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

Toxicology Excellence for Risk Assessment Original Database Human Studies n Graves disease patients n Healthy volunteers Animal Studies n Less than 90 days n Cancer bioassays n Limited developmental/reproductive

Toxicology Excellence for Risk Assessment Original Data Gaps Studies needed to complete database: n at least subchronic bioassay n two-generation reproductive study n developmental toxicity studies in two species

Toxicology Excellence for Risk Assessment Studies to identify critical effect or reduce uncertainty: n developmental neurotoxicity study n genotoxicity study n immunotoxicity study

Toxicology Excellence for Risk Assessment Other major unanswered questions: n shape of dose-response curve in humans n effects from long-term exposure n effects in organs/systems other than thyroid n more complete understanding of kinetics and mechanism

Toxicology Excellence for Risk Assessment First Round of Studies n 90-day subchronic oral bioassay n Two-generation reproductive toxicity n Developmental toxicity in one species n Neurobehavioral developmental n Genotoxicity n Immunotoxicity n PBPK

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

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

Toxicology Excellence for Risk Assessment n What is the effect of perchlorate on fetal/neonatal mental development? n What is shape of dose-response curve in humans?

Toxicology Excellence for Risk Assessment Second Round of Studies n PWG reevaluation of all thyroid histopathology n Predictive immunotoxicity studies n Developmental toxicity study in rats n “Effects study” n Motor activity study n Epidemiology and clinical human studies n PBPK modeling

Toxicology Excellence for Risk Assessment Remaining Data Gaps Studies needed to complete database: n none Studies to identify critical effect or reduce uncertainty: n host resistance assay n explore use of data-derived uncertainty factors following IPCS guidelines

Toxicology Excellence for Risk Assessment Other major unanswered questions: n How do we better integrate the existing human and animal data? n How do thyroid hormones fluctuate over time in animals and how do we explain some seemingly inconsistent findings in the animal studies?

Toxicology Excellence for Risk Assessment n How do we define the breakdown of normal thyroid homeostasis and progression to adversity? n Have we established dose-response curves for this process?

Toxicology Excellence for Risk Assessment Information and Status of Perchlorate Studies