Predicting maternal rat and pup exposures: how different are they?

Abstract

Risk and safety assessments for early life exposures to environmental chemicals or pharmaceuticals based on cross-species extrapolation would greatly benefit from information on chemical dosimetry in the young. Although relevant toxicity studies involve exposures during multiple life stages, the mother's exposure dose is frequently used for extrapolation of rodent toxicity findings to humans and represents a substantial source of uncertainty. A compartmental pharmacokinetic model augmented with biological information on factors changing during lactation and early postweaning was developed. The model uses adult pharmacokinetics, milk distribution, and relevant postnatal biology to predict dosimetry in the young for chemicals. The model addressed three dosing strategies employed in toxicity studies (gavage, constant ppm diet, and adjusted ppm diet) and the impact of different pharmacokinetic properties such as rates of clearance, milk distribution, and volume of distribution on the pup exposure doses and internal dosimetry. Developmental delays in clearance and recirculation of chemical in excreta from the pup to mother were evaluated. Following comparison with data for two chemicals, predictions were made for theoretical chemicals with a range of characteristics. Pup exposure was generally lower than the mother's with a shorter half-life, lower milk transfer, larger volume of distribution, and gavage dosing, while higher with longer half-life, higher milk transfer, smaller volume of distribution, and dietary exposures. The present model demonstrated pup exposures do not always parallel the mother's. The model predictions can be used to help design early life toxicity and pharmacokinetic studies and better interpret study findings.