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Implementing Science and Decisions: Tox21 Paradigm Analysis

Explore the potential clash between "Toxicity Testing in the 21st Century" and "Science and Decisions" visions. Understand Tox21's intersection with EDSP and the Human Genome Project. Delve into advancing risk assessment methods and decision-making processes. Analyze conflicts on low-dose linearity, harmonization of risk assessments, variability assessment, and cumulative risk considerations. Gain insights into positioning risk managers as information scientists within a transparent regulatory environment. Critically examine the integration of non-chemical stressors and complex risk factors. Discover emerging research implications and the transformative impact of the Tox21 paradigm.

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Implementing Science and Decisions: Tox21 Paradigm Analysis

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  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!

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