Manganese (Mn) Technical Advisory Panel Report #2

February 23, 2007

Jeff Fisher, Interim Chair 

Background

	The Hamner Institutes for Health Sciences have undertaken an
investigation of the pharmacokinetic properties manganese (Mn), an
essential element that demonstrates neurotoxicity at high levels of
exposure in both animals and humans. Certain manganese compounds have
been added to gasoline to boost the octane rating and to reduce engine
knocking.  This research will ultimately help inform the establishment
of human exposure guidelines for Mn, taking into account its
pharmacokinetic properties.   

Progress to Date

	Modeling work on Mn has progressed significantly since the last meeting
with the TAP. The conceptual and quantitative portrayal of Mn as an
essential nutrient gives rise to a U shaped dose response curve, where
Mn insufficiency, sufficiency and excess may occur.  Additionally, the
modeling team had a breakthrough in understanding the deceptively simple
kinetics tracer kinetics of Mn by obtaining a better understanding the
‘bulk’ mass transport properties of stable Mn.  The question remains
as to identification of the specific biological determinants that
influence the mass transport of Mn in the body. We believe the modeling
team is headed in the right direction, in that; they will integrate the
component pieces of the models to describe the systemic kinetics of Mn
and the olfactory transport model. 

	To date, a first order transport model has been developed to describe
transport from olfactory mucosa to the brain has been developed (Leavens
et al., 2007).  With the possible exception of the striatum region of
the brain, this initial model appears to describe transport properties
of Mn from the olfactory mucosa reasonably well.  An enhanced model with
a more detailed description of the transport of manganese through the
systemic pathway is being developed discern systemic derived- from
olfactory derived- brain concentrations of Mn and to address inaccurate
or uncertain predictions of manganese concentrations in the striatum. 

	Additional manuscripts discussing the pharmacokinetics of manganese
following inhalation and oral exposure have also been prepared.  Dr.
Teeguarden and his colleagues authored three papers on Mn which describe
the early attempts to understand the kinetics and dosimetry of Mn. 
Teeguarden et al. (2007a) explore the dose dependencies of GI uptake and
clearance from the body for dietary Mn to better understand homeostatic
controls for Mn.  In the second paper Teeguarden et al. (2007b) compare
hepatic processing of Mn after inhalation and oral exposures to better
understand route specific uptake of Mn and to gain insights on how Mn is
processed in the body.  The final paper of Teeguarden et al. (2007c)
attempts to integrate Mn tracer kinetics with dietary or stable Mn. 
Modifications of model structure and model parameters occurred
throughout these papers which were important to gain insights into how
Mn is controlled by the body. 

Another paper is in preparation by Nong et al. describing the
culmination of the modeling efforts on Mn to date and will provide
describe a coherent description of systemic derived- and olfactory
derived- transport of Mn to the brain. 

The modeling team at the Hamner Institutes for Health Sciences under the
direction of Dr. Andersen are exceptionally productive as evidenced by
the number of peer reviewed publications.   These scientific
contributions may establish the research agenda over the next decade for
how to study the kinetics and dynamics of essential nutrients.

Specific Issues for Further Consideration

‘Validate’ new PK model through application to other data sets,
including primate data and pregnancy/lactation data in rodents.  To
address sensitive populations these data sets will become important. (DK
and JF)

Can PK data on calcium inform the development of the manganese PBPK
model? (Relevant data for other metals/transition elements might also be
useful in the overall interpretation of the results for manganese
generated through this research program.) (JF)

The results to date indicate that the fraction of manganese that is
‘bound’ varies in different tissues and depends on the form of
manganese to which the subject is exposed.  It would be helpful to
characterize ‘boundedness’ of Mn as fully as possible, since free Mn
will be more toxic than bound Mn. The biological determinates that are
responsible for the ‘boundedness’ are worthy of further study. (DK
and JF) 

Sensitivity analyses of the current and future models should be
conducted, to identify the most important model parameters. (DK)

The research group should consider the feasibility and desirability of
conducting an uncertainty analysis of the PBPK model for Mn,
demonstrating how uncertainty in input parameters propagates into
uncertainty in predictions of tissue doses.  (This may be important in
the longer term as the PBPK results become applicable for risk
assessment purposes.) (DK)

To the extent possible, factors influencing inter-individual variability
in the kinetics of Mn should be identified. (DK) 

One concept that relates to the U shaped dose response curve for an
essential element is the idea of adaptive response and compensatory
response, which is being used by Dr. Fisher and colleagues to describe
iodide deficiency, sufficiency, and excess as it relates to
hypothyroidism/hyperthyroidism and developmental neurotoxicity. Adaptive
responses are those key physiological processes that maintain
homeostasis. In this case with Mn, perhaps the gut, bile excretion or
even tissue binding all contribute to the regulation of Mn over a range
of specified dietary intake of Mn.  If transient changes or no changes
occur in Mn dosimetry, then complete compensation occurs at the target
tissue and no toxicity is observed. If the adaptive responses are
overwhelmed by too much Mn (or if there is an insufficient supply) then
incomplete compensation may occur at the target tissue and possible
toxicity ensues.  (JF)   

References

Leavens, T.L., Rao, D., Andersen, M.E. & Dorman, D.C. (2007). 
Evaluating transport of manganese from olfactory mucosa to striatum by
pharmacokinetic modeling. Toxicological Sciences. In press.  

Nong, A., Justin G. Teeguarden, Harvey J. Clewell III, David C. Dorman
and Melvin E. Andersen (2007). Pharmacokinetic Modeling of Manganese in
the Rat IV: Assessing Factors that contribute to brain accumulation
during inhalation exposure. J. Tox. Environ. Health, To Be Submitted.

Teeguarden, Justin G. David C. Dorman, Tammie R. Covington, Harvey J.
Clewell, and Melvin E. Andersen (2007a). Pharmacokinetic Modeling of
Manganese I. Dose-Dependencies of Uptake and Elimination.  J. Tox.
Environ. Health, in press.

 Teeguarden, Justin G., David C. Dorman, Andy Nong, Tammie R. Covington,
Harvey J. Clewell, III, and Melvin E. Andersen (2007b).  Pharmacokinetic
Modeling of Manganese II. Hepatic Processing after Ingestion and
Inhalation.  Journal of Toxicology and Environmental Health. In press. 

Teeguarden, Justin G., Jeffrey Gearhart, Harvey J. Clewell III, Tammie
R. Covington, Andy Nong, and Melvin E. Andersen (2007c). 
Pharmacokinetic Modeling of Manganese III. Physiological Approaches
Accounting for Background and Tracer Kinetics. Journal of Toxicology and
Environmental Health. In press.

