Table 2: Overview of “second generation” PBPK models developed for manganese.

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

Develop a multiroute Mn PBPK model for adult rats and monkeys.Blood, brain (striatum, pituitary gland, olfactory bulb, and cerebellum), respiratory tract (olfactory mucosa and lung epithelium), liver, kidneys, bone, and “rest of body” compartments. Saturable Mn binding in all tissues, preferential accumulation of Mn in several brain regions. Deposition of Mn within the respiratory tract and olfactory uptake and “nose-to-brain” Mn transport were based in part on additional models describing regional particle deposition within the respiratory tract. Mn: O, INH Rat Rhesus monkeyRat 14- and 90-day inhalation studies. In monkeys, model parameters were first calibrated using steady-state tissue Mn concentrations from rhesus monkeys fed a diet containing 133 ppm Mn. The model was then applied to simulate 65 exposure days of weekly (6 h/day; 5 days/week) inhalation exposures to soluble MnSO4 at 0.03 to 1.5 mg Mn/m3.[14]
Develop a PBPK model for lactating dam and neonates.Same compartments for the dam and pups as above [6] except for excluding pituitary gland and including mammary gland (dam only). Saturable binding and other model features similar to above [6]. Dietary (e.g., transfer of free Mn in milk) and inhalation inputs to pups. Mn: O, INH RatDams and their offspring were exposed to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m3) for 6 h/day, 7 days/week starting 28 days prior to breeding through postnatal day 18.[15]
Develop a PBPK model that could predict fetal Mn dose and Mn disposition in the dam and fetus following maternal Mn exposure.Same compartments for the dam as above [6] except for excluding the pituitary gland and including the placenta. Fetal model included blood, brain, lung, bone, liver, and “rest of body” compartments. Saturable binding and other model features similar to above [6]. Placental transfer to fetus.Mn: O, INH RatDams fed a 10-ppm Mn diet were exposed to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m3) for 6 h/day, 7 days/week starting 28 days prior to breeding through gestation day 20.[16]

O : oral; INH: inhalation.