Evaluating Placental Transfer and Tissue Concentrations of Manganese in the Pregnant Rat and Fetuses after Inhalation Exposures with a PBPK Model

Abstract

A Physiologically Based Pharmaco Kinetic (PBPK) model, based on a published description of manganese (Mn) kinetics in adult rats, has been developed to describe Mn uptake and tissue distribution in the pregnant dam and fetus during dietary and inhalation exposures. This extension incorporated key physiological processes controlling Mn pharmacokinetics during pregnancy and fetal development. After calibration against tissue Mn concentrations observed during late gestation, the model accurately simulated Mn tissue distribution in the dam and fetus following both diet and inhalation exposures to the pregnant rat. Maternal to fetal transfer of Mn through placenta was described using two pathways: a saturable active transport with high affinity and a simple diffusion. The active transport dominates at basal and lower Mn exposure, whereas at higher Mn exposure, the relative contribution of the diffusion pathway increases. To simulate fetal tissue Mn, tissue-binding parameters and preferential influx/efflux rates in fetal brain were adjusted from the adult model based on differential developmental processes and varying tissue demands for Mn in early life. Model simulations were consistent with observed tissue Mn concentrations in fetal tissues, including brain for diet alone and for combined diet and inhalation. Simulations of Mn in placenta and other maternal tissues in late gestation correlated well with measured tissue concentrations. This model, together with our published models for Mn kinetics during lactation and postnatal development, will help to address concerns about Mn neurotoxicity in potentially sensitive human subpopulation, such as infants and children by providing an estimate of Mn exposure in the population of interest.