Jump to main content
US EPA
United States Environmental Protection Agency
Search
Search
Main menu
Environmental Topics
Laws & Regulations
About EPA
Health & Environmental Research Online (HERO)
Contact Us
Print
Feedback
Export to File
Search:
This record has one attached file:
Add More Files
Attach File(s):
Display Name for File*:
Save
Citation
Tags
HERO ID
711412
Reference Type
Journal Article
Title
Analysis of manganese tracer kinetics and target tissue dosimetry in monkeys and humans with multi-route physiologically based pharmacokinetic models
Author(s)
Schroeter, JD; Nong, A; Yoon, M; Taylor, MD; Dorman, DC; Andersen, ME; Clewell, HJ III
Year
2011
Is Peer Reviewed?
1
Journal
Toxicological Sciences
ISSN:
1096-6080
EISSN:
1096-0929
Volume
120
Issue
2
Page Numbers
481-498
Language
English
PMID
21205636
DOI
10.1093/toxsci/kfq389
Web of Science Id
WOS:000288804800023
Abstract
Manganese (Mn) is an essential nutrient with the capacity for toxicity from excessive exposure. Accumulation of Mn in the striatum, globus pallidus, and other midbrain regions is associated with neurotoxicity following high-dose Mn inhalation. Physiologically based pharmacokinetic (PBPK) models for ingested and inhaled Mn in rats and nonhuman primates were previously developed. The models contained saturable Mn tissue-binding capacities, preferential fluxes of Mn in specific tissues, and homeostatic control processes such as inducible biliary excretion of Mn. In this study, a nonhuman primate model was scaled to humans and was further extended to include iv, ip, and sc exposure routes so that past studies regarding radiolabeled carrier-free (54)MnCl(2) tracer kinetics could be evaluated. Simulation results accurately recapitulated the biphasic elimination behavior for all exposure routes. The PBPK models also provided consistent cross-species descriptions of Mn tracer kinetics across multiple exposure routes. These results indicate that PBPK models can accurately simulate the overall kinetic behavior of Mn and predict conditions where exposures will increase free Mn in various tissues throughout the body. Simulations with the human model indicate that globus pallidus Mn concentrations are unaffected by air concentrations < 10 μg/m(3) Mn. The use of this human Mn PBPK model can become a key component of future human health risk assessment of Mn, allowing the consideration of various exposure routes, natural tissue background levels, and homeostatic controls to explore exposure conditions that lead to increased target tissue levels resulting from Mn overexposure.
Keywords
manganese; PBPK; inhalation exposure; risk assessment; neurotoxicity; pharmacokinetics
Tags
•
Methanol (Non-Cancer)
Cited in Final (2013)
Cited in External Review Draft (2013)
Cited in External Review Draft (2011)
Home
Learn about HERO
Using HERO
Search HERO
Projects in HERO
Risk Assessment
Transparency & Integrity