by the NIS and thyroid function. Thus, the PBPK models that were developed by DOD focused on improving the ability to predict the kinetics of perchlorate and iodide with respect to their interaction at the NIS as the key event identified by EPA over a range of perchlorate exposure that encompasses toxicity studies in animals, therapeutic uses in humans, and relevant environmental exposures.
EPA used that approach in the derivation of an RfD for perchlorate, following established guidelines for the selection of key events, points of departure, and derivation of appropriate uncertainty factors (EPA 2002a,b,c). Although the committee has chosen a different point of departure based on human data (see Chapter 5), it agrees with EPA that PBPK modeling constitutes the best approach to determining the human equivalent exposures and adjustments to default uncertainty factors when RfDs are based on data collected in animals. If future studies with perchlorate are conducted in laboratory animals, the PBPK models developed to date may be important tools for integrating the new data into the existing database on the exposure-dose-response relationships for perchlorate in rats and humans.
EPA provided a thorough description of the PBPK models in its analysis of the health risks associated with potential perchlorate exposures (EPA 2002b). The models were later reviewed by an external peer-review panel (EPA 2002c). In this appendix, the committee reviews only the general properties of the PBPK models developed by DOD, their underlying assumptions, and their general applicability in animal-to-human extrapolations.
Perchlorate does not appear to be metabolized in the body. Once absorbed, it is rapidly distributed into all tissues except fat, with preferential uptake by tissues that contain the NIS, and ultimately cleared unchanged in urine. Thus, the development of the PBPK models for adult rats and humans and potentially sensitive life stages (developing fetus and neonate) followed a logical progression of increasing complexity that linked exposure with key biochemical events as the toxicity and mode of action of perchlorate in animals and humans became better defined and methods of analyzing perchlorate in biologic fluids and tissues improved.