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Slide 1 - Chemical Toxicity Testing The US and Beyond

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					  Some Data Interpretation
Challenges and Opportunities
 Implementing the NAS Vision for
Toxicity Testing in the 21st Century
    ……………………………………………………………….

     The Future of Toxicity Testing in the US
Creating a Roadmap to Implement the NRC Vision
                  and Strategy
                Washington DC
                 June 21, 2010

                  Lauren Zeise
      California Environmental Protection Agency
                 Office of Environmental
               Health Hazard Assessment
            Overview
Some Data Interpretation Challenges
  and Opportunities for…
 1. Post-market lists, hazards, and risk
    identifications
 2. Addressing risk assessment concerns
 3. Interim decision-making absent full
    realization of vision
            Challenge 1: Science-Based
            “Bad Actors” Lists and Laws
• “Bad Actor” Triggers, e.g.
   – Carcinogens: IARC, EPA, NTP,
     or CA Proposition 65
   – Reproductive Toxicants: NTP
     CERHR, CA Proposition 65
• Feed into list creation, e.g.,
   – Hazardous Air Contaminants
   – Drinking Water MCLs
• No direct human or animal
  evidence of effect  Not
  on list (few exceptions)
          Cancer Evidence Labels
 Environmental Protection Agency
   – “suggestive of carcinogenic potential”
   – “likely human carcinogen”
   – “carcinogenic to humans”
 National Toxicology Program
   – “known human carcinogen”
   – “reasonably anticipated to be carcinogenic
     to humans”
 International Agency for Research on Cancer
   – “possibly,” “probably” or “carcinogenic to
     humans”
Examples of Evaluation Guidance
             Evidence Maps to Cancer Classifications
Human          Animal       Indirect,        IARC                   US EPA                    NTP
                            Other
Sufficient     --           --
                                             Carcinogenic to
                            Strong human                             Carcinogenic to     Known to Be Human
                                                    humans
                            mechanistic                                     humans               Carcinogen
                                                   (Group 1)
Limited        Sufficient   data

                            --                     Probably
                                             carcinogenic to
               Sufficient   Strong                  humans
                                                 (Group 2A)
Inadequate     Limited      Strong
                                                                          Likely to be
               Sufficient   --                                        carcinogenic to            Reasonably
                                                                             humans        Anticipated to Be
Limited        Limited      --                      Possibly                             Human Carcinogen
                                             carcinogenic to
                            Strong & same           humans
                            class as other       (Group 2B)
Inadequate     Inadequate   carcinogens

                            Strong/                                       Inadequate
                            convincing                          Information to Assess


Inadequate     Limited      --               Not classifiable             Suggestive           Not classified
Work needed on the disconnect between
risk assessment practice and type of
laboratory data being generated …
                  • Shifts in scientific consensus
                    regarding requirement for direct
                    animal or human cancer evidence
                  • Evolving guidelines and practice for
                    effects assessment
                  • Use of new approach (e.g., by
                    National Toxicology Program and
                    International Agency for Research
                    on Cancer)
                  • Pave the way with strong cases
                    based on structure activity and
                    indirect data
Challenge 2: Addressing risk assessment
               concerns




National Academy of   National Academy
Sciences 2008         of Sciences 2009
                                         Cumulative Impact
                                         Project, Green
                                         Chemistry
Increasing Complexity in Risk Analysis
 Impacts from releases into all              All agents with and without
 media from all sources                 toxicity data (non-zero hazard if
         All Releases                      All agents with same       no
                                                           effect data
                 Multiple facilities   Agents with same
                                                “mode of
                           One            One action”
                           source        agent

                         Average          One
                         person        medium
                Biological
                Susceptibility                  All Media
         Social
         and demographic factors          Cross media transfers
 Community characteristics that                                 Impacts
 increase vulnerability                           over time (into future)

  Adapted from A. D. Kyle, “Becoming more cumulative”
           UC Berkeley CI Symposium, December, 2009
Multiple Exposures Leading to
Common Adverse Outcomes
                  Antiandrogenic compounds and
  Phthalates
                         other risk factors



                     Disturbed
                     Androgen
                      Action



                    Altered male
               reproductive outcomes
Background and Vulnerability Impact on Risk
   • Background      • Vulnerability, e.g., from
      – Biological      – Life stage
      – Exposure        – Genetics
                        – Health disease status




                                                   Advancing Risk Assessment
                                                          Chemical’s risk is
             Environmental Chemical
                    Stressor                              determined by:
Background Exposure           Biological Susceptibility
  (Endogenous and             Health & Disease Status,    Background
     Exogenous)                  Genetics, Age, Sex
                                                          exposures
                                                          Biological
            An
            Individual’s                                  susceptibility
            Response
                                                          Exposure level to
                                                          the chemical
                  Environmental Dose of
                  Chemical Stressor

                    Heterogeneity in
                                                           Includes the
                Background Exposure and
                      Susceptibility
                                                          broad range of
                           Population Dose Response
                                                          stressors
        Fraction of
        Population                                        impacting dose
        Responding
                                                          response
             Environmental Dose of Chemical Stressor
• 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 …
Knowledge                           Methods
• Toxicity-pathway identification   • Address metabolism
• Multiple pathways                 • Chemical-characterization
• Adverse patterns and                tools
  magnitudes of perturbations       • Assays to uncover cell circuitry
• To capture life stages            • Assays for large-scale
• Effects of exposure duration        application
• Low-dose response giving pre-     • Suites of assays
  existing human exposures          • Human-surveillance strategy
• Addressing human variability      • Mathematical models for data
                                      interpretation and
                                      extrapolation
                                    • Test-strategy uncertainty
    Use of emerging data in the interim


           10’s/year

                       100’s/year        10,000’s/day
1-3/year                                                   100,000’s/day
                                                  In vitro, in silico, + structure
                                                  • Comparative analysis for
Work through                                         green chemistry
practical integrated                              • Selected hazard
                       Integration, read across      identifications
approaches to
                            and anchoring         • Cautious regarding over
identify hazards and
estimate risks                                       interpretation
                                                  • Transfer company product
                                                     development rule in/out
                                                     methods to regulatory arena

				
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