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Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-Dawley rats following subchronic (90 days) inhalation exposure

https://doi.org/10.1016/S0041-008X(03)00238-2Get rights and content

Abstract

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn) compound added to unleaded gasoline in Canada. The primary combustion products of MMT are Mn phosphate, Mn sulfate, and a Mn phosphate/Mn sulfate mixture. Concerns have been raised that the combustion products of MMT containing Mn could be neurotoxic, even at low levels of exposure. The objective of this study is to investigate exposure-response relationships for bioaccumulation and locomotor effects following subchronic inhalation exposure to a mixture of manganese phosphates/sulfate mixture. A control group and three groups of 30 male Sprague-Dawley rats were exposed in inhalation chambers for a period of 13 weeks, 5 days per week, 6 h a day. Exposure concentrations were 3000, 300, and 30 μg/m3. At the end of the exposure period, locomotor activity and resting time tests were conducted for 36 h using a computerized autotrack system. Rats were then euthanized by exsanguination and Mn concentrations in different tissues (liver, lung, testis, and kidney) and blood and brain (caudate putamen, globus pallidus, olfactory bulb, frontal cortex, and cerebellum) were determined by neutron activation analysis. Increased manganese concentrations were observed in blood, kidney, lung, testis, and in all brain sections in the highest exposure group. Mn in the lung and in the olfactory bulb were dose dependent. Our data indicate that the olfactory bulb accumulated more Mn than other brain regions following inhalation exposure. Locomotor activity was increased at 3000 μg/m3, but no difference was observed in resting time among the exposed groups. At the end of the experiment, rats exposed to 300 and 3000 μg/m3 exhibited significantly decreased body weight in comparison with the control group. Biochemical profiles also revealed some significant differences in certain parameters, specifically alkaline phospatase, urea, and chlorate.

Introduction

Methylcyclopentadienyl manganese tricarbonyl (MMT) is one of the main sources of inorganic manganese (Mn) contamination in urban air, mainly in areas with high traffic density (Joselow et al., 1978). The main combustion products of MMT are essentially Mn-phosphate, Mn-sulfate, and a Mn-phosphate/sulfate mixture (Zayed et al., 1999). Exposure to high concentrations of atmospheric Mn can lead to adverse health outcomes, notably respiratory and neurological effects. Exposure to concentrations of >1 mg of Mn/m3 among miners and other industrial workers has been shown to persuade adverse respiratory, neurological, and reproductive effects (Iregren, 1999). The clinical syndrome of manganese neurotoxicity (manganism) can be divided into an early phase characterized by obvious mood and behavior changes, and a later stage somewhat similar to Parkinson's disease that is characterized by dystonia and severe gait disorder (Pal et al., 1999). However, little is known about the potential health effects that may result from long-term low-level exposure of populations through ambient air. Certain subpopulations such as children and patients with chronic liver disease could be more susceptible to different levels of Mn contamination.

It is clear that the route of exposure can influence the distribution, metabolism, and potential for neurotoxicity of Mn-containing compounds (Roels et al., 1997). Inhalation exposure is more efficient than ingestion at transporting Mn to the brain. Pharmacokinetic factors that may contribute to the increased efficiency of brain Mn delivery following inhalation include greater Mn absorption from the lungs and slower clearance of absorbed Mn from the circulation (Andersen et al., 1999). Moreover, inhalation exposure to soluble forms of Mn results in higher brain Mn concentration compared with insoluble form of Mn (Dorman et al., 2001). One study has shown that after intratracheal instillation, a surrogate for inhalation exposure, Mn concentrations were higher in brain following the administration of the soluble salt MnCl2, than following the administration of the insoluble oxide MnO2. Striatal Mn concentrations increased by 205% and 48% following MnCl2 and MnO2 administration, respectively (Roels et al., 1997).

The main brain target for Mn toxicity is the basal ganglia (caudate nucleus, globus pallidus, and putamen), which is involved in motricity. Disturbances of the basal ganglia can lead to unintentional contraction of the skeletal muscles, such as tremor and muscular rigidity, as in Parkinson's disease. Few studies have been conducted to describe the distribution of brain Mn following inhalation of different Mn species, the main route by which Mn intoxication occurs in workers. It seems likely that the neurotoxicity of inhaled Mn may be related to an uptake of this metal into the brain via olfactory neurons. The olfactory bulb in rats plays a significant role in the uptake of inhaled Mn and subsequent delivery to the brain (Tjälve and Henriksson, 1999). However, the route of delivery of Mn to the brain is not clear in human. The primary objective of this study is to determine the effects of subchronic exposure to an Mn phosphate/sulfate mixture on Mn tissue concentrations and locomotor activity.

Section snippets

Chemicals

Manganese phosphate/sulfate mixture, a fine crystalline powder, which includes Mn5(PO4)2(PO3(OH))24H2Ohureaulite mineral form, and manganese (II) sulfate monohydrate (MnSO4 · H2O), were obtained from Alfa Aesar (Johnson Matthey Company) and combined 50/50 (wt/wt). The chemistry of the mixture was confirmed by scanning electron microscopy (SEM) and energy dispersive x-ray spectrometry (EDS). Mn in both compounds has the same oxidation state (II). Whereas manganese sulfate is relatively water

Mn in the inhalation chamber

The average Mn concentrations obtained in this study were 34.8 ± 9.2, 290.8 ± 76.8, and 2841 ± 529 μg/m3 for target concentrations of 30, 300, and 3000 μg/m3 of Mn phosphate/sulfate mixture, respectively. Based on the cascade impactor, 80% of the Mn phosphate/sulfate mixture particles in the inhalation chamber were smaller than 1.55 μm in aerodynamic diameter (Table 1). Overall mean daily chamber temperatures ranged at 22–25°C, and relative humidity ranged at 25–40%. The results indicated that

Discussion

Different MMT combustion products are produced depending on fuel combustion and engine and catalytic converter thermodynamics. It is now well accepted that Mn is emitted from the tailpipe primarily as a mixture of Mn phosphate and Mn sulfate particles, with size ranging between 0.2 and 10 μm in aerodynamic diameters (Zayed et al., 1999). In the present study, 100% of the particles were <10 μm, while 87% were <3.5 μm.

In this study, equal weights of Mn phosphate and Mn sulfate were introduced

Acknowledgements

This research was supported by the Toxic Substances Research Initiative (TSRI), a research program managed jointly by Health Canada and Environment Canada. Additional support was provided by Dr. D. Krewski, who is the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa, and G. Carrier, Chair of Risk Assessment Toxicology at the University of Montreal.

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