Chapter 13:Modeling Manganese Kinetics for Human Health Risk Assessment

Manganese (Mn) is an essential element that is also toxic under conditions where body burden becomes sufficient to saturate homeostatic processes regulating excretion. The primary health concern regarding Mn overexposure is neurotoxicity, often expressed by varying degrees of motor or cognitive deficits. Target tissue concentration is the critical determinant for Mn toxicity, regardless of exposure route. Physiologically based pharmacokinetic (PBPK) models provide a means to predict the internal dose at the target tissue and extrapolate across subpopulations and/or exposure conditions. Recently a variety of PBPK models have been developed for Mn (e.g. adult, pregnant, lactating, and neonatal rats; non-human primates; and adult, pregnant, lactating, and neonatal humans). These models can predict exposure conditions that would lead to toxicologically significant increases in tissue Mn concentrations compared with those associated with normal dietary intake. This is done by incorporating uptake both from normal daily ingestion and additional exposure and homeostatic regulation of tissue levels that may lead to adaptive changes or tissue level excursions when it is overwhelmed. A review of Mn pharmacokinetic data used for model development, the PBPK modeling process incorporating Mn homeostasis in various exposure conditions and subpopulations, and the application of the models to Mn risk assessment is provided in this chapter.