Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

Table 3

Overview of human PBPK models developed for manganese.

Model goal(s)	Brief model description	Route(s) of exposure^‡ and species	Mn pharmacokinetic data set(s) used in model development	Reference
Refine the multi-route Mn PBPK model for monkeys and extend to human beings.	Blood, brain (globus pallidus, pituitary gland, olfactory bulb, and cerebellum), respiratory tract (olfactory mucosa and lung epithelium), liver, kidneys, bone, and “rest of body” compartments. More extensive description of gastrointestinal tract (gut lumen and epithelium) and peritoneal cavity. 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; ^54Mn: IV, IP, O, SC Rhesus monkey Human	Monkey inhalation study used previously [6]. Whole-body elimination or fecal excretion data available from ^54Mn tracer kinetic studies in monkeys and people	[19]
Develop a PBPK model that could predict fetal Mn dose and Mn disposition in women and fetus following maternal Mn exposure.	Lactation and gestation models similar to those developed for rodents [15, 16]. Same compartments for women as above [9] except for excluding the pituitary gland and including the placenta and mammary gland. Fetal model included blood, brain, lung, bone, liver, and “rest of body” compartments. Saturable binding and other model features similar to above [9]. Key model features included: placental Mn transfer via active transport, lactational transfer of Mn used diffusion-mediated secretion, higher gut absorption in nursing neonates, low but inducible biliary excretion of Mn in neonates, transition of neonatal features of gut absorption and biliary excretion to those of adults, and enhanced brain uptake of Mn during fetal and postnatal development.	Mn: O, INH Human	Variety of data obtained in people including: reported brain Mn concentration at birth and children, Mn concentrations in the umbilical cord, milk, newborn blood, bone, and other tissues.; Age appropriate tissue weights and blood flows.	[20]

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