Low level methylmercury exposure affects neuropsychological function in adults

In recent years there has been a growing appreciation for acquired risk factors for neurologic disease and neuropsychological dysfunction, including exposures to environmental neurotoxicants such as the heavy metals. In this investigation, we studied the effects of environmental exposures to methylmercury (MeHg) via diet on neurocognitive status in adults. This study is of critical importance as worldwide concerns have focused on MeHg exposures. In many regions of the world, elemental mercury is used in small scale gold mining and MeHg is a byproduct of the contamination of aquatic systems by these mining processes [1]. Worldwide, adults as well as children are exposed to MeHg through the diet [2, 3].

An intensive gold rush began in the early 1980s in the Pantanal and Amazon Regions of Brazil [4]. Although declines in global prices for gold have led to decreased mining in recent years, previous mining activity continues to have consequences for the environment and its inhabitants. Small scale or informal gold mining, known in Portuguese as garimpagem, has significantly increased environmental mercury levels in water, sediments, and fish [5]. In this process, metallic mercury (Hg⁰) is used to recover particulate gold from alluvial deposits by crude amalgamation [6, 7]. During amalgamation and crude refining, significant amounts of Hg⁰ are discharged into the surrounding water, soil and air [5–8]. In aquatic systems inorganic mercury is converted to MeHg by bacteria in sediments, bioaccumulated in fish and biomagnified through the aquatic food chain [3].

The neurotoxic effects of MeHg especially during intrauterine development, have been demonstrated in both human and animal studies [3, 10]. MeHg exposure is associated with a wide range of central nervous system dysfunctions in both children and adults [11]. Recent studies suggest an increased susceptibility of the developing nervous system to low level exposures, particularly during prenatal development [[12–14], reviewed by [7]]. Neuropsychological data from most of these studies indicate that children exposed during prenatal development performed more poorly on several neuropsychological measures including concentration, fine motor speed, and verbal memory than non-exposed children (but see ref [15]]. However the specific effects of environmental MeHg exposures in adults are less well characterized.

In adults, MeHg exposure is thought to cause selective damage relatively restricted to the granule cells of the cerebellum and neurons in the visual cortex [11, 16]. In studies at Minamata, Japan, where the population consumed MeHg contaminated fish, high levels of prenatal exposure caused diffuse cerebral and cerebellar damage in infants and children. In contrast, the relatively few adults studied postmortem had more restricted and focal cerebral lesions [17]. The most common clinical signs observed in adults in the Minamata episode were paresthesia, ataxia, gait disturbance, sensory disturbances, tremors, visual and hearing impairments [18]. Formal neuropsychological assessments in adults were not reported. In 1971, a number of people in Iraq were exposed to organomercury-treated seed grain that was used mistakenly to make bread [19]. The predominant symptom noted in adults was paresthesia, which typically emerged after a latent period of 16 to 38 days [11]. The most severely affected individuals presented with ataxia, blurred vision, slurred speech and hearing difficulties [10, 11]. Standardized neuropsychological assessments were not conducted. Based upon these events and other data from occupational studies, the World Health Organization proposed that limiting exposure to a maximum hair mercury concentration of 50 to 125 μg/g would prevent paresthesia [9]. The International Programme on Chemical Safety maintained this recommendation in its criteria document published in 1990 [20].

However, these recommendations are based upon very high exposure episodes that resulted in hair mercury concentrations in the range of hundreds of micrograms per gram [2]. A critical contemporary issue in environmental health is the determination of the level at which MeHg is toxic in persons with chronic low level exposure, which primarily results from consumption of contaminated fish [21]. Recent studies of chronic low level MeHg exposures in adults suggest that a guidance level of 50 μg/g in hair may not be protective. Specifically, hair mercury concentrations below 50 μg/g have been associated with neurobehavioral disturbances in aspects of visual (chromatic discrimination, contrast sensitivity and peripheral fields) and psychomotor functions (tremor, dexterity, grip strength, complex movement sequences, hand-eye coordination, and rapid alternating movement) [6, 22–26]. Further studies are needed to delineate the potential neurocognitive effects associated with low level MeHg exposure for adults, in order to provide a rational basis for safety levels.

To this end, we evaluated the neurocognitive status of riverine populations in the Pantanal region of Brazil. These communities are dependent upon fish as a main source of food and protein [27, 28]. As a result of decades of small scale gold mining and deforestation in this region, as well as in Amazonia, many aquatic systems are contaminated with mercury and many fish species contain relatively high levels of mercury [28–32]. The results presented in this paper are part of a larger regional project on "Mercury Contamination Risks Via Food Chain in Baixada Cuiabana, Pantanal – Brazil". In this project, mercury levels have been measured in humans (blood, urine, hair), fish, water, and sediments. Levels of MeHg in humans have been studied with respect to diet, fish consumption, sociodemographic information, self-reported symptoms and morbidity, and neurological and neurocognitive status [27]. Fish consumed in this region contain a mean of 0.7 μg/g in the edible portion of carnivorous species, or 0. 08 μg/g in herbivorous species [27]. The substantial amount of data available on these exposures makes this a useful context for epidemiologic research.

The results of this study indicate that adults exposed to MeHg through fish consumption may have observable deficits in neurobehavioral performance measures, without detectable alterations in mood or affect. Since this is a cross sectional study, it is not possible to determine the extent to which these effects were associated with current exposures, as measured by analysis of Hg in hair at the scalp, with prior exposures earlier in life (particularly in utero), or both. However, prior exposures were not likely to wholly explain the results of this study of adults. First, length of residence in the region was not significantly associated with either hair mercury level or outcome. Second, the major period of gold mining in this region began in the 1980s [4, 8, 34], so that exposure to MeHg in fish, downstream from mining sites, was unlikely to have begun until some time after the mid 1980s, allowing for hydrologic dispersion of mercury and contamination of the aquatic food chain, at which point all of the persons in this cohort were already born. However, a longitudinal study is necessary to fully determine the role of timing of exposure in these observed outcomes.

The possibility of adverse effects in adults at lower levels of mercury exposure than those relied upon for occupational guidance has been raised by other studies in Brazil of fish-consuming populations [6, 23–26]. Several of these studies have considered diet and nutrition as covariates [23, 24]. The populations in this study are not undernourished or grossly deficient in nutrient intake. In general, health status is good to excellent, with the exception of risks of infection by endemic parasites and helminths [36, 45]. Alcohol consumption was relatively low in this population, with 80% reporting no alcohol consumption and no subjects reporting heavy consumption. No subjects were excluded on the basis of alcohol consumption. Consideration of either infection or alcohol consumption did not alter the observed associations between mercury exposure and neuropsychological outcomes in this study.

The strongest effects of mercury on persons in this study were detected on tests of fine motor speed and dexterity (Bead Threading) and response inhibition (errors of commission or "false alarms" on the timed visual search and attention tasks). The size of the effects increased with hair mercury concentration, consistent with a dose-dependent effect. Based upon extant data [particularly as reported in [23], we anticipated that the neuropsychological effects of Hg exposure in adults would be in domains of attention and concentration, memory, and psychomotor speed and dexterity. Hence, these functions were the focus of our screening battery. Post-hoc analyses were performed on Digit Span and Paired Associative Learning measures for purposes of clarification and interpretation of our findings, as well as for hypothesis generation for future studies. Since the Digit Span subtest was correlated with hair Hg, we conducted a post hoc analysis to determine if simple attention (as measured by Digits Forward] or more complex attention and concentration (Digits Reverse) explained the findings. Our post hoc analysis indicated that the test component requiring greater demands on the attentional system (Digits Reverse) probably explained the correlation. Since memory has been previously reported to be affected by mercury exposure, and since we found no correlation between hair Hg and the Associative Learning subtest of the WMS we conducted post-hoc analysis to determine in memory correlations were found with the harder word associations (Difficult Pairs). They were not, and in fact, correlations were observed between hair Hg and the easy associations. These results may therefore reflect other factors such as motivational issues in the population. Visuomotor disturbances have also been described in similar exposure situations [6, 25, 26]. Decrements in performance on the visually guided fine motor speed and dexterity task (Bead Threading) were also found, while gross motor functions (placing disks, marking dots) were unaffected. These results are consistent with earlier studies [[22], also reviewed by [44]], which have suggested that mercury disrupts the cerebellum (a brain region associated with accurately aimed and smoothly executed coordinated movement) [46].

Mercury exposure appears to be associated with increased responding, that is, both correct responses and commission errors. Errors of commission generally reflect disturbances in response inhibition or inhibitory control Possible disturbances in select aspects of memory were also observed (working memory, new learning), which is consistent with previously reported findings in workers exposed to mercury vapor [47]. Because of differences in exposure, it is difficult to compare these results with studies of adults chronically exposed to inorganic mercury in the workplace, who have demonstrated cognitive impairments, including deficits in attention and executive function, short term memory, visuospatial ability, and motor function [16, 47].

For most of the tests, the size of the effects – β coefficient – for the whole population is relatively small. However, when the population is stratified on the basis of the WHO standard, a relatively large effect of mercury exposure is observed, similar to findings for the effects of lead in children [48]. Also, the risk of performing below the median on neuropsychological tests of fine motor speed, logical memory, and digit span (backward) is generally increased in persons with higher hair mercury. These stratified analyses were undertaken to further elucidate the potential public health importance of these relatively low levels of exposure to MeHg in adults. Testing associations between exposure and outcome as continuous variables provides more sensitive information on potential effects at low exposures, as demonstrated in the regression analyses, but these dichotomized analyses may be relevant to public health policy. Recent proposals for public health policy, such as advisory levels for fish consumption, have generally assumed that children are significantly more sensitive than adults to the neurotoxic effects of MeHg [2, 3, 20, 49]. However, this study suggests that adults may be as sensitive as children to MeHg. Although there are differences in the tests used, some of the tests that evaluated similar domains or function showed decreased performance in adults (our study) and children [12–14] related to attention, fine motor function and memory. Of course the neurotoxic effects of MeHg in children differ significantly from those in adults, because of the specific properties of MeHg as a neurodevelopmental toxicant [3, 10, 49]; we draw the comparison to note the importance of preventing MeHg exposures to adults as well as children.

This is the first study of adults exposed to low levels of MeHg, using neuropsychological tests comparable in sensitivity to the methods used in the Faeroes and Seychelles studies. Usually, motor function and visual field are the primary outcomes evaluated in cases of adult exposure, often in occupational settings of much higher exposures to inorganic mercury compounds. As in similar research on other environmental neurotoxicants, it is important to distinguish individual risk from population risk. Decreases in mean scores may be too small to detect or to evaluate as to clinical significance for one individual, but they may be quite important when considered in terms of the impact on the population distribution of the affected function, as has been shown for lead [49]. If this is the case, then the public health impacts of MeHg exposure at levels often encountered by adults in North America [2] may be inducing adverse effects on neurobehavioral performance. Further studies are necessary in order to confirm these findings and to understand the mechanisms by which MeHg can affect central nervous system function in adults.