Normally, MMT in fuel is destroyed during combustion resulting in the formation of inorganic Mn compounds. In early studies, MMT was reported to combust predominantly to Mn tetraoxide. More recent tests indicate combustion also to Mn phosphate and Mn sulphate with lesser oxides at higher oxidation states. Given particulate inorganic Mn emissions resulting from MMT use and that Mn is likely to reach target organs, it is prudent that a review of MMT as an AVSR should include a toxicological review of Mn.
Manganese is found in rock, soil, water and air and constitutes 0.1% of the Earths crust (NAS 1973). Manganese is generally not found as a base metal but is present as a variety of compounds such as oxides, sulphides, chlorides, carbonates, silicates, sulphates, nitrates and borates (NAS 1973). Different salts of Mn have a wide range of solubilities and are absorbed through biological membranes at different rates. Elemental Mn can exist in seven oxidation states depending on the compound, the majority of environmental Mn exposures being to Mn (II) and Mn (IV).
Atmospheric Mn is produced primarily from industrial emissions as particulate matter, with a mass median equivalent diameter of less than 5 m, 50% of which is smaller than 2 m (USEPA 1984; WHO 2000). Average airborne concentrations of Mn range from ~0.5-14 ng/m3 in remote locations, to ~40 ng/m3 in rural areas, and ~65-166 ng/m3 in urban locations. Airborne Mn concentrations can rise to ~8000 ng/m3 in source-dominated areas such as foundries (USEPA 1984; Stokes et al., 1988). WHO (1981) has estimated the mean daily intake of Mn from air in the general US population is less than 2 g/day. This rises to 10 g/day (24 h peak values exceed 100 g/day) for individuals living near industrial areas that utilise Mn.
Exhaustive reviews of Mn and Mn compounds have been conducted in “Toxicological Profile for Manganese (Update)” (ATSDR 2000) and the Concise International Chemical Assessment Document 12 – “Manganese and Its Compounds” (WHO 1999). The following toxicological information is based primarily on this latter document.
Manganese is an essential element and part of a normal diet of humans and animals. It plays a role in protein and energy metabolism, metabolic regulation, bone mineralisation, nervous system function and free radical neutralisation. Manganese is absorbed in the gastrointestinal tract after ingestion and also across the alveoli of the lungs after inhalation of Mn-containing dust or fumes. Manganese is transported in the plasma by transferrin, can cross the blood-brain barrier and placenta and tends to concentrate in the brain as well as tissues rich in mitochondria, such as the liver and kidney (WHO 1981). Dermal uptake of Mn or inorganic Mn compounds is considered extremely limited in the absence of an absorbable solvent. Dietary Mn intake is an important exposure route. In humans, the fraction of Mn absorbed in the gastrointestinal tract is variable but is in the order of 3-5%. The extent of absorption via inhalation is determined by particle size and the location of pulmonary deposition. Particles of sufficiently small size to deposit in the lower airways are likely to be absorbed whilst larger particles confined to the upper airways may be transported vertically to the throat via the mucociliary elevator then swallowed and absorbed in the gastrointestinal tract.
Absorption of inorganic Mn compounds is dependent on the route of exposure as well as the chemical species. For example, in rodents, absorption of Mn chloride as measured by Mn levels in blood and brain occurs readily via oral, intraperitoneal or intratracheal routes. In contrast, while Mn dioxide is also absorbed significantly via intraperitoneal or intratracheal routes, poor absorption occurs via the oral route. Also, highly elevated Mn levels in the brain follow intratracheal but not oral administration of either Mn species. Single dose kinetic studies also show that Mn chloride is absorbed rapidly particularly via the intratracheal route compared to the oral route whereas Mn dioxide is absorbed relatively slowly. Also, although pulmonary clearance rates following intratracheal instillation in rats appear to be similar for the sulphate, phosphate and tetraoxide forms of Mn (half-time less than 0.5 days), the mechanisms of clearance i.e. absorptive (dissolution) versus nonabsorptive (mechanical transport) for each may be different (Vitarella et al., 2000a). These data underline differences in absorption of different inorganic Mn species via different routes and in particular the importance of inhalation exposure when considering neurological impacts of excessive Mn.
Separate rodent studies show that absorption of Mn may occur also in the intranasal airways and the uptake by olfactory neurons may serve as a pathway for Mn uptake bypassing the blood-brain barrier. Recently, with neutron activation analysis, Vitarella et al. (2000b) showed particular accumulation of Mn in the olfactory bulb in rats following inhalation of Mn phosphate over 14 days. Brenneman et al (2000) also confirmed transport of Mn to the brain via the olfactory pathway in a unilateral nasal occlusion model in rats subject to a single 90 minute nose-only exposure to a Mn chloride isotope. Other inhalation studies in the rat indicate that aqueous solubility is predictive of Mn absorption in the lung and transport to the brain with exposure to more soluble forms of Mn such as Mn sulphate resulting in higher brain Mn compared to insoluble forms such as Mn tetraoxide (Dorman et al., 2001).
Absorption is also affected by diet. In humans, low dietary iron is associated with increased Mn absorption, probably because iron and Mn share the same transport mechanism in the gut. Similar results are observed in animals where Mn uptake is increased by iron deficiency and decreased by pre-exposure to high dietary Mn levels. In chicks, high dietary intakes of phosphorus and calcium also have been shown to depress Mn uptake. Additionally, absorption is age-dependent. Human infants, especially premature infants, retain a higher proportion of Mn than adults (Dorner et al., 1989, cited in ATSDR, 2000).
Once absorbed, adult humans normally maintain stable tissue levels of Mn through regulation of Mn excretion. Manganese is removed from the blood by the liver where it is conjugated with bile and excreted into the small intestine. The majority is then removed in faeces. Some of the Mn in the intestine is also reabsorbed via the hepatic portal circulation. Excretion of Mn also occurs via urine, milk and sweat. In humans, the whole-body clearance half-life of Mn is 37.5 days, while that for the head is 54 days (Cotzias et al., 1968, cited in WHO 1981).
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