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Problem Formulation to Dose-Response: Advances via the ARA Beyond Science and Decisions Workshops Presented by: M.E. (Bette) Meek bmeek@uottawa.ca . NAS Committee:Advancing Risk Assessment - Background. “Chemical Risk assessment at a crossroads” Facing substantial challenges, e.g.,

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slide1

Problem Formulation to Dose-Response: Advances via the ARA Beyond Science and Decisions Workshops

Presented by:

M.E. (Bette) Meek

bmeek@uottawa.ca

nas committee advancing risk assessment background
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
slide3

“Fit for Purpose”

Broader range of options and array of impacts

Individual, population

Purpose oriented

Figure S-1 A framework for risk based decision making that maximizes the utility of risk assessment

unified approach to default dose response assessment use of defaults
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”
slide5

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

challenge
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
slide7

The Need to Move On

Revised NAS 4-Step Paradigm

Problem Formulation

Weight of Evidence

D-R/Temporal Relationships

Consistency, Specificity

Biological Plausibility

Uncertainty

Hazard Characterization

Dose Response Assessment

& Characterization

Exposure Assessment

& Characterization

Weight of Evidence

D-R/Temporal Relationships

Consistency, Specificity

Biological Plausibility

Uncertainty

Risk Assessment & Characterization

Hazard Characterization (early focus not only on effect but how the effect is induced - mode of action)

slide8

Problem Formulation for Grouping

Nature of exposure?

Is exposure likely?

Co-exposure within a relevant timeframe?

Rationale for considering compounds in an assessment group?

Uncertainty,

Sensitivity

Assessment

Tiered Exposure

Tiered Hazard

Assessments

Assessments

Yes, no further

Tier 0

Tier 0

Simple semi-quantitative estimates of exposure

Default dose addition for all components

action required

Tier 1

Tier 1

Generic exposure scenarios using conservative point estimates

Refined potency based on individual POD, refinement of POD

Is the margin of exposure adequate?

Increasing refinement of exposure

Increasing refinement of hazard

Tier 2

Tier 2

Refined exposure assessment, increased use

of actual measured data

More refined potency (RFP) and grouping based on MOA

No, continue with iterative

refinement as needed

(i.e. more complex exposure & hazard models)

Tier 3

Tier 3

PBPK or BBDR; probabilistic

Probabilistic exposure

estimates

estimates of risk

slide9

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?

Postulated MOAs

D-R/Temporal Relationships

Consistency, Specificity

Biological Plausibility

“Key Events” established based on “Hill Criteria”

Confidence?

Implications of Kinetic & Dynamic Data for

Dose– Response

Comparison

of “Key Events” & relevant biology between animals & humans

Confidence?

Confidence?

engaging the risk assessment community evolution of moa hr analysis
Engaging the Risk Assessment CommunityEvolution 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
objectives ara project engagement evolution
Objectives – ARA ProjectEngagement/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
roles responsibilities
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
process output 3 workshops
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
process output learnings
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
process output cont d
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

slide16

“Fit for Purpose”

Broader range of options and array of impacts

Individual, population

Purpose oriented

Figure S-1 A framework for risk based decision making that maximizes the utility of risk assessment

slide18

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

slide21
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)

Rat Dose

NOAEL/LOAEL

Hays et al. 2008; Reg. Tox. Pharm. 51 (3 Suppl. 1):S4.

Screening tool!

BERfD

Human Blood

Level

Tolerable Human

Dose – RfD

slide22

Problem Formulation for Grouping

Nature of exposure?

Is exposure likely?

Co-exposure within a relevant timeframe?

Rationale for considering compounds in an assessment group?

Uncertainty

Assessment

Tiered Exposure

Tiered Hazard

Assessments

Assessments

Yes, no further

Tier 0

Tier 0

Simple semi-quantitative estimates of exposure

Default dose addition for all components

action required

Tier 1

Tier 1

Generic exposure scenarios using conservative point estimates

Refined potency based on individual POD, refinement of POD

Is the margin of exposure adequate?

Increasing refinement of exposure

Increasing refinement of hazard

Tier 2

Tier 2

Refined exposure assessment, increased use

of actual measured data

More refined potency (RFP) and grouping based on MOA

No, continue with iterative

refinement as needed

(i.e. more complex exposure & hazard models)

Tier 3

Tier 3

PBPK or BBDR; probabilistic

Probabilistic exposure

estimates

estimates of risk

two risk assessment approaches investigated
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
slide24

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
slide25

Problem Formulation for Grouping

Nature of exposure?

Is exposure likely?

Co-exposure within a relevant timeframe?

Rationale for considering compounds in an assessment group?

Uncertainty

Assessment

Tiered Exposure

Tiered Hazard

Assessments

Assessments

Yes, no further

Tier 0

Tier 0

Simple semi-quantitative estimates of exposure

Default dose addition for all components

action required

Tier 1

Tier 1

Generic exposure scenarios using conservative point estimates

Refined potency based on individual POD, refinement of POD

Is the margin of exposure adequate?

Increasing refinement of exposure

Increasing refinement of hazard

Tier 2

Tier 2

Refined exposure assessment, increased use

of actual measured data

More refined potency (RFP) and grouping based on MOA

No, continue with iterative

refinement as needed

(i.e. more complex exposure & hazard models)

Tier 3

Tier 3

PBPK or BBDR; probabilistic

Probabilistic exposure

estimates

estimates of risk

relevance to advancements in risk assessment
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)
forward looking assessment
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?
ara steering committee
ARA Steering Committee
  • 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
dose response advisory committee
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
expert panel
Expert Panel
  • 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
more information
More Information?

ARA Dose Response Framework – (working beta) 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

Guidance for CSAF

http://www.who.int/ipcs/methods/harmonization/areas/uncertainty/en/index.html

Combined Exposures

Meek et al. (2011) Reg Tox Pharm 60: S1-S14