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

Pharmacokinetic endpointKey Finding(s)

Chemical form of manganeseLung uptake and brain (tissue) delivery is highly influenced by solubility (sulfate ≫ phosphate > tetroxide)
Dose and duration dependencesManganese 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 controlManganese concentration in brain remains controlled at low levels of exposure and accumulates at air concentrations >10–50 μg/m3
Dose metricsDose rate rather than cumulative dose appears to be the appropriate dose metric at low levels of exposure
Route of exposureThe 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 transportInhaled manganese is taken up by the nasal olfactory epithelium and transported directly via the olfactory nerve to the olfactory bulb
Species differencesDespite specific pharmacokinetic differences between rats and nonhuman primates, similar overall pharmacokinetic responses to and homeostatic controls of manganese were observed across species