2 2. Manganese Toxicology: Public Health Concerns about MMT Manganese is an essential trace metal that is required for normal amino acid, lipid, protein, and carbohydrate metabolism. Under certain high-dose exposure conditions or disease states (e.g., hepatobiliary dysfunction), however, manganese can induce adverse neurological, reproductive, and respiratory eﬀects in humans [3]. Manganese toxicity is dependent on the dose to target tissue and develops after inhalation, oral, and parenteral exposure; however, this paper will focus predominantly on inhalation. Atmo- spheric sources of manganese include manmade and natural sources including wind erosion of dusts and soils. Industries associated with manganese emissions include ferroalloy production, iron and steel foundries, and power plant and coke oven combustion emissions. Ambient (background) levels of manganese in rural and urban air range from 0.005 to 0.07 µg Mn/m3 [4]. Neurological eﬀects occur at lower dose levels than other adverse eﬀects, so consideration of these eﬀects drives the human health risk assessment of inhaled manganese [4– 6]. The earliest manifestations of manganese neurotoxicity (manganism) include fatigue, headache, muscle cramps, loss of appetite, apathy, insomnia, and diminished libido. As manganese exposure continues and the disease progresses, patients may develop dystonia, bradykinesia, rigidity, gait disorders, postural instability, micrographia, and muscle tremors (for review see [7]). These signs are associated with primary involvement of the globus pallidus. Individuals with chronic manganese neurotoxicity resemble patients with Parkinson’s disease; however, these syndromes can be distinguished both clinically and with neuroimaging studies [7]. Although these syndromes are clinically distinct, some studies suggest that manganese overexposure may pose a risk factor for Parkinson’s disease [7, 8]. A variety of inhalation exposure scenarios exist for manganese from occupational settings with mid- to high- dose exposures to much lower exposures found in the general environment. Forms of manganese include but are not lim- ited to manganese dioxide (MnO2) and other oxides, man- ganese sulfate (MnSO4), manganese phosphates (MnPO4), and organometallic manganese compounds. Absent underly- ing hepatobiliary disease, frank manganese neurotoxicity has been observed in workers that have been chronically exposed to dusts or fumes that contain high levels (>1 mg Mn/m3) of manganese [4]. More subtle neurobehavioral eﬀects have been reported in welders and other workers at lower (∼0.2 mg Mn/m3) exposure concentrations [9]. One of the more inﬂuential occupational studies was performed by Roels and coworkers [10]. This cross-sectional study of male workers was used by the USEPA as their critical study for deriving their chronic inhalation reference concentration for manganese (RfC) of 0.05 µg/m3 that was last updated in 1993 [6]. According to USEPA, an RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious eﬀects during a lifetime. Roels Journal of Toxicology et al. [10] assessed employees from a Belgian alkaline battery production plant and controls from a polymer processing plant. Personal air samplers in the battery plant indicated an 8 hr time weighted average (TWA) exposure of 0.215 mg/m3 for respirable manganese. An average cumulative exposure of 1.2 mg/m3·years of respirable manganese was associated with decrements in some neurofunctional performances (e.g., mean reaction times, eye-hand coordination and muscles tremor scores) between the exposed group and the control group. Health Canada current risk assessment relied on a study of Italian ferroalloy workers performed by Lucchini and coworkers [11] for the derivation of their RfC for manganese [5]. Lucchini examined several cohorts of workers (furnace, casting, and welding job functions) between 1981 and 1997. Manganese exposures for all classes of workers dropped appreciably during this time. For exam- ple, the geometric mean manganese concentrations (in total dust) went from 167 to 54.7 µg/m3 in the maintenance area where welding was performed. An exposure concentration of approximately 71 µg Mn/m3 was derived from an estimated cumulative exposure index. Lucchini reported an associa- tion between occupational manganese exposure and some neurological eﬀects including higher symptom reporting, increased tremor frequency, altered motor function, and impaired memory. Bailey and colleagues [12] published an alternative RfC value of 2–7 µg Mn/m3 that was based upon their use of epidemiological studies published after 1992. The American Conference of Industrial Hygienists (ACGIH) threshold limit value (TLV) for elemental manganese and related inorganic compounds is 0.2 mg Mn/m3 [13]. This standard is set as a time-weighted average for an 8 hr shift 5 days per week designed to protect workers in occupational settings. Ambient manganese exposure data are needed to assess the potential public health impacts of MMT in fuel. Several of the most signiﬁcant studies were performed in Canadian cities when MMT was widely used in the local fuel supply. For example, an extremely large eﬀort using probabilistic sampling techniques measured manganese exposure levels in Toronto residents when all fuel contained MMT [14]. The results of this study and related analyses of data from personal samplers [15, 16] suggest that the median annualized nonoccupational exposure concentration was 0.008 µg/m3 with the highest long-term exposures at or near 0.022 µg/m3. as a respirable fraction (PM2.5). Roadway measurement of soil manganese concentrations did not reveal a measurable increase in manganese levels along urban Toronto highways [17]. Studies from Australia have shed additional light on the impact of MMT on atmospheric manganese concentrations [18, 19]. Gulson and coworkers reported no signiﬁcant changes in environmental samples or blood manganese concentrations in children following the introduction of MMT in Sydney. Concerns regarding the use of MMT as a gasoline fuel additive have also been inﬂuenced by the USA experience of tetraethyl lead in gasoline. Concerns about automotive emissions of lead prompted the USEPA in 1973 to phase out the use of lead in gasoline [20]. The experience with tetraethyl lead created an environment of distrust between