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ToxSci Advance Access originally published online on September 2, 2009
Toxicological Sciences 2009 112(1):23-43; doi:10.1093/toxsci/kfp197
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Lactational Transfer of Manganese in Rats: Predicting Manganese Tissue Concentration in the Dam and Pups from Inhalation Exposure with a Pharmacokinetic Model

Miyoung Yoon*,1, Andy Nong*, Harvey J. Clewell, III*, Michael D. Taylor{dagger}, David C. Dorman*,{ddagger} and Melvin E. Andersen*

* Center for Human Health Assessment, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 {dagger} Afton Chemical, Richmond, Virginia 23219 {ddagger} College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606

1 To whom correspondence should be addressed at The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709-2137. Fax: (919) 558-1300. E-mail: myoon{at}thehamner.org.

Received January 28, 2009; accepted August 10, 2009


  Abstract

Manganese (Mn) is an essential element. However, excess Mn causes neurotoxicity. Fetuses and neonates have been discussed as potentially sensitive subpopulations for Mn. In the present study, a previously published physiologically based pharmacokinetic model for Mn in adult rats was extended to examine exposure conditions that could lead to increased central nervous system Mn in developing rats. The basic structure had saturable tissue binding, homeostatic control of uptake and excretion, and tissue-specific increases in Mn from inhalation. Modifications made for lactating dam and pups included differential tissue-binding capacities in developing pups, increased absorption of dietary Mn in lactating dam, and more efficient gastrointestinal absorption and lower basal biliary excretion in pups. Enhancement of biliary excretion in pups was also required to accurately simulate tissue Mn during early postnatal inhalation. Overall, these changes were concordant with the biology of Mn and other essential metals during development. The resulting model simulations match a variety of published studies on maternal Mn homeostasis during lactation, milk Mn levels, and changing patterns of neonatal tissue Mn for normal dietary intake and with Mn inhalation. Our successful description of Mn kinetics across these life stages suggests that the present model can help describe the relationship between dose of exposure and target tissue Mn concentrations across different developmental stages and its potential risks and assess whether infants and children should be regarded as susceptible populations for Mn inhalation.

Key Words: manganese; inhalation exposure; postnatal period; enhanced biliary excretion; homeostasis during lactation; PBPK.


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