“Benchmarking” Exposure Priority Setting Tools

U.S. EPA Exposure Based Chemical Prioritization WorkshopApril 6th/10

M.E. (Bette) MeekMcLaughlin CentreUniversity of Ottawa

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

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

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)

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

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,

etc. 15

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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

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

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)

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

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

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

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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