Multiple Exposure Route 

Manganese PBPK Models for 

Monkeys and Humans

Jeff Schroeter

Mn TAP Meeting

October 31, 2013
• Mn is an essential nutrient that is required for numerous 

physiological functions

• The primary source of Mn exposure is through the diet

• Human consumption ranges from 1-10 mg/day with a small 

fraction absorbed by the GI tract 

• Homeostatic controls regulate absorption and excretion to 

maintain stable tissue levels despite dietary fluctuations

• Neurotoxicity can occur when Mn intake exceeds 

elimination  accumulation in midbrain regions (e.g., globus 

pallidus

Introduction
• Concerns exist as to whether inhalation exposure to high 

Mn levels leads to enhanced brain accumulation due to 

deposited particles bypassing the GI tract

• PBPK models were developed to describe Mn tissue 

dosimetry resulting from dietary and inhalation exposure

• Models were based on a multitude of Mn pharmacokinetic 

studies and 54Mn tracer clearance studies in rats, monkeys, 

and humans

Introduction
• A series of pharmacokinetic modeling studies described 

Mn kinetics using compartmental models (Teeguarden et 

al., 2007)

• PBPK model of the adult rat (Nong et al., 2008)

• PBPK models of adult rats and monkeys (Nong et al., 

2009)

• PBPK models of monkeys and humans (Schroeter et 

al., 2011)

Manganese PBPK Model History
• Multi-dose route capability: inhalation, diet, and oral 

exposure; iv, ip, and subq injection

• Homeostatic control processes (inducible biliary 

excretion)

• Saturable tissue binding capacities

• Preferential fluxes in various tissues

 Can be used to predict exposure scenarios that result in 

increased brain Mn concentrations

Manganese PBPK Model Highlights

Monkey

• Anatomical parameters from the literature

• Basal Mn tissue concentrations from Dorman et al. (2006)

•

54Mn tracer kinetic studies were used to calibrate fractional 

dietary uptake (Fdietup) and the biliary excretion rate 

constant (kbilec)

• Diffusion parameters, dissociation rate constants, and 

tissue binding capacities were calibrated to the 

pharmacokinetic data from Dorman et al. (2006)

Manganese PBPK Model Development
Human

• Anatomical parameters were either scaled from the 

monkey or obtained from the literature

• An average body weight of 70 kg for adults was used

• Basal Mn tissue concentrations from cadaver studies

• Dietary intake was set to 3 mg Mn/day

• Dietary absorption was calibrated to whole-body 

elimination kinetics of 54Mn

• Rate constants were scaled from the monkey model

Manganese PBPK Model Development
• IP injection (Dastur et al., 1971)

 - 200 μCi 54Mn given ip

- 12 monkeys, average BW=2.5 kg

- whole-body retention measured for 278 days

• IV injection (Furchner et al., 1966)

- 0.6 μCi 54Mn given iv

- 3 monkeys, average BW = 8.5 kg

- whole-body retention measured for one year

• Oral exposure (Furchner et al., 1966)

- 0.6 μCi 54Mn given orally

- 3 monkeys, average BW = 7 kg

- whole-body retention measured for 60 days

54Mn Tracer Studies in Monkeys
• Subcutaneous injection (Newland et al., 1987)

- 6-week continuous exposure to 200 μCi 54Mn and 400 mg Mn

(MnCl2 solution) administered subcutaneously with osmotic pump

- one monkey, BW = 5 kg

- fecal activity was measured for ~150 days

• Inhalation exposure (Newland et al., 1987)

- Monkeys were endotracheally exposed to nebulized MnCl2

aerosol for 30 minutes; Monkey A: 24 μCi 54Mn, Monkey B: 60 μCi

54Mn

- Monkey A: BW = 3.1, Monkey B: BW = 2.5 kg

- fecal activity was reported for ~250 days post-exposure

54Mn Tracer Studies in Monkeys
IP results
IV results
Oral results
Subcutaneous exposure
Inhalation exposure
Summary of 54Mn Tracer Studies in Monkeys

• Small changes were made to fractional dietary uptake 

and the biliary excretion rate constant to account for 

changes in Mn diet and monkey body weights in the 

different studies

• All other parameters in the PBPK model were unchanged 

to maintain a consistent description of Mn kinetics

• Biphasic elimination curves were observed for all 

exposure routes

• The PBPK model accurately replicated the elimination 

curves for all exposure routes

 
• Mahoney and Small (1968): 3 normal subjects were 

given an iv dose of 2.5 μCi 54Mn

• Mena et al. (1967): 8 healthy individuals were given an iv 

dose of 20 μCi 54Mn

• No information on gender, BW, or Mn in diet

• Whole-body retention was measured for > 30 days

• Elimination curves were used to calibrate fractional 

dietary uptake (Fdietup = 0.06) and the biliary excretion 

rate constant (kbilec = 0.051)

54Mn Tracer Studies in Humans
54Mn Tracer Studies in Humans
Mahoney and Small (1968):

• One subject on a reduced calorie diet (800 cal/day) for 6 

months prior to exposure – assume 1 mg/day Mn in diet

• Reduced calorie diet was continued throughout the study 

(~ 90 days)

• 60 days after iv dose of 2.5 μCi 54Mn, the subject 

ingested 800 mg/day supplemental Mn for 35 days

 Fdietup reduced from 0.062 to 0.00046 to account for 

decreased absorption of high oral Mn dose

54Mn Tracer Studies in Humans
54Mn Tracer Studies in Humans
54Mn Tracer Studies in Humans

Mahoney and Small (1968):

• One subject on a normal diet was pre-loaded with 300 

mg/day Mn 10 days prior to iv dose of 2.5 μCi 54Mn

• This regimen continued throughout the experiment for 40 

more days

 Fdietup was reduced by 28% per day for 15 days 

starting with the high-dose Mn ingestion. Final Fdietup

value was 0.00043
54Mn Tracer Studies in Humans
54Mn Tracer Studies in Humans

Mahoney and Small (1968):

• Iron-deficient subject: 50 days after iv dose of 2.5 μCi 

54Mn, iron therapy was initiated with 400 mg/day Fe

 Fdietup was increased during the iron-deficient phase 

(Fdietup = 0.075) and decreased (Fdietup = 0.035) after 

initiation of iron therapy 
54Mn Tracer Studies in Humans
• Six women ingested a meal labeled with 0.1 MBq 54Mn 

(Davidsson et al., 1988)

• Whole-body retention was measured for 30 days

•Oral 54Mn exposures were used to calibrate GI 

parameters in the PBPK model

 

54Mn Tracer Studies in Humans
54Mn Tracer Studies in Humans
• Plasma Mn concentrations were measured in men 

consuming different levels of dietary Mn (Freeland-Graves, 

1994)

Days mg/day Mn

1-21 2.36

22-42 2.89

43-63 2.06

64-101 1.21

102-112 3.79

113-125 2.65

 

54Mn Tracer Studies in Humans
54Mn Tracer Studies in Humans
Monkey Inhalation Exposures

Dorman et al. (2006):

• Monkeys were exposed to 0, 0.06, 0.3, or 1.5 Mg Mn/m3

of MnSO4for 6 hours/day, 5 days/week for 13 weeks

• Monkeys were maintained on a 133 ppm Mn diet

PBPK model parameters were calibrated using tissue Mn 

concentrations during and after the exposure period
Monkey Inhalation Exposures

1.5 mg Mn/m3
Monkey Inhalation Exposures
Human Inhalation Exposures

• Dietary absorption and biliary excretion were calibrated 

to 54Mn whole-body retention data

• Rate constants were scaled from the monkey and were 

further adjusted to fit basal Mn tissue levels

• 3 mg/day Mn in diet

• Exposure scenario: 1.5 Mg Mn/m3 of MnSO4for 8 

hours/day, 5 days/week for 13 weeks
Human Inhalation Exposures

1.5 mg Mn/m3
Human Inhalation Exposures

Globus pallidus
Human Inhalation Exposures

iv dose of 54Mn given on day 0
Interspecies Comparison

Total/free/bound Mn
Interspecies Comparison
Sensitivity Analysis
Summary

• The PBPK models provide consistent multi-species 

descriptions of Mn tracer kinetics and tissue Mn 

concentrations among multiple dose routes

• The PBPK models account for background tissue levels 

associated with normal dietary Mn exposure and simulate 

simultaneous exposure by ingestion and inhalation

• Simulation results recapitulate the rapid increase in tissue 

Mn from high inhalation concentrations and the subsequent 

return to basal levels

• The models can be used to evaluate exposure conditions 

that result in increased brain Mn tissue concentrations