“benchmarking” exposure priority setting tools u.s. epa exposure based chemical prioritization...
TRANSCRIPT
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“Benchmarking” Exposure Priority Setting Tools
U.S. EPA Exposure Based Chemical Prioritization WorkshopApril 6th/10
M.E. (Bette) MeekMcLaughlin CentreUniversity of Ottawa
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Outline• Context
– Increasing Efficiency
• What We’ve Learned from Exposure Profiling– Drawing on Canadian experience
• “Benchmarking”– “Groundtruthing”
• Some Potential Options in Moving Forward
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The 4-Step Paradigm Risk Assessment
Hazard Identification
Risk Assessment & Characterization
Exposure Assessment & Characterization
Dose Response Assessment& Characterization
Introduced in the mid 1980’s by the U.S. National Academy of Sciences
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Risk Assessment –
Qualitative/Quantitative • Hazard Identification (qualitative - is it toxic?)
– Effects seen in animals and/or humans• Dose Response Analyses (quantitative – how
toxic to humans?)– Shape of the dose response curve
• Range of observation & inference
– Quantitative relevance to humans• Exposure Estimation• Risk Characterization
– Comparison of Exposure and Effect
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McLaughlin CentreUniversity of Ottawa
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Risk Assessment(organizing & analyzing to set
priorities & guide management)
• hazard identification/
characterization • dose-response• exposure
estimation• risk
characterization
• political • social • economic • Engineering
Risk Management
(decision & action)
Increased Efficiency
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Keep in Mind:
• The appropriate performance indicator for chemicals programs is not priority setting, testing nor assessment but rather:
• Effective and efficient management of risk– Now
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Evolving Mandates for Existing ChemicalsDealing with “grandfathered” chemicals
• Canada
– “Categorization” (i.e., systematic priority setting) for 23, 000 chemicals by Sept., 2006 under the Canadian Environmental Protection Act (CEPA)
• Environmental, Consumer
• 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 the Toxic Substances Control Act (TOSCA)
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Implications of Regulatory Developments to Consider All Chemicals
• Need for increased efficiency in risk assessment & management– Processing much larger numbers of substances
• Requires more integrated approach across compounds (less chemical-specific; more contextually relevant)
• More/better predictive tools & more efficient testing
– Drawing on new technologies• Requires a shift in approaches, testing and assessment
strategies
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The NAS 4-Step Paradigm
The Need to Move On
Hazard Characterization
Risk Assessment & Characterization
Exposure Assessment & Characterization
Dose Response Assessment& Characterization
Earlier focus on exposure & how effects are induced (mode of action)
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The Challenge to the Risk Assessment Community
We need to be much more:
• Efficient
• Predictive
• Application Driven (i.e., risk management)
• Reponsive, &
• Communicative
McLaughlin CentreUniversity of Ottawa
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The Challenge to the Risk Assessment Community (Cont/d)
• Broadly drawing upon the existing experience on relatively limited numbers of chemicals, to “inform” efficient assessment and management of the remainder
• Essential basis for “benchmarking”
• CEPA “Categorization” of Existing Chemicals offered unique opportunity– Required consideration of “all”
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CATEGORIZATION of the Domestic Substances List (DSL) (First Phase) (n=23,000)
Decisions of Other
Jurisdictions
Public Nominations
No further action under this program
CEPA-Toxic
No further action under this program
CEPA-Toxic
IN-DEPTH ASSESSMENT - Priority Substances List (Third Phase)
Risk Management
Risk Management
Greatest Potentialfor Human Exposure
Substances that are Persistent or Bioaccumulative
“Inherently Toxic”to Humans
“Inherently Toxic” tonon-Human Organisms
SCREENING ASSESSMENT (Second Phase)
CEPA 1999 Existing Substances Program
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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
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
Potential for exposure influential in setting prioritiesIncluded simple use profiling for all 23, 000 chemicals, more complex use
profiling for priorities
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The Simple Exposure Tool - SimET
• SimET is the tool by which we “binned” and relatively ranked all 23,000 substances
• Based on three different lines of evidence, derived from the limited information provided for all substances on the DSL:– quantity (estimated annual quantity of use, Q),– number of submitters (S)– use (sum of normalized expert ranked use
codes, U), reflecting two workshops• “Ground-truthed” against more robust and recent data on
use– Commercial chemical profiles– Mandated use surveys
• Use far more important than volume as the critical driver
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Potential for Exposure (Greatest, Intermediate & Lowest)
Quantity (kg/year)
Number of Submitters
Sum of Expert Ranked Use Codes
GPE > 100 000 Top 10% Top 10%
IPE > 10 000 n.a. Top 30%
LPE All All All
Score for each substance = ∑ (use x relative ranking for PE )– e.g., direct consumer use, dispersive environmental, industrial,
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Post Categorization Refinement of Exposure (Complex Tool)
Objective:• Multi-tiered approach for consumer and environmental
exposure– generic scenarios, defaults and most common use/product
categories in early stages• E.g., sentinel products - consumer product that yields
the highest exposure for one of its component substances
– Increasing refinement in subsequent stagesMethodology:
– Comparison of algorithms and default values in consumer exposure tools as basis for iterative approach
• 8 models/algorithms• Range of sources of default values
– Development of use profiles for hundreds of chemicals based on robust search strategies
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Chemical Identity
Physical/ChemicalProperties
Substance Profile
ProductionQuantity
Measures of Dose-Response for Critical Effects
Priority for Assessment
Production Quantity Bin+Release Factor
Emissions
Near-field Far-field
Human Exposure
Sentinel Products
SP1 SP2 SP3 SPn
Far Field
Age Specific Variables
Overview of Early Tier
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Tier 1 Model Comparison – Sample of Most Common Product Categories
Product Category Route of Exposure ComET ConsExpo ECETOC CEM SDA
Personal Care and Over-the-Counter Products
Mucous membrane contact products Inhalation
(lipstick, toothpaste/mouthwash, eye makeup, contact cleaner) Dermal
X X X
Oral X X
Leave-on Products Inhalation X X X
(creams, deodorant, hair preparations, face make-up, powder) Dermal
X X X
Oral
Rinse-off Products Inhalation
(soaps, shampoo/conditioner, cleansers) Dermal X X X X
Oral
Over-the-Counter Products Inhalation
(wipes, shaving aids, oral dosing, topical dosing, lubricants) Dermal
X X X
Oral X X
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What Did We Learn re Exposure “Surrogates”?
• Simple use profiling can be discriminating • Importance of consumer vs. environmental exposure
• Persistence/bioaccumulation ≠ exposure
• Volume ≠ exposure; use profiling more influential• implications for selection criteria for current testing
programs • Importance of early and iterative use profiling
• Much of the information is publically available
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What Did We Learn re Exposure Tools?
Criteria for consideration of algorithms and default values:• Transparency, Defensibility• “Validation”/Acceptance and Use• Scope• Relevance• Complexity for various iterations
Observations:• Transparency was limited
– “expert judgment”• No consistency in default values, or algorithms for “screening” vs.
more robust models– Limited incentive to harmonize or draw upon the work of others
• Range of coverage is limited• Early tiers for consumer exposure provided limited additional
discrimination 20
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The Challenge to the Risk Assessment Community (Cont/d)
So, how do we get there?
• Broadly drawing upon the existing experience on relatively limited numbers of chemicals, to “inform” efficient assessment and management of the remainder
• Essential basis for “benchmarking”
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Potential for “Benchmarking”
• Relative rankings for “potential for exposure” for 23, 000 substances (use “weighted”)
• More detailed use profiling for several hundred substances
• Detailed multimedia exposure estimates for a proportion (approx. 100 Priority Substances), including:– Compilation of phys/chem properties– Probabilistic estimates based on national monitoring data for a
portion– Measured consumer exposure for a portion– Some with biomonitoring data
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Individual sublists are then rank ordered using the PE Score(the highest score = the highest priority)
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Considerations for “Benchmarking”• Select chemicals for quantitative “anchoring” of
“surrogates” balancing:– broadest representation of “chemical space”
• i.e., range and nature of uses, physical/chemical properties
• Availability of data, as a basis for robust exposure estimates
– Monitoring, biomonitoring
• Objective is to select for the simplest and most discriminating “determinants” of exposure
• “Designing” to limit exposure
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Evolution of Risk Assessment
RA/RM ParadigmGuidelines/Methods
Dosimetry/PbPK
RA/RM ParadigmGuidelines/Methods
Dosimetry/PbPK
1980s
Mode of ActionSusceptible Populations
Mixtures
Mode of ActionSusceptible Populations
Mixtures
Toxicity PathwaysIntegrated Approaches
CompTox
Toxicity PathwaysIntegrated Approaches
CompTox
1990s
2000s21st
Century
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 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)
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Barriers to Change
• A function (in part) of:– The past focus on “Hazard” – Traditional approaches “codified” “institutionalized”
(requiring limited expert interpretation), easy to explain to stakeholders & somewhat consistent
– Lack of long term planning for regulatory science• Meeting short term deadlines for numbers of assessments
vs. longer term investment in predictive methodology
– Communication: Lack of “user friendly” tools– Lack of coordination of regulatory risk
assessment/research
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The Future of Chemical Risk Assessment
• Optimistic re the availability of more predictive tools drawing on greater exposure and biological knowledge
• Less optimistic re the will and capability to efficiently implement change – Collective leadership
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IPCS Framework for Combined Exposure to Multiple Chemicals
Early and Continuing Consideration of Exposure
Criteria for Considering an Assessment Group• What is the nature of exposure and are the components
known?• Is exposure unlikely or very low taking into account the
context? Is there a likelihood of co-exposure within a relevant time frame ?
• What is the reason to believe that components act similarly or interact?– Information on chemical structure– Hazard or other biological data (tox or efficacy)
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Yes, no further action required
No, continue
Input from exposure or hazard
assessments(iterative process)
Is the margin of exposure adequate
?
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)Sample Tiered Exposure and Hazard Considerations
Mixture or Component Based
Tier 0
Simple semi-quantitative estimates of
exposure
Tier 1
Generic exposure scenarios using
conservative point estimates
Tier 2
Tier 3
Probabilistic Exposure Estimates
Tiered Exposure Assessments
Tier 0
Dose addition for all components
Tier 2
More refined potency (RPF) 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
Tiered Hazard Assessments
Refined exposure assessment, increased use of actual measured
data
See text for details 30
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More Information?
• Existing Substances Division Website – http://www.hc-sc.gc.ca/exsd-dse
• IPCS Harmonization Websitehttp://www.who.int/ipcs/methods/harmonization/index.html
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A.1 Models and Sources of Algorithms Considered
• ComET (developed by Health Canada and The LifeLine Group)
• ConsExpo v. 4.0• ECETOC (from Targeted Risk Assessment 2004
Technical Report No. 93)• Soap and Detergent Association 2005• EAU – Cosmetic Workbooks (Health Canada’s
Environmental Assessment Unit)• CEM v. 1.2 (from US EPA E-FAST)• U.S. EPA 1997 (Exposure Factors Handbook Volume I)• Health Canada 1995 (Handbook for Exposure
Calculations)32
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A.2 Default Values Considered• Versar Inc., 1986. Standard Scenarios for Estimating
Exposure to Chemical Substances During Use of Consumer Products, Volume I and II
• ConsExpo v 4.0 (and RIVM Factsheets)• SDA (Soap and Detergent Association) 2005. Exposure and
Risk Screening Methods for Consumer Product Ingredients • ECETOC 2004. Targeted Risk Assessment, Technical Report
No. 93 • ComET (Health Canada/LifeLine)• US EPA 1997. Exposure Factors Handbook Volume III –
General Factors • EAU (Environmental Assessment Unit – Health Canada)
2005. The Cosmetics Exposure Workbook • Various books on product formulations to obtain weight
fractions
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