Developing Risk Assessment Beyond Science and Decisions

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Developing Risk AssessmentBeyond Science
and Decisions

• M.E. (Bette) Meek
• McLaughlin Centre
• University of Ottawa
• bmeek_at_uottawa.ca

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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

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The Committees Vision
Science and DecisionsAdvancing Risk Assessment
Final Report Released, 2008
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NAS CommitteeAdvancing 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

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NAS CommitteeAdvancing 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

Efficiency/Tiering?
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NAS CommitteeAdvancing 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

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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?

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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?

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The NAS 4-Step Paradigm The Need to Move On
Hazard Identification
Exposure Assessment Characterization
Dose Response Assessment Characterization
Risk Assessment Characterization

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Revised NAS 4-Step Paradigm
Hazard Characterization
Exposure Assessment Characterization
Dose Response Assessment Characterization
Risk Assessment Characterization

Hazard Characterization (including mode of
action) permits us to be more predictive
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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

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The Committees Vision
Toxicity Testing in the 21st CenturyA Vision
and A Strategy
Final Report Released June 12, 2007
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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

The entire process to protect against political
interference, engage stakeholders and meet time
constraints (Details to follow)
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NAS CommitteeAdvancing 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

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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 dont have predictive data
  about how chemicals induce their effects
• Recognizing that the scientific basis of defaults
  is nebulous, at best,

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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)

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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

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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)

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NAS CommitteeAdvancing 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

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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 exposuretheir 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

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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

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Figure 5.8 New unified process for selecting
approach and methods for dose-response assessment
for cancer and noncancer .
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Default
Biologically(MoA) Based

• 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

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Mode of Action (MoA) information is core to
evolution of the risk assessment paradigm
Understand Human Relevance Susceptibility Dose
Extrapolation
Mode of Action Toxicity Pathways Identify Key
Events
Promote Harmonized approach for all endpoints
Inform Multiple Chemical Risks
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Exposure-Response Continuum(Source to Outcome
Pathway)
Mode of Action involves identification of several
key events between exposure and effect
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IPCS/ILSI MOA/HR (WOE) Framework
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
Implications of Kinetic Dynamic Data for Dose
Response
Comparison of Key Events relevant biology
between animals humans
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Implications for Dose-Response Analysis
What is the shape of the dose-response curve in
the range of both observation and inference for
the rate limiting key events, based on an
understanding of MOA?
Key Event
Tumours
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Default to Biologically Based

• Default

• Biologically Based
• Key Events

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NAS CommitteeAdvancing 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

Efficiency/Tiering?
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Efficiency/Tiering?
Figure 5.8 New unified process for selecting
approach and methods for dose-response assessment
for cancer and noncancer .
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The Need for EfficiencyEvolving 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

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CEPA 1999 Existing Substances Program
CATEGORIZATION of the Domestic Substances List
(DSL) (First Phase) (n23,000)
INCREASING REFINEMENT OF PRIORITIES COMPLEXITY
OF ASSESSMENT
Decisions of Other Jurisdictions
Public Nominations
Greatest Potential for Human Exposure
Substances that are Persistent or Bioaccumulative
DECREASING NUMBERS OF SUBSTANCES
Inherently Toxic to Humans
Inherently Toxic to non-Human Organisms
SCREENING ASSESSMENT (Second Phase)
No further action under this program
Risk Management
CEPA-Toxic
IN-DEPTH ASSESSMENT - Priority Substances List
(Third Phase)
DECREASING UNCERTAINTY
No further action under this program
CEPA-Toxic
Risk Management
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Simple and Complex Priority Setting Tools
EXPOSURE Simple Exposure Tool (SimET) - Relative
ranking of all DSL substances based on submitters
(S),quantity (Q) and expert ranked use
(ERU) Complex Exposure Tool (ComET) -
Quantitative plausible maximum age-specific
estimates of environmental and consumer exposure
for individuals based on use scenario (sentinel
products), phys/chem properties bioavailability
Potential for exposure influential in setting
priorities Included simple use profiling for all
23, 000 chemicals, more complex use profiling for
priorities
HAZARD Simple Hazard Tool (SimHaz) -
Identification of high or low hazard compounds by
various agencies based on weight of evidence and
expert opinion/consensus Complex Hazard Tool
(ComHaz) - Hierarchical approach for multiple
endpoints data sources (e.g., (Q)SAR) including
preliminary weight of evidence framework
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?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

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Post CategorizationWhats 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

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Post CategorizationWhats Changed? (contd)

• 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

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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

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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/inde
  x.html
• http//www.hc-sc.gc.ca/exsd-dse
• http//www.ilsi.org/ResearchFoundation

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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

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Problem Formulation - Process
Dialogue/Engagement with Risk Assessors/Risk
Managers/Advisors/Peers
First Questions

1. What is the problem?
2. What factors need to be considered?
3. What is the role of risk assessment in decision
   making?

Establish the Focus and Scope of the Risk
Assessment
Is the preliminary focus acceptable?
No Role
Risk Assessment to be considered in decision
making
Yes
No
Develop Risk Assessment Procedures
Proceed with Risk Assessment
Make decision another way Seek stakeholder and
peer input
Perform Risk Assessment
Risk Management
Peer Review
Has the problem been addressed?
Develop Risk Characterization Approach and Tools
No
Yes
Implement Risk Management Decisions
Iterate
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Establish the Focus and Scope of the Risk
Assessment

• Management Constraints
• Regulatory considerations
• Objectives
• Screening or full
• Broad or narrow
• Time and resources
• Socio-economic considerations
• Political considerations

• Characterization of Assessment
• Assimilate universe of known data
• Consider relevant exposure scenarios
• Determine degree of acceptable uncertainty
• Plan for addressing uncertainty
• Develop communications plan
• Development of preliminary hypotheses

Seek stakeholder and peer input
Seek stakeholder and peer input
No
Develop Approach Is the preliminary approach
acceptable?
Seek stakeholder and peer input

• Forms of Assessment
• Examples
• Semi-Quantitative/Quantitative
• Deterministic/Probabilistic
• PB/PK
• MOA

Seek stakeholder and peer input
Yes
Proceed with Risk Assessment
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PCS Combined Exposures Framework Sample Tiered
Exposure and Hazard Considerations
Yes, no further action required
Tiered Exposure
Tiered Hazard
Assessments
Assessments
Tier 0
Tier 0
Simple semi-quantitative estimates of exposure
Dose addition for all components
Input from exposure or hazard assessments (iterati
ve process) Is the margin of exposure adequate ?
Tier 1
Tier 1
Refined potency based on individual POD,
refinement of POD
Generic exposure scenarios using conservative
point estimates
Increasing refinement of hazard models (MOA)
Increasing refinement of exposure models
Tier 2
Tier 2

Refined exposure assessment, increased use of
actual measured data
More refined potency (RPF) and grouping based on
MOA
Tier 3
Tier 3
PBPK or BBDR probabilistic estimates of risk
No, continue
Probabilistic Exposure Estimates
Framework includes also a decision tree for when
to consider combined effects of multiple chemicals
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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?

Problem Formulation
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Evolution of Risk Assessment
21st Century
1980s
2000s
1990s
RA/RM Paradigm Guidelines/Methods Dosimetry/PbPK
Mode of Action Susceptible Populations Mixtures
Toxicity Pathways Integrated Approaches CompTox
1983
1994
2007
2009
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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 1980s
• Several NAS EPA reports
• Incorporation of PBPK modelling
• Since the late 1980s
• Formal consideration of mode of action chemical
  specific adjustment factors (National
  International)
• Since the late 1990s
• Tiered assessment (94 NAS report)
• Problem formulation
• EPA Guidance on Risk Characterization (2000)

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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

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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

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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
• Its often easier to make recommendations than to
  implement them
• Constraints may not be well recognized
• There isnt continuity
• Who explains and develops?

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About Advisory Groups

• So
• Follow-up is essential
• Engaging the broadest range of expertise possible
  , or
• All of the good work is for nought!

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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

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Objective of the Project/Workshop (Contd)

• 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

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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

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Suggested Criteria for Consideration of Case
Studies (Contd)

• Engaging as broad a range of stakeholders as
  possible, and
• Likely to be successfully completed

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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