Multi-dose-route, multi-species pharmacokinetic models for manganese and their use in risk assessment.
Manganese (Mn) is an essential element that may be toxic in conditions of overexposure. Nearly 10 years ago, some of the authors of this article published a proposed methodology to perform a tissue-dose-based risk assessment and a detailed list of data needs necessary to perform the assessment. Since that time, a substantial body of Mn pharmacokinetic (PK) data has been generated in rats and nonhuman primates, allowing for the construction of physiologically based pharmacokinetic (PBPK) models for Mn. This study reviews the development of the Mn PBPK models, reassesses the previously identified data needs, and details potential uses of these models in risk assessment of Mn. Based upon numerous animal experiments, pharmacokinetic (PK) models have effectively simulated tissue kinetics of Mn from both inhaled and oral Mn intake. PK models achieve this by incorporating homeostatic control processes, saturable tissue binding capacities, and preferential fluxes in various tissue regions. While minor data gaps still exist, the models captured the main dose-dependent characteristics of Mn disposition in rodents and monkeys and provide a structure to parameterize an equivalent PK description in humans. These models are organized to contribute to a tissue-dose based risk assessment of Mn that simultaneously considers ingestion and inhalation kinetics of Mn along with homeostatic control of Mn.
Andersen
Melvin E
ME
The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709-2137, USA.
Dorman
David C
DC
Clewell
Harvey J
HJ
Taylor
Michael D
MD
Nong
Andy
A
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D000882:Haplorhini; D006801:Humans; D008345:Manganese / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008954:Models, Biological; D009751:Nutritional Requirements; D051381:Rats; D018570:Risk Assessment; D014018:Tissue Distribution
D008345:Manganese