Report of the Technical Advisory Panel Meeting for Manganese PBPK Models

The Hamner Institute for Health Sciences

Research Triangle Park, NC

October 31, 2013

Objectives

The Technical Advisory Panel (TAP) for manganese PBPK models developed over a period of time by the 

Hamner Institute for Health Sciences has provided scientific review and comment during the course of 

the model development process. The TAP empaneled to evaluate the latest PBPK models include: Drs. 

Daniel Krewski (chair), Jeffery Fisher, and Lynne Haber.

The current TAP meeting was convened to evaluate PBPK models developed by Schroeter et al. (2011) 

for adult monkeys and humans, and the human models incorporating fetal and neonatal exposure in 

humans developed by Yoon et al. (2011). The TAP was asked specifically to comment on the extent to 

which the models have been validated, as well as their suitability for application in human health risk 

assessment. The TAP was also asked to comment on the completeness of the documentation available 

for these two models. 

Three supplementary presentations on ongoing work were also considered, specifically: 1) a planned 

experiment to evaluate the effect of route of exposure (dietary/drinking water ad libitum/gavage) on 

manganese excretion and tissue concentrations; 2) an advanced uncertainty analysis of Mn PBPK models 

for rodents and humans; and 3) a reparametrized PBPK model for Mn involving faster dissociation and 

association constants.

TAP Evaluation

Completed PBPK Models

The completion of the two models described by Schroeter et al. (2011) and Yoon et al. (2011) represents 

the successful completion of many years of work, which involved the initial development, refinement, 

and validation of these complex PBPK models. 

The TAP considered that the PBPK model developed by Schroeter et al. (2011) to provide a plausible 

description of the pharmacokinetics of manganese in adult human and non-human primates. Model 

simulations against measured Mn elimination curves served to validate the model quite well. Based on 

its general biological plausibility and ability to describe experimental data the TAP considered the model 

suitable for risk assessment purposes. 

The models provide considerable insight into the pharmacokinetics of manganese, including the 

identification of kinetic process that are dose-dependent. For example, the saturation of binding 

processes and the induction of biliary elimination at high plasma concentrations resulting in increased 

elimination of manganese at high doses is well described within the model. The model also clearly 
describes the relative importance of different routes of exposure to Mn, and the subsequent 

concentration of manganese at key target tissues as a function of different exposure patterns. 

An attractive feature of the model is its ability to predict Mn concentration in the following four 

different brain areas: globus pallidus, pituitary, cerebellum, and olfactory bulb. Although the model 

includes an omnibus compartment labelled ‘rest of body’, which includes a mix of heterogeneous 

tissues, the limited mass of manganese in this compartment results in this not being an 

oversimplification that would appreciably distort model predictions. 

The model is well documented, with the code having been successfully used by several organizations 

that the model has been provided to. The TAP did, however, recommend additional transparency in 

documentation, specifically: 1) the model diagram could be enhanced by colour coding those 

parameters that are dose-dependent (Fdietup and biliary excretion); 2) figure legends for the model 

diagrams should explicitly note that the association/dissociation constants (ka and kd) are tissue specific, 

and that kin and kout vary for each brain region; and 3) an explanation of how dietary or stable 

manganese and radiolabeled manganese were modelled together should be provided. As the research 

team moves forward to risk assessment applications, using the simplified structure of key elements of 

the model described by Meek et al. (2013) would be useful in communicating the model. 

The model by Yoon et al. (2011) represents perhaps the most complex PBPK model developed to date, 

incorporating detailed descriptions of fetal and neonatal exposure through the addition of separate 

compartments for these two critical life stages. Despite their complexity, the models were clearly 

described. Although the models involve an unusually large number of parameters because of the 

inclusion of additional compartments, the authors have found sufficient data sources to permit the 

estimation of all of the model parameters; independent verification of the model also appears to have 

been demonstrated using data not involved in model development, although the details of this 

verification might be made more transparent. 

These models also provide important insights into exposure at different life stages: based on the results 

presented, foetal and neonatal tissue doses were comparable to, or less than, adult doses. 

Both models use default respiratory parameters from MPPT deposition modeling (i.e., under resting 

conditions), which differ from defaults used by EPA for risk assessment purposes (i.e., under light 

activity). The deposition modeling was correctly done in the verification process where the human 

subjects were at rest; however, if this model were to be used in risk assessment, it would be more 

appropriate to use the respiratory parameters used by EPA. [The EPA defaults are based on 16 breaths 

per minute and 813 mL tidal volume (RIVM, 2002).]

Ongoing Work

The TAP considered the three ongoing activities described by the investigators to be of importance in 

further evaluating, and possibly refining, the two models discuss above. The proposed drinking water 

study comparing dietary, drinking water, and gavage dosing will be of great value in determining if these 

three routes of exposure result in different tissue concentrations of Mn; should this be the case, the 
PBPK models might be extended to distinguish between these three exposure routes. [On a technical 

note regarding the design of this study, the TAP suggests that consideration be given to increasing the 

number of animals in the drinking water group slightly, to allow for the possibility that actual 

manganese doses for some animals in this group might be notably less than intended, because of 

manipulation of the drinking water supply by the experimental animals during the course of the study.]

The planned uncertainty/variability analysis using sequential Bayesian methods and MCMC techniques is 

state-of-the-art, and will provide valuable information on those model parameters contributing most to 

uncertainty and variability in predicted tissue doses.

The alternative model based on higher dissociation/association constants not only appears to be more 

biologically plausible, but also appears to provide a slightly better fit to the available data. While this 

alternative model – currently available only for the adult rat – represents a refinement of the current 

model, the current model (which is available for human and non-human primates) is still sufficiently 

accurate to be useful in risk assessment applications. 

Conclusion

The work described above represents a significant achievement on the part of the investigators in 

developing and validating a series of PBPK models for manganese to the point where they are now 

suitable for risk assessment applications. These models – currently available for the adult rat, monkey, 

and human, along with life-stage specific components for the rat and human models – have been wellvalidated according to current standards in this field, and have been subjected to sensitivity analyses 

that demonstrate reasonable model robustness. Although ongoing work can be expected to result in 

future model refinements, the current suite of models are sufficiently mature for use risk assessment.

An important aspect of this work has been the ongoing interaction between EPA, which requested that 

this work be conducted by industry, and the investigators at the Hamner Institutes. This interaction has

resulted in much useful dialogue that has been conducive to the achievement of a suite of models that 

have the potential to lead to improvements in the manner in which potential Mn health risks are 

characterized and evaluated. 

References

Meek, M.E., Barton, H.A., Bessems, J.G., Lipscomb, J.C. & Krishnan, K. (2013). Case study illustrating the 

WHO IPCS guidance on characterization and application of physiologically based models in risk 

assessment. Regulatory Toxicology and Pharmacology 66, 116-129. 

RIVM (2002). From concentration to dose: Factors influencing airborne particulate matter deposition in 

humans and rats. RIVM report 650010031/2002. Winter-Sorkina and Cassee.

Schroeter, J.D., Nong, A., Yoon, M., Taylor, M.D., Dorman, D.C., Andersen, M.A. & Clewell, H.J. III (2011).

Analysis of manganese tracer kinetics and target tissue dosimetry in monkeys and humans with multiroute physiologically based pharmacokinetic models. Toxicological Sciences 120, 481-498. 
Yoon, M., Schroeter, J.D., Nong, A., Taylor, M.D., Dorman, D.C., Andersen, M.E. & Clewell, H.J. III (2011). 

Physiologically based pharmacokinetic modeling of fetal and neonatal manganese exposure in humans: 

describing manganese homeostasis during development. Toxicological Sciences 122, 297-316.