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

Table 1

Overview of the pharmacokinetic studies conducted in response to the Alternative Tier 2 test program for MMT. The following forms of manganese (Mn) were used in these studies: Mn tetroxide, Mn sulfate, and Mn phosphate. Some studies also involved intravenous administration of radiolabeled Mn chloride (⁵⁴MnCl₂) to assess whole-body (WB) clearance.

Pharmacokinetic endpoint of interest	Regulatory Status	Animal Species	Manganese species and exposure conditions	Primary publication(s)
Particle solubility and dissolution kinetics	Voluntary	Rat	Phosphate, sulfate, and tetraoxide—intratracheal instillation; 0, 0.04, 0.08, or 0.16 μg Mn/g; Rats killed at 0, 1, 3, or 14 d	[42]
Exposure-response and WB clearance	Voluntary	Rat	Phosphate inhalation; 6 h/d for either 5 d/wk or 7 d/wk at 0, 0.03, 0.3, or 3 mg Mn/m^3 for up to 14 d	[43]
Particle solubility and WB clearance	Voluntary	Rat	Sulfate and tetroxide inhalation; 6 h/d for 7 d/wk at 0, 0.03, 0.3, or 3 mg Mn/m^3 for 14 d	[44]
Diet-inhalation interaction and WB clearance	Voluntary	Rat	Sulfate or tetroxide inhalation; 6 h/d for 7 d/wk at 0, 0.03, or 0.3 mg Mn/m^3 for 14 d; Low (2 ppm), sufficient (10 ppm), or high (100 ppm) Mn diets	[45, 46]
Olfactory transport of Mn	Voluntary	Rat	Chloride and phosphate inhalation ~0.5 mg Mn/m^3 for 90 min; Occluded nostril model	[47, 48]
Individual susceptibility WB clearance; Nasal pathology	Required	Rat	Inhalation; Exposed 6 h/d for 5 d/wk to sulfate at 0.01, 0.1, or 0.5 mg Mn/m^3 or phosphate at 0.1 mg Mn/m^3 for up to 90 d; Adult male, adult female, and senescent male	[49, 50]
Individual susceptibility	Required	Rat	Sulfate inhalation; Exposed 6 h/d for 7 d/wk at 0, 0.05, 0.5, or 1 mg Mn/m^3 throughout the majority of pregnancy or lactation.	[41, 51]
Species differences; Brain imaging; Respiratory tract pathology and neurochemistry	Required	Rhesus monkey	Sulfate inhalation; Exposed 6 h/d for 5 d/wk at 0, 0.06, 0.3, or 1.5 mg Mn/m^3 for up to 90 d.	[34–38]