The Future of Toxicity Testing in the US

1. 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

2. Overview Some Data Interpretation Challenges and Opportunities for… • Post-market lists, hazards, and risk identifications • Addressing risk assessment concerns • Interim decision-making absent full realization of vision

3. 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)

4. 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”

5. Examples of Evaluation Guidance

6. Evidence Maps to Cancer Classifications

7. 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

8. Challenge 2: Addressing risk assessment concerns National Academy of Sciences 2008 National Academy of Sciences 2009 Cumulative Impact Project, Green Chemistry

9. Increasing Complexity in Risk Analysis Impacts from releases into all media from all sources All agents with and without toxicity data (non-zero hazard if no data All Releases All agents with same effect Multiple facilities Agents with same “mode of action” Onesource One agent Community characteristics that increase vulnerability Social and demographic factors Biological Susceptibility Average person Cross media transfers Impacts over time (into future) One medium All Media Adapted from A. D. Kyle, “Becoming more cumulative” UC Berkeley CI Symposium, December, 2009

10. Multiple Exposures Leading to Common Adverse Outcomes Phthalates Antiandrogenic compounds and other risk factors Disturbed Androgen Action Altered male reproductive outcomes

11. Background Biological Exposure Vulnerability, e.g., from Life stage Genetics Health disease status Background and Vulnerability Impact on Risk Advancing Risk Assessment

12. Chemical’s risk is determined by: • Background exposures • Biological susceptibility • Exposure level to the chemical • Includes the broad range of stressors impacting dose response Environmental Chemical Stressor Background Exposure (Endogenous and Exogenous) Biological Susceptibility Health & Disease Status, Genetics, Age, Sex An Individual’s Response Environmental Dose of Chemical Stressor Heterogeneity in Background Exposure and Susceptibility Population Dose Response Fraction of Population Responding Environmental Dose of Chemical Stressor

13. 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

14. Needed for full realization of vision … • Knowledge • Toxicity-pathway identification • Multiple pathways • Adverse patterns and magnitudes of perturbations • To capture life stages • Effects of exposure duration • Low-dose response giving pre-existing human exposures • Addressing human variability Methods • Address metabolism • Chemical-characterization tools • Assays to uncover cell circuitry • Assays for large-scale application • Suites of assays • Human-surveillance strategy • Mathematical models for data interpretation and extrapolation • Test-strategy uncertainty

15. 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 green chemistry • Selected hazard identifications • Cautious regarding over interpretation • Transfer company product development rule in/out methods to regulatory arena Work through practical integrated approaches to identify hazards and estimate risks Integration, read across and anchoring