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ToxSci Advance Access published online on March 19, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm061
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Evaluating Transport of Manganese from Olfactory Mucosa to Striatum by Pharmacokinetic Modeling

Teresa L. Leavens*, Deepa Rao{dagger}, Melvin E. Andersen{ddagger} and David C. Dorman§

* CIIT Centers for Health Research, Research Triangle Park, NC, 27709, email tleavens{at}ciit.org {dagger} Current affiliation: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, 53706, email: rao{at}svm.vetmed.wisc.edu {ddagger} CIIT Centers for Health Research, Research Triangle Park, NC, 27709, email: mandersen{at}ciit.org § CIIT Centers for Health Research, Research Triangle Park, NC, 27709, email: dorman{at}ciit.org

Corresponding author: Teresa Leavens, Ph.D. CIIT Centers for Health Research, RTP, North Carolina 27709, P (919)558-1344, F (919)558-1300, Email tleavens{at}ciit.org

Received December 28, 2006; revision received March 1, 2007; accepted March 8, 2007


  Abstract

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, 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 54MnCl2 or 54MnHPO4 with both nostrils patent or one nostril occluded. The model-derived elimination rate constant from the olfactory mucosa was higher for the chloride salt (0.022 h-1) compared with the phosphate salt (0.011 h-1), 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 54MnHPO4 and 8 days following exposure to 54MnCl2. 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 54MnHPO4 or 54MnCl2 exposure, respectively.

Key Words: Manganese; Olfactory Transport; Pharmacokinetic Model.


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[Abstract] [Full Text] [PDF]


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