Implementing “Science & Decisions” under the Tox 21 paradigm: dueling visions?

1. Implementing “Science & Decisions” under the Tox 21 paradigm: dueling visions? Invited Commentary Erik R. Janus Director, Human Health Policy CropLife America

2. The challenge before us • The next several years will see some very serious discussion revolving around the implementation of 2 potentially “dueling visions”: • 2007: “Toxicity Testing in the 21st Century” • 2009: “Science and Decisions”

3. The Tox 21 Vision

4. The future is now! • Tox 21 meets EDSP • Currently used to inform the regulatory process through prioritization of chemicals for further dedication of more intense efforts • Tox 21 meets the Human Genome Project • Top-down/backwards mapping of disease loci found in OMIM (see work of Holly Mortensen at NCCT) While the full realization of the Tox 21 vision may be over a decade, the future is indeed here now.

5. Advancing Risk Assessment and Decision Making • Nobody disagrees with the need to update the 1983 “Red Book” (in fact, this should happened a decade ago!) • There still remains a need to make decisions in the face of incomplete information – What is the best technical way to do this? Does this match the best “societal” way to do this?

6. Increasing utility is paramount • Must be driven by the needs of the REGULATORS in a TRANSPARENT and STAKEHOLDER-DRIVEN manner • Does the current EPA NexGen risk assessment planning process meet this definition? (again, who should be the referee here?) • Should NAS be the lead here? ILSI? TERA? SRA?

7. Putting decisions back into the hands of risk managers • Its about time we seriously treat risk assessment output as one stream into a risk manager’s decision framework • Tomorrow’s risk managers will have to be information scientists (or info-savvy at bare minimum), in addition to knowing the relevant life sciences (biology, environmental chemistry, etc.) and risk methods

8. Some potential conflicts … • Low dose linearity • Harmonization of cancer & non-cancer approaches • Tiered approach to variability assessment • Cumulative risk assessment & non-chemical stressors

9. Low dose linearity • Direct conflict • Ongoing new research (such as the microarray work presented at SOT 2009) continues to show thresholds at the gene level • One can no longer assume linearity in the low dose region in these cases

10. Harmonization of risk assessments • One suggestion that the Science & Decisions report makes is the harmonization of cancer & non-cancer approaches. • Good point, potentially moot. • As we progress towards mechanistically based regulatory schemes, products will be regulated on their most sensitive molecular effect (thus the harmonization occurs by default under the Tox 21 paradigm)

11. Variability assessment • Taking a tiered approach to assessment of natural human variability may conflict in the near-term with ongoing efforts to more thoroughly understand and apply population-level genomic data • Example: PON1 variability & the metabolism of chlorpyrifos • Top-down disease loci analysis (from OMIM, for example) coupled with MOA data may help

12. Cumulative risk & non-chemical stressors • Assessment of cumulative risk should be done strictly on “common” perturbation pathways, which can be informed by human data (epi, HBM) • We must be careful to avoid open-ended assessments that pose interpretability issues (e.g. “endocrine disruptors”) • It’s unclear how non-chemical stressors become incorporated into this process • BUT … don’t all non-chemical stressors results in some quantifiable physiological response ? (which again, theoretically can be eludcidated through the Tox 21 paradigm)

13. Play Ball!