Evaluating transport of manganese from olfactory mucosa to striatum by pharmacokinetic modeling

Increased brain manganese (Mn) following inhalation can result from direct transport via olfactory neurons and blood delivery. Human health risk assessments for Mn should consider the relative importance of these pathways. The objective of this study was to develop a pharmacokinetic model describing the olfactory transport and blood delivery of Mn in rats following acute MnCl2 or MnHPO4 inhalation. Model compartments included the olfactory mucosa (OM), olfactory bulb, olfactory tract and tubercle, and striatum. Intercompartmental transport of Mn was described as ipsilateral, anterograde movement to deeper brain regions. Each compartment contained free and bound Mn and included blood influx and efflux. First-order rate constants were used to describe transport. Model parameters were estimated by comparing the model with published experimental data in rats exposed by inhalation to (MnCl2)-Mn-54 or (MnHPO4)-Mn-54 with both nostrils patent or one nostril occluded. The model-derived elimination rate constant from the OM was higher for the chloride salt (0.022 per hour) compared with the phosphate salt (0.011 per hour), consistent with their relative solubilities. Rate constants for Mn transport among the other compartments were similar for both Mn forms. Our results indicate that direct olfactory transport provided the majority of Mn tracer in the olfactory regions during the 21 days following exposure to (MnHPO4)-Mn-54 and 8 days following exposure to (MnCl2)-Mn-54. Only a small fraction of Mn tracer from the tract and tubercle was predicted to be delivered to the striatum, 3 and 0.1% following (MnHPO4)-Mn-54 or (MnCl2)-Mn-54 exposure, respectively.