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MODELING TOXICOKINETICS FOR CROSS-SPECIES EXTRAPOLATION OF DEVELOPMENTAL EFFECTS
Impact/Purpose:
This research will incorporate a range of pharmacokinetic modeling methods including noncompartmental analyses and classical and physiologically-based pharmacokinetic modeling to describe dosimetry in early life-stages relevant to onegeneration toxicity studies (i.e. maternal exposure resulting in fetal exposure, lactation exposure of pups after birth, and exposures of growing pups). Perfluooctanoate (PFOA) and related compounds will be used as initial prototype chemicals due to the importance of effects observed in offspring, which are used as endpoints in risk assessments. Lactational exposure will be modeled first because dosimetry during this period has not yet been evaluated. A physiologically based pharmacokinetic (PBPK) model for PFOA will be developed to characterize dosimetry during these different lifestages and identify data gaps that limit the ability of the model to address both rats and humans. Finally, this early life stage model will be used to evaluate dosimetry during different early life periods for a selected group of other prototype compounds for which developmental toxicities are observed. Prototype compounds would be selected to have a range of pharmacokinetic and physical chemical properties. This analysis will aid in the evaluation of the uncertainties in the default risk assessment approach based upon maternal exposure.
Description:
Animal toxicology studies used to evaluate the potential for effects due to exposures during developmental periods are extrapolated to humans based upon the maternal exposure dose. The approach does not address whether the toxicokinetics are similar across species during the relevant critical developmental window. In this research program we will develop toxicokinetic models for estimating internal dosimetry during early life stages to serve as a basis for improved interspecies extrapolation. Absent information specifying the critical window, estimates of internal dosimetry during the in utero, lactational, and early post-weaning periods will characterize the uncertainty in evaluations based upon maternal exposure dose. With information on the critical window, models may describe toxicokinetic and toxicodynamic processes in the relevant toxicological species and humans permitting improved quantification.