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Perchlorate Data Gaps

Perchlorate Data Gaps. Joan Dollarhide, M.S., MSTC, J.D. Toxicology Excellence for Risk Assessment ( TERA ). Original Database. Human Studies Graves disease patients Healthy volunteers Animal Studies Less than 90 days Cancer bioassays Limited developmental/reproductive.

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Perchlorate Data Gaps

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  1. Perchlorate Data Gaps Joan Dollarhide, M.S., MSTC, J.D. Toxicology Excellence for Risk Assessment (TERA)

  2. Original Database Human Studies • Graves disease patients • Healthy volunteers Animal Studies • Less than 90 days • Cancer bioassays • Limited developmental/reproductive

  3. Original Data Gaps Studies needed to complete database: • at least subchronic bioassay • two-generation reproductive study • developmental toxicity studies in two species

  4. Studies to identify critical effect or reduce uncertainty: • developmental neurotoxicity study • genotoxicity study • immunotoxicity study

  5. Other major unanswered questions: • shape of dose-response curve in humans • effects from long-term exposure • effects in organs/systems other than thyroid • more complete understanding of kinetics and mechanism

  6. First Round of Studies • 90-day subchronic oral bioassay • Two-generation reproductive toxicity • Developmental toxicity in one species • Neurobehavioral developmental • Genotoxicity • Immunotoxicity • PBPK

  7. Remaining Data Gaps Studies needed to complete database: • developmental toxicity studies in a second species Studies to identify critical effect or reduce uncertainty: • establish separate dose-response curves for thyroid hypertrophy and hyperplasia • predictive immunotoxicity study

  8. Other major unanswered questions: • If dam is hypothyroid at time of conception, what are effects on fetal/neonatal thyroid and neurological development? • Is perchlorate transferred to pup via milk? • How do serum hormone levels correlate with thyroid pathology and neurohistopathology (fetal only)?

  9. What is the effect of perchlorate on fetal/neonatal mental development? • What is shape of dose-response curve in humans?

  10. Second Round of Studies • PWG reevaluation of all thyroid histopathology • Predictive immunotoxicity studies • Developmental toxicity study in rats • “Effects study” • Motor activity study • Epidemiology and clinical human studies • PBPK modeling

  11. Remaining Data Gaps Studies needed to complete database: • none Studies to identify critical effect or reduce uncertainty: • host resistance assay • explore use of data-derived uncertainty factors following IPCS guidelines

  12. Other major unanswered questions: • How do we better integrate the existing human and animal data? • How do thyroid hormones fluctuate over time in animals and how do we explain some seemingly inconsistent findings in the animal studies?

  13. How do we define the breakdown of normal thyroid homeostasis and progression to adversity? • Have we established dose-response curves for this process?

  14. Information and Status of Perchlorate Studies http://www.tera.org/perchlorate

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