Toxicokinetic Investigations of Direct Olfactory Transport of Inhaled Manganese

Manganese (Mn) is an essential element but a potential neurotoxicant when inhaled in high concentrations.  Worker exposures can occur in the steel production industry as well as the mining and processing of Mn ores. Mn neurotoxicity presents post-mortem as elevated Mn levels in the basal ganglia or corpus striatum. This is associated with neuronal loss, an extrapyramidal movement disorder, and psychiatric symptoms.

Manganese may enter the brain systemically through the blood brain barrier (BBB) or by direct olfactory transport via the olfactory neuron. The olfactory route may or may not enhance the efficiency of the inhalation route. This route bypasses the blood brain barrier (BBB) as inhaled compounds are taken up and conveyed along cell processes of olfactory neurons through the cribiform plate to synaptic junctions with neurons of the olfactory bulb.

The investigators developed the unilateral nasal occlusion model to investigate the potential of direct olfactory transport of Mn into the brain. This model allows the investigators to conduct a unilateral nasal exposure (exposure to one side of the nose) and lung along with systemic exposure to an inhaled toxicant.  The other nasal passage (occluded side) would present a much lower dose of the toxicant to the olfactory system and consequently, to the brain. The investigators compared brain concentrations on the patent versus occluded sides (in contrast to hematogenous pathways).

In this research, rats were exposed to a single 90-minute nose-only exposure to a ⁵⁴MnCl₂ aerosol at an average mass concentration of 0.54 mg Mn/m³ at an average particle size (MMAD) of 2.51 um. The left and right sides of the nose and brain including the olfactory pathway and striatum were sampled at 0,1,2,4 & 8 days post exposure. Control animals were left unoccluded. The experimental group needed a nasal plug to prevent nasal deposition of the ⁵⁴MnCl₂ on the occluded side (right side).  The authors used gamma spectroscopy and autoradiography to compare levels of ⁵⁴Mn on the left and right sides of the nose and brain in addition to determining the contribution of olfactory uptake to brain ⁵⁴Mn levels.

This study found that the olfactory route contributes the majority (>90%) of the ⁵⁴Mn found in the olfactory pathway but not in the striatum of the rat brain up to 8 days post exposure.  The data suggests that direct olfactory transport does not significantly contribute to striatal Mn levels.  The data also suggests that, although the rat is a good animal model for olfactory transport, it is a poor model for Mn neurotoxicity in humans since it fails to accumulate Mn in the striatum.  Furthermore, the rat does not demonstrate the behavioral nor pathological changes characteristic of human and non-human primates manganism.

  

Source: Brenneman, K. A., Wong, B. A., Buccellato, M. A., Costa, E. R., Gross, E. A., and Dorman, D. C. (2000).  Direct Olfactory Transport of Inhaled Manganese (⁵⁴MnCl₂) to the Rat Brain: Toxicokinetic Investigations in a Unilateral Nasal Occlusion Model. Toxicol. Appl. Pharmacol. 169, 238-248.

By:    Arlene L. Weiss, MS, DABT

          Contributing Editor