Some Data Interpretation Some Data Interpretation Challenges and Opportunities Challenges and Opportunities

Implementing the NAS Vision for Implementing the NAS Vision for Toxicity Testing in the 21Toxicity Testing in the 21stst Century Century

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OverviewOverview

Some Data Interpretation Challenges Some Data Interpretation Challenges and Opportunities for…and Opportunities for…1.1. Post-market lists, hazards, and risk Post-market lists, hazards, and risk

identificationsidentifications2.2. Addressing risk assessment concernsAddressing risk assessment concerns3.3. Interim decision-making absent full Interim decision-making absent full

realization of visionrealization of vision

Challenge 1: Science-BasedChallenge 1: Science-Based“Bad Actors” Lists and Laws“Bad Actors” Lists and Laws

• ““Bad Actor” Triggers, e.g.Bad Actor” Triggers, e.g.– Carcinogens: IARC, EPA, NTP, Carcinogens: IARC, EPA, NTP,

or CA Proposition 65 or CA Proposition 65 – Reproductive Toxicants: NTP Reproductive Toxicants: NTP

CERHR, CA Proposition 65 CERHR, CA Proposition 65 • Feed into list creation, e.g.,Feed into list creation, e.g.,

– Hazardous Air ContaminantsHazardous Air Contaminants– Drinking Water MCLsDrinking Water MCLs

• No direct human or animal No direct human or animal evidence of effect evidence of effect Not on Not on list (few exceptions) list (few exceptions)

Cancer Evidence LabelsCancer Evidence Labels Environmental Protection AgencyEnvironmental Protection Agency

– ““suggestive of carcinogenic potential” suggestive of carcinogenic potential” – ““likely human carcinogen” likely human carcinogen” – ““carcinogenic to humans”carcinogenic to humans”

National Toxicology Program National Toxicology Program – ““known human carcinogen” known human carcinogen” – ““reasonably anticipated to be carcinogenic reasonably anticipated to be carcinogenic

to humans”to humans” International Agency for Research on CancerInternational Agency for Research on Cancer

– ““possibly,” “probably” or “carcinogenic to possibly,” “probably” or “carcinogenic to humans”humans”

Examples of Evaluation Guidance

Evidence Maps to Cancer ClassificationsEvidence Maps to Cancer ClassificationsHuman Animal Indirect,

OtherIARC US EPA NTP

Sufficient -- --Carcinogenic to

humans (Group 1)

Carcinogenic to humans

Known to Be Human Carcinogen

Limited Sufficient

Strong human mechanistic data

-- Probably carcinogenic to

humans (Group 2A)

Likely to be carcinogenic to

humansReasonably

Anticipated to Be Human Carcinogen

Inadequate

Sufficient Strong

Limited Strong

Possibly carcinogenic to

humans (Group 2B)

Sufficient --

Limited Limited --

Inadequate Inadequate

Strong & same class as other carcinogens

Strong/ convincing

Inadequate Information to Assess

Inadequate Limited -- Not classifiable Suggestive Not classified

Work needed on the disconnect between Work needed on the disconnect between risk assessment practice and type of risk assessment practice and type of laboratory data being generated …laboratory data being generated …

• Shifts in scientific consensus Shifts in scientific consensus regarding requirement for regarding requirement for directdirect animal or human cancer evidence animal or human cancer evidence

• Evolving guidelines and practice for Evolving guidelines and practice for effects assessment effects assessment

• Use of new approach (e.g., by Use of new approach (e.g., by National Toxicology Program and National Toxicology Program and International Agency for Research International Agency for Research on Cancer)on Cancer)

• Pave the way with strong cases Pave the way with strong cases based on structure activity and based on structure activity and indirect dataindirect data

Challenge 2: Addressing risk assessment Challenge 2: Addressing risk assessment concernsconcerns

National Academy of National Academy of Sciences 2008Sciences 2008

National Academy National Academy of Sciences 2009of Sciences 2009 Cumulative Impact Cumulative Impact

Project, Green Project, Green ChemistryChemistry

All agents with and without toxicity data (non-zero hazard if

no data

Impacts over time (into future)

Community characteristics that increase vulnerability

Impacts from releases into all media from all sources

Social and demographic factors Cross media transfers

All agents with same effect

All Releases

Biological Susceptibility All Media

Agents with same “mode of

action”

Multiple facilities

One source

One agent

One medium

Average person

Increasing Complexity in Risk AnalysisIncreasing Complexity in Risk Analysis

Adapted from A. D. Kyle, “Becoming more cumulative” Adapted from A. D. Kyle, “Becoming more cumulative” UC Berkeley CI Symposium, December, 2009UC Berkeley CI Symposium, December, 2009

Multiple Exposures Leading to Multiple Exposures Leading to Common Adverse OutcomesCommon Adverse Outcomes

PhthalatesPhthalatesPhthalatesPhthalates Antiandrogenic compounds and Antiandrogenic compounds and other risk factorsother risk factors

Antiandrogenic compounds and Antiandrogenic compounds and other risk factorsother risk factors

Disturbed Disturbed Androgen Androgen

ActionAction

Altered male Altered male reproductive outcomesreproductive outcomes

Background and Vulnerability Impact on Risk Background and Vulnerability Impact on Risk

• Background Background – BiologicalBiological– ExposureExposure

• Vulnerability, e.g., fromVulnerability, e.g., from– Life stageLife stage– Genetics Genetics – Health disease statusHealth disease status

Advancing Risk AssessmentAdvancing Risk Assessment

Environmental Chemical Stressor

Background Exposure (Endogenous and

Exogenous)

Biological SusceptibilityHealth & Disease Status,

Genetics, Age, Sex

Environmental Dose of Chemical Stressor

An Individual’s Response

Heterogeneity in Background Exposure and

Susceptibility

Fraction of Population Responding

Environmental Dose of Chemical Stressor

Population Dose Response

Chemical’s risk is Chemical’s risk is determined by:determined by:Background Background exposuresexposuresBiological Biological susceptibilitysusceptibilityExposure level to Exposure level to the chemicalthe chemical

Includes the Includes the broad range of broad range of stressors stressors impacting dose impacting dose responseresponse

• Data interpretation for risk or safety evaluation assessment of a single chemical Needs to consider multi-stressor environment Involves assessment of population data

on health factors Is a key area for stakeholder involvement

* This will be less complex when anchoring to well studied and characterized chemicals

Needed for full realization of vision …Needed for full realization of vision …

MethodsMethods• Address metabolismAddress metabolism• Chemical-characterization toolsChemical-characterization tools• Assays to uncover cell circuitryAssays to uncover cell circuitry• Assays for large-scale applicationAssays for large-scale application• Suites of assaysSuites of assays• Human-surveillance strategyHuman-surveillance strategy• Mathematical models for data Mathematical models for data

interpretation and extrapolationinterpretation and extrapolation• Test-strategy uncertaintyTest-strategy uncertainty

KnowledgeKnowledge• Toxicity-pathway Toxicity-pathway

identificationidentification• Multiple pathways Multiple pathways • Adverse patterns and Adverse patterns and

magnitudes of perturbationsmagnitudes of perturbations• To capture life stagesTo capture life stages• Effects of exposure duration Effects of exposure duration • Low-dose response giving pre-Low-dose response giving pre-

existing human exposuresexisting human exposures• Addressing human variability Addressing human variability

10’s/year

100’s/year

100,000’s/dayIn vitro, in silico, + structureIn vitro, in silico, + structure• Comparative analysis for Comparative analysis for

green chemistry green chemistry • Selected hazard Selected hazard

identificationsidentifications• Cautious regarding over Cautious regarding over

interpretationinterpretation• Transfer company product Transfer company product

development rule in/out development rule in/out methods to regulatory arenamethods to regulatory arena

1-3/year10,000’s/day

Use of emerging data in the interimUse of emerging data in the interim

Work through Work through practical integrated practical integrated approaches to approaches to identify hazards and identify hazards and estimate risksestimate risks

Integration, read across Integration, read across and anchoringand anchoring