Table 1: Overview of initial “first generation” pharmacokinetic models developed for manganese.

Model goal(s)Brief model descriptionRoute(s) of exposure and speciesMn pharmacokinetic data set(s) used in model developmentReference

Describe dose dependent gastrointestinal uptake and biliary elimination of MnTwo-compartment distribution model that described Mn movement between the intestinal lumen and the liver using simple rate constants ( 𝑘 i n and 𝑘 o u t ).Mn: O, INH
54Mn: IV Rodent
Tracer studies evaluating 54Mn whole-body elimination kinetics including a dietary Mn balance study, two biliary elimination studies, and one acute and one chronic study.[9]
Develop quantitative descriptions of Mn delivered to the liver from the systemic circulation.Gut lumen, liver blood, systemic blood, and a tissue compartments. Model parameters described gut uptake, 54Mn tracer kinetics, and hepatic extraction of Mn from oral and systemic pools. Mn: O, INH
54Mn: IV Rodent
Animals exposed to either inhaled or dietary Mn. These studies also evaluated 54Mn whole-body elimination kinetics.[10]
Describe the olfactory transport of Mn.Compartments included: blood, olfactory epithelium, olfactory bulb, olfactory tract and tubercle, and striatum. Each compartment included a free and bound fraction. 54Mn: INH RatRats exposed (90 min) nose-only to either exposure to 54MnCl2 or 54MnHPO4.[11]
Develop the basic structure of a multiroute PBPK model for Mn.Blood, brain, respiratory tract (nasal and lung), liver, kidneys, bone, and muscle (rest of body) compartments consisting of a “shallow” tissue pool in rapid equilibration with blood and a “deep” tissue store, connected to the shallow pool by transfer rate constants [1]. 54Mn: IP, INH RodentRodent tracer studies describing 54Mn distribution to various tissues and 54Mn elimination kinetics.[12]
Develop a multiroute Mn PBPK model for adult rats.Same compartments as above [4]. Model A used simple rate constants [1] to describe inter-compartmental movement of Mn. Model B had tissue binding kinetics described by dissociation and association constants ( 𝑘 𝑑 and 𝑘 𝑎 ), and maximum concentration of binding capacity ( 𝐵 m a x ).Mn: O, INH
54Mn: IV Rat
Rats fed on diets containing 2 to 100 ppm Mn, Rats fed a diet containing 125 ppm Mn and exposed via inhalation at 0.0 to 3.00 mg Mn/m3 each day for 14 d. Rats exposed to 0.1 or 0.5 mg Mn/m3 for 6 h/d, 5 d/wk over a 90-day period.[13]

O : oral; IP: intraperitoneal; IV: intravenous; INH: inhalation. Where applicable, Mn tracer form and route of exposure have also been provided.