canadian Environmental Protection Act (CEPA) Europe Registration, Evaluation and Authorization of Chemicals (REACH) (2007) Volume trigger and hazard based Consistency between Existing and New Chemicals Industry Responsibility U.S. Voluntary Testing Initiatives Renewal of TOSCA 32

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34. 34 Simple and Complex Priority Setting Tools

35. ?Efficiency - Screening Health Assessments Includes early (formal) Issue Identification to focus resources Draws on work completed in other jurisdictions Considers weight of evidence of hazard and �margins of exposure� (comparing upper bounding estimates of exposure to lowest effect levels) High hazard, proposed �toxic� Margin wide, �set aside� Margin small, additional assessment (Priority Substance) Decision making on the basis of adequacy of the margins, based on consideration and clear delineation of confidence/uncertainties 35

36. Post CategorizationWhat�s Changed? Priorities not necessarily what we expected The value of a �risk-based� framework to consider all chemicals Consumer vs. environmental exposure/profile Volume ? exposure Persistence/bioaccumulation ? exposure Integrated approach across compounds (less chemical-specific; more contextually relevant) Drawing to much greater extent on profiles of substances with similar uses, properties and hazards 36

37. Post CategorizationWhat�s Changed? (cont�d) Focus Strategically targetting testing and �right sizing� risk management Only as much research/survey/assessment as is required to set a substance aside as a non-priority or to inform risk management increasing efficiency Full assessments where required Even for these few, early focus 37

38. Other Relevant Initiatives International initiatives on mode of action (MOA)/extension to dose response (IPCS/ILSI) (supported by HC; US EPA) MOA and Key Events Frameworks; CSAF PCS Coordinating Predictive Use of MOA In collaboration with OECD/others ILSI/Health Canada initiative on Problem Formulation/Issue Identification(2007) IPCS Combined Exposures Framework In collaboration with OECD/others 38

39. Other Relevant Initiatives IPCS Tiered Uncertainty Analysis (2007) IPCS Characterizing and Applying PBPK Models in Chemical Risk Assessment http://www.who.int/ipcs/methods/harmonization/index.html http://www.hc-sc.gc.ca/exsd-dse http://www.ilsi.org/ResearchFoundation 39

40. The Role of Formal Issue IdentificationMore than a Statement of the Issue; A Process Early Consideration of All Relevant (assimilated) information/expertise Relying as much as possible on existing assessments, �peers� Determining need for risk assessment based on consideration of factors such as nature and feasibility of risk management Determining focus and scope of risk assessment, based on potential options for management Ensuring that any assessment meets the considered need Communication and formal engagement Stakeholders/risk managers/public 40

41. Problem Formulation - Process

44. Some Outstanding Questions on the NAS Analysis Were all of the relevant options along the continuum of straight �default� to more mode of action based approaches to dose-response analysis adequately considered? Were their attendant relative uncertainties characterized? Was the analysis considered in the context of tiered, efficient assessment strategies?

45. Evolution of Risk Assessment

46. How Quickly does Risk Assessment Evolve? In 1984, the �benchmark dose� was introduced Now receiving widespread acceptance 25 yrs. later Much guidance, many recommendations on analysis of uncertainty since the 1980�s Several NAS & EPA reports Incorporation of PBPK modelling Since the late 1980�s Formal consideration of mode of action; chemical specific adjustment factors (National & International) Since the late 1990�s Tiered assessment (�94 NAS report) Problem formulation EPA Guidance on Risk Characterization (2000) 46

47. Barriers to Change A function (in part) of: The traditional (default) approach is �simple�, easy to explain to stakeholders & somewhat consistent Can be �codified� �institutionalized� (requires limited expert interpretation) Lack of long term planning for regulatory science Meeting short term deadlines for numbers of assessments vs. understanding efficiencies of longer term investment in methodology Sometimes predicated on science policy basis, without transparency Lack of coordination of regulatory risk assessment/research 47

48. About Advisory Groups on Risk Assessment Methodology They bring extraordinary amounts of multidisciplinary expertise to the table They work extraordinarily hard, and They offer insights that might not have otherwise been realized 48

49. About Advisory Groups However: Much expertise resides in Governments who commission the input They (& others) cannot contribute directly Time is often limited Sometimes leading to partial analysis, contradictions It�s often easier to make recommendations than to implement them Constraints may not be well recognized There isn�t continuity Who explains and develops? 49

50. About Advisory Groups So: Follow-up is essential Engaging the broadest range of expertise possible , or All of the good work is for nought! 50

51. Objective of the Project/Workshop Goal? To increase the efficiency, scientific credibility and utility of chemical risk assessment, addressing particularly problem formulation and dose-response analysis based upon: the NAS Report on Science and Decisions, and other relevant science-based initiatives, nationally & internationally 51

52. Objective of the Project/Workshop (Cont�d) How? Through development of guidance based on application in case study, drawing broadly upon available knowledge Consideration at this workshop of case study proposals in break out groups 52

53. Suggested Criteria for Consideration of Case Studies Addressing the broadest range of problem formulations/applications in risk assessment Addressing the broadest range of issues identified in the NAS report and other relevant initiatives through methodology which is �fit for purpose� (i.e., efficient) Ease of implementation 53

54. Suggested Criteria for Consideration of Case Studies (Cont�d) Engaging as broad a range of stakeholders as possible, and Likely to be successfully completed 54

55. Nature of the Case Studies Testing of assumptions in the NAS report Increasingly informed mode of action analysis along a continuum from default to biologically based case specific models including criteria for adequacy of data, based on existing cases Developing risk estimates using existing (or slightly modified) default methodology for RFDs/RFCs, and Tier 0/Tier 1 approaches with existing methodology AEGLs, screening More efficient integration of data from a variety of sources Categorical, Fusion Based 55 //