Human Health Risk Assessment for Inhaled Manganese: document summary
Cat. No.: H128-1/10-600E
HC Pub.: 100122
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Manganese (CAS 7439-96-5) is a metal that is found naturally in air, water, soil and in living systems. Biologically, manganese (Mn) is an essential mineral and is required for the functioning of a number of enzyme families. In addition to its essential role within the body, manganese is a well documented toxicant in humans at sufficiently high levels of exposure. Although manganese can be toxic to a number of organ systems including the reproductive and respiratory systems, the critical target organ is the central nervous system (CNS), where manganese accumulates within the basal ganglia of the brain. Very high levels of exposure can result in a clinical and severely debilitating neurological disease known as manganism. More moderate levels of exposure can result in worsening of subclinical neurological function including fine motor control, tremor, memory and cognitive ability, consistent with damage to the basal ganglia.
Review of the Science
Ingested manganese is subject to homeostatic controls, both at the point of absorption from the gastrointestinal tract as well as via biliary excretion (ingested manganese passes through the liver prior to entering systemic circulation). Only a small percentage of an oral dose of manganese enters systemic circulation. Conversely, inhaled manganese enters systemic circulation directly, making the manganese available for distribution to and accumulation in the body's tissues, including the brain. Manganese delivery to the brain can occur across the blood-brain barrier, through the choroid plexus and via direct olfactory transport. In the case of the latter, inhaled manganese deposited on the olfactory epithelium can be transported directly along the olfactory system to the olfactory bulb within the brain, providing a direct interface between the nervous system and the external environment.
Toxicological studies of manganese have used animal models to investigate the neuropathological, behavioural, developmental, and genotoxic effects of exposure to this metal. These studies have also examined how factors such as chemical form and valence affect toxicity, and how age, gender, diet and disease affect susceptibility. In general, the majority of toxicology studies have been performed with rodents using high exposure doses and small treatment groups. Some studies have used nonhuman primates, and an increasing amount of mechanistic in vitro work has been carried out with neural cell lines. The principal behavioural effect reported in manganese-exposed rodents is transient modification of spontaneous motor activity. Studies with nonhuman primates, though fewer, provide more detailed behavioural analyses, with symptoms of manganese intoxication often resembling those reported in humans. Hyperactivity is reported as a common early symptom, progressing to abnormal movements, muscular rigidity and limb flexion.
Based on data from toxicology studies with nonhuman primates and rodents, it can be hypothesized that a number of interrelated processes are set in motion as manganese intoxication progresses: i) cellular energy supplies are depleted by mitochondrial disruption and interference with oxidative phosphorylation and the citric acid cycle; ii) oxidative stress is induced by interference with cellular respiration, the oxidation of dopamine, and/or reduced antioxidant function; iii) cellular iron and calcium homeostasis are disrupted; iv) impaired astrocyte function leads to increased extracellular glutamate concentration and potential excitotoxicity; and v) apoptosis and/or necrosis is triggered in active neurons leading to cell death. The end result of these toxic processes is cytotoxicity and selective neurodegeneration in regions of the brain that accumulate manganese, in turn leading to an alteration in CNS neurotransmission that gives rise to the behavioural effects associated with manganese intoxication.
The effects of manganese exposure on human health have been investigated in a large number of epidemiological studies. These have primarily evaluated the impact of manganese exposure on subclinical neurofunctional outcomes such as fine motor control, tremor, memory and aspects of cognitive ability. Of the many endpoints examined, measures of fine motor control, particularly of the fingers, hands and wrists, as well as tremor, have been most consistently affected by manganese exposure. Although most studies have made use of occupationally exposed populations, studies in the general population have shown an association between blood manganese levels and neurofunction in adults and children, as well as an elevated prevalence of parkinsonian symptoms in populations living in the vicinity of a large manganese industry.
Results from a population-based study of personal exposure in Toronto (1996) revealed that about 10% of adults had personal exposures greater than 0.05 µg Mn/m³ in PM10 and greater than 0.014 µg Mn/m³ in PM2.5. (PMx refers to particulate matter with a mass mean aerodynamic diameter of x microns.) Between 2003 and 2005, annual average ambient manganese levels in Canadian cities without major manganese-emitting industries ranged from 0.003-0.025 µg/m³ in PM10 and from 0.002-0.014 in PM2.5. In some areas of cities with major manganese-emitting industries such as Hamilton and Sault Ste. Marie, the annual average level of PM10 manganese in air (2003-2005) has ranged from 0.06-0.22 µg/m³ in PM10. There is only limited information on personal exposure to manganese in locations with large manganese-emitters.
Derivation of a reference concentration for inhaled manganese
A study of Italian ferroalloy workers (Lucchini et al., 1999) was identified as the critical study for a quantitative risk assessment of the neurotoxic effects of manganese and the derivation of a new reference concentration for manganese. This dataset includes exposure variables, neurofunctional outcome variables, serum prolactin, and confounder variables. Dose-response assessment was carried out with benchmark concentration analysis methodology. Two exposure metrics were used: 1) work history average respirable manganese (ARE); and 2) average respirable manganese over the five years prior to testing (ARE5). ARE5 was investigated based on biological evidence of the clearance of manganese from the brain over months to several years. The analysis revealed three significant dose-response models for ARE (three tests of fine motor control) and ten significant dose-response models for ARE5, including six tests of fine motor control, two aspects of memory tests, one test of mental arithmetic and serum prolactin.
Results from the benchmark concentration analysis were used in the derivation of the new reference concentration for inhaled manganese. Benchmark concentration analysis results were adjusted to account for conversion from an occupational exposure regime (5/7 days per week and 8/24 hours per day) to constant exposure as experienced by the general population. One uncertainty factor of 10 was applied to the benchmark concentration analysis results to account for interindividual variability in response to manganese. Specifically, evidence regarding the possible enhanced susceptibility of the elderly, infants and children, individuals with asymptomatic pre-parkinsonism, individuals with chronic liver disease or on parenteral nutrition, females and individuals with iron deficiency was considered. A second uncertainty factor of 10 was applied to account for the following limitations in the database: a) the general population may be exposed to more soluble forms of manganese, which can enhance delivery of manganese to the brain; b) the lack of extensive studies of the effect of prenatal exposure to manganese; and c) the impact of manganese exposure on serum prolactin. Results from the dose-response models with ARE5, a more sensitive measure of the critical manganese exposure affecting the health outcomes, yield reference concentrations of 0.05-0.08 µg/m³.
This review and analysis concludes that the new Health Canada reference concentration for inhaled manganese is 0.05 µg/m³ in PM3.5. This value reflects the concentration to which the general population, including sensitive subgroups, can be exposed for a lifetime without appreciable harm.
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