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Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

2   Toxicokinetics

Manganese is a natural component of the environment and an essential element in the nutrition of humans and animals. No formal recommended dietary allowance exists for manganese. However, the Scientific Committee for Food of the EU has estimated 1 to 10 mg Mn/day as an acceptable range of intake. This level is equivalent to the usual daily intake. Manganese is involved in basic enzymatic processes including oxidative phosphorylation, decarboxylation, hydrolysis, Krebs cycle reactions, and the metabolism of carbohydrates. The concentration of manganese in the body is under normal circumstances held relatively constant by alterations in the rate and amount of manganese absorbed from the gastrointestinal tract, and by its distribution and rate of excretion (homeostasis). In children under one year of age, the homeostatic mechanisms may not have fully developed. (ATSDR 2000, Beliles 1994, SCF 2000).

2.1   Absorption

Manganese absorption occurs primarily through the diet. However, absorption via the lungs can be significant for occupationally exposed persons or for those exposed to excess levels of airborne manganese, such as downwind of a manganese point source (ATSDR 2000).

2.1.1   Inhalation

Inhalation of inorganic manganese may be in the form of aerosols or attached to particles, which may reach the lungs depending on the aerosol or particle size, shape, density, hygroscopicity, and electric charge. The deposition pattern in the respiratory tract of inhaled inorganic manganese is related to particle size. In humans, large particles (aerodynamic diameter of 5-30 mm) are mainly deposited in the upper airways while smaller particles (5 mm or less) may reach the lower airways. Particles that are deposited in the lower airways are probably mainly absorbed, while particles deposited in the upper airways may be moved by mucociliary transport to the throat, where they are swallowed and enter the stomach. A study has reported that more than 60% of particulate manganese trioxide inhaled by human volunteers was transferred to the gastrointestinal tract. No studies measuring the absolute amount of absorbed manganese following inhalation have been found. Manganese chloride is more readily absorbed than manganese dioxide following intratracheal instillation indicating that the absorption following inhalation is higher for more soluble forms of inorganic manganese. (ATSDR 2000, Beliles 1994).

2.1.2   Oral intake

Of ingested inorganic manganese only about 3-5% is absorbed from the gastro-intestinal tract in humans. There are many factors influencing the absorption such as water solubility of the compounds in ques­tion, age, and the level of manganese and other trace elements such as iron in the gut. (ATSDR 2000, Beliles 1994).

Studies with rodents show that the absorption and/or retention of manganese are higher in neonates, but returns to the level of older animals at approximately post-gestational day 17-18. Available studies do not provide adequate data to determine when this transition takes place in human infants. (ATSDR 2000, Beliles 1994).

In persons with iron defi­ciency, manganese absorption is increased probably because iron and manganese are absorbed by the same transport system in the gut. In some animal studies, calcium and phosphorus have depressed the manganese uptake. In rats fed a diet deficient in manganese, the absorption was at least two-fold higher than in rats ingesting an adequate amount of manganese. (ATSDR 2000, Beliles 1994).

2.1.3   Dermal contact

Manganese uptake across intact skin would be expected to be extremely limited (ATSDR 2000).

2.2   Distribution

In healthy humans, tissue concentrations of manganese range mainly between 0.1 and 1 mg Mn/kg wet weight with the highest levels in the liver, pancreas, and kidney and the lowest levels in bone and fat. (ATSDR 2000, Beliles 1994).

2.2.1   Inhalation

Seventy male CD rats were exposed nose-only for 90 minutes to an aerosol of radiolabelled manganese chloride particles at 0.54 mg Mn/m³. Half of the animals had both nostrils patent while the other half had the right nostril plugged to prevent nasal deposition of manganese chloride on the occluded side. At 0, 1, 2, 4, and 8 days post-exposure, the left and right sides of the nose and brain, including the olfactory pathway and striatum were sampled and analysed for the level of manganese. High levels of manganese were observed in the olfactory bulb and tract/tubercle on the side or sides with an open nostril within 1-2 days following inhalation consistent with direct olfactory transport of inhaled manganese from the nasal cavity to the brain bypassing the blood-brain barrier. The difference between the manganese level on the occluded and unoccluded side of the olfactory pathway was more than 90%. Only minor differences in the manganese level were seen between the left and right sides of the striatum in unilaterally occluded rats. Besides the brain, other organs (lungs, liver, kidneys, pancreas) also had increased tissue manganese concentrations following inhalation exposure. (Brenneman et al. 2000).

Groups of 6 adult male Sprague-Dawley rats were exposed to airborne manganese phosphate particles at 0, 0.03, 0.3 or 3 mg Mn/m³ for 6 hours/day for 2 weeks. Increased manganese concentrations were reported in olfactory bulb, lung, and striatum at the middle dose and also in cerebellum, femur, skeletal muscle, plasma, and erythrocytes at the high dose at the cessation of exposure. The liver manganese concentration was unaffected by inhalation exposure to manganese phosphate. (Vitarella et al. 2000).

Sprague-Dawley rats got an intranasal instillation with 0.004 mg Mn/kg b.w. of manganese chloride. The olfactory bulb contained the vast majority of measured manganese at 1, 3, and 7 days post-dosing (90, 69, and 47%, respectively) with a value decreasing to 16% at 12 weeks. At the same time-points, the basal forebrain contained 6, 21, and 28% of measured manganese, respectively. Manganese levels in the cerebral cortex, hypothalamus, striatum, and hippocampus were also maximal at 7 days post-dosing. Liver and kidney each contained about 1% of the measured manganese during the first 7 days. (Tjälve et al. 1996 – quoted from ATSDR 2000).

Following intranasal injection of manganese chloride into one nostril, manganese was dose-dependently accumulated in the olfactory bulb and tubercle (Gianutsos et al. 1997 – quoted from ATSDR 2000).

Rats were instilled intratracheally with manganese chloride or manganese dioxide at 1.22 mg Mn/kg b.w. once a week for 4 weeks. Compared to control rats, an increase of the manganese level was measured in striatum, blood, cortex, and cerebellum. (Roels et al. 1997 – quoted from ATSDR 2000).

Preferential accumulation of manganese in specific locations of the brain (including the caudate nucleus, globus pallidus, and the substantia nigra) was noted in 1 monkey exposed to an aerosol of manganese chloride (9-17 mg Mn/m³) several hours/day for 3-5 months (Newland et al. 1989 – quoted from ATSDR 2000).

2.2.2   Oral intake

Dietary manganese, absorbed mainly as Mn(II), enters portal circulation from the gastrointestinal tract and is bound to a-macroglobulin or albumin in the plasma. After transportation to the liver, the major portion of Mn(II) is secreted in bile, but some may be oxidized to Mn(III), which enters the circulation conjugated with plasma transferrin. (Aschner & Aschner 1991 – quoted from ATSDR 2000).

Studies in animals indicate that prolonged oral exposure to manganese compounds results in increased manganese levels in the tissues, but that the magnitude of the increase diminishes over time (ATSDR 2000).

Manganese in the form of manganese chloride or manganese dioxide is distributed more readily to the brain following intratracheal exposure compared to oral exposure by gavage (Roels et al 1997 – quoted from ATSDR 2000).

Mice and rats chronically fed manganese sulphate generally had elevated tissue levels of manganese. The manganese levels in the liver and kidney were higher than the levels in the brain. (NTP 1993 – quoted from ATSDR 2000).

Excess manganese (following oral exposure in humans with liver diseases) was accumulated in certain regions of the brain (basal ganglia, especially the globus pallidus and the substantia nigra) (ATSDR 2000). 

2.2.3   Dermal contact

No data were found.

2.2.4   Other routes

Studies with intraperitoneal and intravenous injections of inorganic manganese to monkeys, calves and rats have been performed. The distribution of manganese may vary depending on the route of exposure. For instance it has been shown that calves injected intravenously had a higher concentration of manganese in the liverand pancreas than calves fed manganese. Rats injected intraperitoneally had more manganese in the pancreas and less in the liver than rats fed manganese. Administration of manganese dioxide intraperitoneally to rats resulted in greater concentration of manganese in the brain than did manganese chloride. In a monkey study with intraperitoneal administration, manganese was found in all tissues studied with the highest level in pancreas, kidney and liver and the lowest level in the blood. (ATSDR 2000). 

2.3   Elimination

In general, biliary excretion is the main pathway by which absorbed manganese reaches the intestines where most of the element is excreted in the faeces. However, some of the manganese in the intestine is reabsorbed through enterohepatic circulation. Small amounts of manganese can also be found in urine, sweat, and milk. (ATSDR 2000).

2.3.1   Inhalation

In humans inhaling manganese chloride or manganese trioxide, about 60% of the material originally deposited in the lungs was excreted in the faeces within 4 days. In several studies, occupationally exposed men had significantly higher urine manganese levels compared to unexposed men. (ATSDR 2000).

Rats instilled intratracheally with manganese chloride or manganese tetroxide excreted about 50% of the dose in the faeces within 3-7 days (Drown et al. 1986 – quoted from ATSDR 2000).

Monkeys exposed to an aerosol of manganese chloride excreted most of the manganese with a half-life of less than half a day. However, a portion of the compound was retained in the lung and brain and was cleared with a half-life of 12-250 days. No further details were given. (Newland et al. 1987 – quoted from ATSDR 2000).

2.3.2   Oral intake

Humans who ingested tracer levels of radioactive manganese excreted the manganese with a half-life of 13-37 days (ATSDR 2000).

2.3.3   Dermal contact

No data were found.

2.3.4   Other routes

Rats exposed to manganese chloride by intravenous injection excreted 50% of the dose in the faeces within 1 day and 85% by day 23. Only minimal levels were excreted in the urine (<0.1% of the dose within 5 days). (Klaassen 1974, Dastur et al. 1971 – both quoted from ATSDR 2000).

2.4   Mode of action

The central nervous system is the primary target of manganese toxicity. In humans manganese causes neurochemical and neuropathological changes predominantly in the globus pallidus in the basal ganglia resulting in symptoms similar to but still different from parkinsonism. Although it is known that manganese is a cellulartoxicant that can impair transport systems, enzyme activities, and receptor functions, the principal manner in which manganese neurotoxicity occurs has not been clearly established. Several possibilities have been proposed. These include enhancement of the oxidation of dopamine and other catecholamines, which increases production of free radicals and reactive oxygen species, thereby causing oxidative stress and damage to the cell, following the depletion of cellular antioxidant defence systems. Other hypotheses involve damage predominantly to the mitochondria. (ATSDR 2000).

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