Using Human Life Stage PBPK/PD Model Predictions of Perchlorate-Induced Iodide Inhibition to Inform Risk Assessment in Sensitive Populations

摘要

Iodide inhibition was considered to be the key biochemical event preceding disruption of thyroid hormone homeostasis. The RfD was based on the No Observable Effect Level (NOEL) of 0.007 mg/kg-day, which resulted in no significant iodide inhibition in normal adults. An uncertainty factor of 10 was applied to the NOEL to account for intraspecies variability, including life- stage specific susceptibility. Recently, existing physiologically based pharmacokinetics/pharmacodynamic (PBPK/PD) models across life-stages in rat and in adult human were expanded to describe inhibition kinetics during-perinatal development in humans. Chemical-specific parameters were estimated from life-stage and species-specific relationships established in previously published PBPK/PD models. The human perinatal models successfully simulate literature radioiodide data for gestation and lactation, as well as data from populations exposed to perchlorate contaminated drinking water. These validated models were used to examine the effect of developmental stage on susceptibility to thyroid perturbation across a range of doses. At environmentally relevant doses, the perinatal woman, fetus and nursing infant are predicted to have higher blood perchlorate concentrations and greater thyroid iodide uptake inhibition than either the non-pregnant adult or older child. At exposure levels equal to the NOEL and RfD, the PBPK/PD model predicted iodide inhibition in fetuses is within normal variation (less than 10%) and insignificant (less than 1%), respectively, indicating that the newly adopted RfD is in fact protective of the population most sensitive to thyroid inhibition.