Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

Table 2

Notable scientific contributions derived from the MMT Alternative Tier 2 test program.

Pharmacokinetic endpoint	Key Finding(s)
Chemical form of manganese	Lung uptake and brain (tissue) delivery is highly influenced by solubility (sulfate ≫ phosphate > tetroxide)
Dose and duration dependences	Manganese uptake and elimination rates depend on exposure dose and exposure duration; Delivery to the brain and development of pseudosteady manganese concentrations develop rapidly; Biliary excretion shows similar time and concentration dependencies.
Homeostatic control	Manganese concentration in brain remains controlled at low levels of exposure and accumulates at air concentrations >10–50 μg/m^3
Dose metrics	Dose rate rather than cumulative dose appears to be the appropriate dose metric at low levels of exposure
Route of exposure	The observed pharmacokinetic differences between dietary and inhaled manganese can be attributed to rates of uptake and elimination required to achieve the same target tissue doses
Olfactory transport	Inhaled manganese is taken up by the nasal olfactory epithelium and transported directly via the olfactory nerve to the olfactory bulb
Species differences	Despite specific pharmacokinetic differences between rats and nonhuman primates, similar overall pharmacokinetic responses to and homeostatic controls of manganese were observed across species