Priority Existing Chemical

k.2Human health effects

The neurological dysfunction of manganism appears to be related to both dose and duration of Mn exposure. Initial signs may be vague and non-specific with complaints of general weakness, muscle pain, irritability, apathy and headache. Loss of libido, impotence, compulsive, aggressive or destructive behaviour may also occur. Dysfunction of basal ganglia may occur next as indicated by altered gait, clumsy limb movements, fine tremor, slow and halting speech and dull and expressionless facial expressions. A characteristic staggering gait with erect spine may develop further accompanied occasionally by psychological disturbances.

Isolated case reports describe manganism following occupational exposure to dusts or fumes containing inorganic Mn in mining, alloy machining or battery manufacture workers and also in individuals consuming water containing elevated Mn. However, long-term match-controlled epidemiological studies are able to confirm subtle neurological abnormalities in the absence of overt signs of manganism. Neurobehavioural tests such as the WHO Neurobehavioural Core Test Battery, Swedish Performance Evaluation System as well as supplementary manual dexterity and questionnaire evaluations uncover subclinical alterations in neurological performance and behavioural indicators associated with inhalation of Mn dusts or fumes. Subclinical nervous system toxicity through to overt manganism have been observed after inhalational exposure to total Mn dust levels ranging from 0.14-1.0 mg/m³ for the former and from 2-22 mg/m³ for the latter with exposure durations of 1-35 years.

In response to difficulties in detecting the subtle neurobehavioural alterations of manganism, magnetic resonance imaging (MRI) has been used in an attempt to detect early signs of Mn exposure. In male workers exposed occupationally (mean exposure > 10 years) to Mn dioxide dust (personal monitoring mean total atmospheric Mn 387 μg/m³; blood Mn 14.8 μg/L; n = 11), Dietz et al. (2001) reported that despite the inability to detect changes in electrophysiology, MRI scans revealed increases in the ratio of globus pallidus to subcortical frontal white matter signal intensity (pallidal index) in Mn exposed workers compared to matched control subjects (personal monitoring mean total atmospheric Mn 10 μg/m³; blood Mn 11 μg/L; n = 11). These changes are similar to those described by Kim et al. (1999) who reported increases in pallidal index during MRI scans of asymptomatic Mn workers (blood Mn 14.2 μg/L; n = 89) but not unexposed manual workers (blood Mn 11.7 μg/L; n = 16). Such changes in imaging are noteworthy as they reflect recent exposure to Mn and deposition of Mn in a brain area noted for association with Parkinsonian-like symptoms.

Few data are available regarding reversibility of neurological effects. The progression of clinical symptoms of manganism in five surviving workers 9-10 years removed from chronic 3-13 year exposure to Mn in a ferroalloy plant was documented by Huang et al. (1998) (cited in ATSDR, 2000). Despite dramatic decreases in blood and tissue Mn concentrations, neurologic examinations revealed a continuing deterioration of health indicated by abnormalities in gait, rigidity and writing, suggesting progression and permanence of neurological effects from frank Mn exposure.

In a prospective study of a cohort of affected Mn dioxide exposed workers at a battery plant, Roels et al. (1999) reported that a decrease in levels of Mn in total dust over 8 years was associated with normalisation of hand-forearm movement ability in a low exposure subgroup (personal monitoring mean total atmospheric Mn approximately 400 μg/m³). However, medium (mean total Mn approximately 600 μg/m³) and high (mean total Mn approximately 2000 μg/m³) exposure subgroups showed no or only partial improvement in neurophysiological tests over this period.

In addition to neurological effects, acute and long-term inhalation of particulate Mn is associated with inflammatory responses in lungs. Symptoms and signs include reductions in lung function parameters, cough, bronchitis and pneumonia. Pneumonia is reported from acute and long-term inhalation exposure mostly in occupational settings but also in residential populations in proximity to Mn sources. A threshold level for respiratory effects has not been established. It is possible that pulmonary irritation, inflammation and increased susceptibility to infection may not be caused by Mn itself but may be a secondary effect of the inhalation of matter in particulate form.

Reproductive effects are also associated with excessive Mn exposure. Impotence and loss of libido are common symptoms in male workers showing clinical manganism following chronic occupational exposure. Chronic occupational exposure of males has been linked with impaired fertility as measured by decreases in numbers of children per married couple. However, dose-response data are unavailable and so a threshold level for reproductive effects in humans is not definable. Also, few data are available regarding reproductive effects in women.

Several recent reports suggest a possible link between Mn exposure and the development of the human prion disease known as Creutzfeldt-Jakob disease (CJD) (Brown 2001). It has been established that prion protein when isolated from brain tissue is bound to copper and that this interaction is necessary for the normal functioning of the protein as an antioxidant (Brown et al. 2001). A central characteristic of prion disease is the conversion of the normal prion protein to a corrupted form (Prusiner 1998). Experimental evidence suggests that the corrupted prion protein lacks antioxidant activity, is resistant to proteinases, and aggregates to form fibrils (Prusiner 1982; Brown et al. 1997). It was subsequently demonstrated in vitro that the prion protein can bind Mn and this interaction promotes the conversion to the corrupted form (Brown et al 2000). Other evidence for a possible link between Mn and CJD is provided from epidemiological studies. For example, Purdy (2000) reports that areas in the UK that have unusually high incidence of prion disease also have high Mn and low copper content in soil and plants. The reverse was noted for low prion disease areas. A second example comes from Slovakia, where people living in areas that have a high degree of industrial Mn contamination also have elevated body Mn levels. These same areas are known to experience an unusually high incidence of sporadic CJD (Mitrova 1991; Purdy 2000). Overall, although a link is suggested, data are not sufficient to define a causal relationship between Mn exposure and CJD.

The critical effect of chronic exposure to Mn is neurotoxicity although the pathogenic mechanisms are not fully understood. Manganese-related neurobehavioural effects are reported at lower doses in humans compared to animals suggesting that humans are more sensitive to Mn. However, such differences may also be related to differences in the sensitivity of test methods used to detect neurobehavioural effects in humans compared to animals.

The most reliable and robust epidemiological study for Mn exposure is Roels et al. (1992). In this study, neurofunctional endpoints were examined in 92 male workers exposed to Mn dioxide dust at an alkaline battery factory. Manganese workers were compared to a group of 104 age-matched control workers not exposed to neurotoxic chemicals or lung irritants recruited from a polymer processing plant. The prevalence of neuropsychological and respiratory symptoms and changes in lung ventilatory parameters, neurofunctional performances (visual reaction time, eye-hand coordination, hand steadiness, audioverbal short term memory) and several biological parameters including luteinising hormone, follicle stimulating hormone and prolactin concentrations in serum, blood counts and Mn concentrations in blood and urine were examined. For each worker, current exposure and lifetime integrated exposure to respirable and total airborne Mn dust were also determined. This allowed grouping of exposed workers according to lifetime integrated exposures to respirable Mn dust (<600, 600-1 200, >1 200 μg Mn/m³ x year) and total Mn dust (<2 500, 2 500-6 000, >6 000 μg Mn/m³ x year).

Manganese concentrations in blood and urine were significantly higher in the battery workers compared to control workers. In individual workers, however, Mn levels in blood or urine were not related to external exposure parameters. In comparison to control workers, Mn workers showed significantly poorer performance for visual reaction time, eye-hand coordination and hand steadiness. Underperformance was related to lifetime integrated exposures to total and respirable Mn dust, being most significant in the highest dose group.

From these data, a dose-response relationship was derived. A lower 95% confidence limit was estimated around the level of Mn exposure expected to result in a 5% response rate and this value (30 μg/m³) was considered a surrogate for a NOAEL for neurological effects (WHO 1999; 2000).

Other dose-response estimates based on Roels et al. (1992) have derived a NOAEL of 32 μg/m³ and LOAEL of 50 μg/m³ (WHO 1999).