Evaluation of neurobehavioral impairment in methylmercury-treated KK-Ay mice by dynamic weight-bearing test.

Methylmercury (MeHg) is known to cause neurobehavioral impairment in human and experimental animals. We previously reported that MeHg (5 mg Hg/kg) induced severe neurobehavioral dysfunction in 4-week-old KK-Ay mice, although it is difficult to evaluate quantitatively the neurobehavioral impairment in MeHg-treated KK-Ay mice because of their obesity. The aim of this study was to evaluate MeHg-induced neurobehavioral dysfunction in KK-Ay mice using the dynamic weight-bearing test, which analyzes the animal's weight distribution between the four limbs. Male 12-week-old KK-Ay mice were treated with MeHg (5 mg Hg/kg) three times per week for 5 weeks. Body weight loss began after approximately 2 weeks of MeHg treatment, and decreased significantly at 4 weeks. Seven of the nine MeHg-treated mice exhibited overt neurological symptoms such as ataxia and gait disturbance. The weight-bearing load was lower for the forelimb than for the hindlimb at baseline and until 1 week after MeHg treatment was initiated. In weeks 2-4, the dynamic weight-bearing loads on the forelimb and hindlimb were similar. The load on the forelimb exceeded the load on the hindlimb after 5 weeks of treatment. This finding indicates that the dynamic weight-bearing test is useful for semi-quantitative evaluation of neurobehavioral impairment in MeHg-treated rodents, and is less stressful for the animals. Infiltration of CD204-positive macrophages was observed in the sciatic nerve of MeHg-treated mice, suggesting that CD204 can serve as a useful marker of tissue injury in peripheral nerves and a possible target in regenerating peripheral nerves and controlling neuropathies.

Is mercury in Tibetan Medicine toxic? Clinical, neurocognitive and biochemical results of an initial cross-sectional study.

Mercury an important therapeutic substance in Tibetan Medicine undergoes complex "detoxification" prior to inclusion in multi-ingredient formulas. In an initial cross-sectional study, patients taking Tibetan Medicine for various conditions were evaluated for mercury toxicity. Two groups were identified: Group 1, patients taking " Tsothel" the most important detoxified mercury preparation and Group 2, patients taking other mercury preparations or mercury free Tibetan Medicine. Atomic fluorescence spectrometry of Tibetan Medicine showed mercury consumption 130 µg/kg/day (Group 1) and 30 µg/kg/day (Group 2) ( P ≤ 0.001), levels above EPA (RfDs) suggested threshold (0.3 µg/kg /day) for oral chronic exposure. Mean duration of Tibetan Medicine treatment was 9 ± 17 months (range 3-116) (Group 1) and 5 ± 1.96 months (range 1-114) (Group 2) (NS) with cumulative days of mercury containing Tibetan Medicine, 764 days ± 1214 (range 135-7330) vs. 103 days ± 111 (range 0-426), respectively ( P ≤ 0.001). Comparison of treatment groups with healthy referents (Group 3) not taking Tibetan Medicine showed no significant differences in prevalence of 23 non-specific symptoms of mercury toxicity, abnormal neurological, cardiovascular and dental findings and no correlation with mercury exposure variables; consumption, cumulative treatment days, blood/ urine Hg. Liver and renal function tests in treatment groups were not significantly increased compared to referents, with mean urine Beta2 Microglobulin within the normal range and not significantly associated with Hg exposure variables after correcting for confounding variables. Neurocognitive testing showed no significant intergroup differences for Wechsler Memory Scale, Grooved Pegboard, Visual Retention, but Group1 scores were better for Mini-Mental, Brief Word Learning, Verbal Fluency after correcting for confounding variables. These results suggest mercury containing Tibetan Medicine does not have appreciable adverse effects and may exert a possible beneficial effect on neurocognitive function. Since evidence of mercury as a toxic heavy metal, however, is well known, further analysis of literature on mercury use in other Asian traditional systems is highly suggested prior to further studies.

Commentary on the abuse of metal chelation therapy in patients with autism spectrum disorders.

Approximately half a million patients with autism spectrum disorders are subjected to chelation therapy in the US annually. The overwhelming majority of such cases are chelated for non-accepted medical indications. These patients may seek evaluation when a urine sample is assayed after the administration of a chelating agent and the values obtained have been improperly compared to references ranges for non-chelated urines, causing falsely elevated results. Legitimate practitioners confronted with such data must decide, preferably in consultation with the patient or their guardian(s), whether to do further testing using legitimate methodology or to simply dismiss the results of the improper testing. Bayesian principles tell us that further testing is likely to yield results within normal reference ranges. However, under some circumstances, it is useful to do such testing in order to demonstrate that there is no need for chelation therapy. Unnecessary chelation therapy is expensive, can cause significant acute adverse effects, and may be associated with long-term consequences.

Modification of neurobehavioral effects of mercury by genetic polymorphisms of metallothionein in children.

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that genetic variants of metallothionein (MT) that are reported to affect Hg toxicokinetics in adults would modify the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the completion of the clinical trial, we performed genotyping assays for variants of MT isoforms MT1M (rs2270837) and MT2A (rs10636) on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant interactions or independent main effects for Hg exposure and either of the MT gene variants were observed. In contrast, among boys, numerous significant interaction effects between variants of MT1M and MT2A, alone and combined, with Hg exposure were observed spanning multiple domains of neurobehavioral function. All dose-response associations between Hg exposure and test performance were restricted to boys and were in the direction of impaired performance. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with relatively common genetic variants of MT, and may have important public health implications for future strategies aimed at protecting children and adolescents from the potential health risks associated with Hg exposure. We note that because urinary Hg reflects a composite exposure index that cannot be attributed to a specific source, these findings do not support an association between Hg in dental amalgams specifically and the adverse neurobehavioral outcomes observed.

Low-level mercury exposure and peripheral nerve function.

BACKGROUND: Mercury is known to be neurotoxic at high levels. There have been few studies of potential peripheral neurotoxicity among persons with exposure to elemental mercury at or near background levels. OBJECTIVES: The present study sought to examine the association between urinary mercury concentration and peripheral nerve function as assessed by sensory nerve conduction studies in a large group of dental professionals. METHODS: From 1997 through 2006 urine mercury measurements and sensory nerve conduction of the median and ulnar nerves in the dominant hand were performed, and questionnaires were completed, on the same day in a convenience sample of dental professionals who attended annual conventions of the American Dental Association. Linear regression models, including repeated measures models, were used to assess the association of urine mercury with measured nerve function. RESULTS: 3594 observations from 2656 subjects were available for analyses. Urine mercury levels in our study population were higher than, but substantially overlap with, the general population. The only stable significant positive association involved median (not ulnar) sensory peak latency, and only for the model that was based on initial observations and exclusion of subjects with imputed BMI. The present study found no significant association between median or ulnar amplitudes and urine mercury concentration. CONCLUSIONS: At levels of urine mercury that overlap with the general population we found no consistent effect of urine mercury concentration on objectively measured sensory nerve function.

An investigation of modifying effects of single nucleotide polymorphisms in metabolism-related genes on the relationship between peripheral nerve function and mercury levels in urine and hair.

Mercury (Hg) is a potent neurotoxicant. We hypothesized that single nucleotide polymorphisms (SNPs) in genes coding glutathione-related proteins, selenoproteins and metallothioneins may modify the relationship of mercury biomarkers with changes in peripheral nerve function. Dental professionals (n=515) were recruited in 2009 and 2010. Sensory nerve function (onset latency, peak latency and amplitude) of the median, ulnar and sural nerves was recorded. Samples of urine, hair and DNA were collected. Covariates related to demographics, nerve function and elemental and methyl-mercury exposure were also collected. Subjects included 244 dentists (47.4%) and 269 non-dentists (52.2%; mostly dental hygienists and dental assistants). The mean mercury levels in urine (1.06 µg/L) and hair (0.51 µg/g) were not significantly different from the US general population (0.95 µg/L and 0.47 µg/g, respectively). In multivariate linear models predicting nerve function adjusting for covariates, only 3 out of a total of 504 models showed stable and statistically significant interaction of SNPs with mercury biomarkers. Overall, given the possibility of false positives, the results suggested little evidence of effect modification of the SNPs on the relationship between mercury biomarkers with peripheral nerve function at exposure levels that are relevant to the general US population.

Human mercury exposure associated with small-scale gold mining in Burkina Faso.

PURPOSE: In Burkina Faso, gold ore is one of the main sources of income for an important part of the active population. Artisan gold miners use mercury in the extraction, a toxic metal whose human health risks are well known. The aim of the present study was to assess mercury exposure as well as to understand the exposure determinants of gold miners in Burkinabe small-scale mines. METHODS: The examined gold miners' population on the different selected gold mining sites was composed by persons who were directly and indirectly related to gold mining activities. But measurement of urinary mercury was performed on workers most susceptible to be exposed to mercury. Thus, occupational exposure to mercury was evaluated among ninety-three workers belonging to eight different gold mining sites spread in six regions of Burkina Faso. Among others, work-related exposure determinants were taken into account for each person during urine sampling as for example amalgamating or heating mercury. All participants were medically examined by a local medical team in order to identify possible symptoms related to the toxic effect of mercury. RESULTS: Mercury levels were high, showing that 69% of the measurements exceeded the ACGIH (American Conference of Industrial Hygienists) biological exposure indice (BEI) of 35 µg per g of creatinine (µg/g-Cr) (prior to shift) while 16% even exceeded 350 µg/g-Cr. Basically, unspecific but also specific symptoms related to mercury toxicity could be underlined among the persons who were directly related to gold mining activities. Only one-third among the studied subpopulation reported about less than three symptoms possibly associated to mercury exposure and nearly half of them suffered from at least five of these symptoms. Ore washers were more involved in the direct handling of mercury while gold dealers in the final gold recovery activities. These differences may explain the overexposure observed in gold dealers and indicate that the refining process is the major source of exposure. CONCLUSIONS: This study attests that mercury exposure still is an issue of concern. North-South collaborations should encourage knowledge exchange between developing and developed countries, for a cleaner artisanal gold mining process and thus for reducing human health and environmental hazards due to mercury use.

Symptoms of intoxication in dentists associated with exposure to low levels of mercury.

The present study examined the effects of occupational exposure of a group of dentists to low levels of mercury. The study population consisted of 106 dentists and 94 general practitioners (referent group), from private and public clinics in Shiraz city. Subjects were requested to complete a questionnaire on demographic variables, suspicious symptoms of intoxication and work practices. Additionally, atmospheric and urinary concentrations of mercury were measured by Atomic Absorption Spectroscopy technique. The data were analysed by χ(2) test, independent sample t-test and multivariate logistic regression analysis, where applicable. Both groups were similar as far as most demographic and socioeconomic variables, but age and number of personal amalgam fillings, were concerned. Median of atmospheric concentration of mercury was found to be 3.35 µg/m(3). Likewise, the urinary concentration of mercury in dentists was estimated to be 3.16 µg/g creatinine. This value was significantly higher than that of the referent group. Similarly, analysis of the data revealed that neuropsychological, muscular, respiratory, cardiovascular and dermal symptoms were more prevalent in dentists. Our findings indicate that occupational exposure of dentists to mercury, even at low levels, is associated with a significant increase in the prevalence of symptoms of intoxication.

A biomarker of mercury body-burden correlated with diagnostic domain specific clinical symptoms of autism spectrum disorder.

The study purpose was to compare the quantitative results from tests for urinary porphyrins, where some of these porphyrins are known biomarkers of heavy metal toxicity, to the independent assessments from a recognized quantitative measurement, the Autism Treatment Evaluation Checklist (ATEC), of specific domains of autistic disorders symptoms (Speech/Language, Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) in a group of children having a clinical diagnosis of autism spectrum disorder (ASD). After a Childhood Autism Rating Scale (CARS) evaluation to assess the development of each child in this study and aid in confirming their classification, and an ATEC was completed by a parent, a urinary porphyrin profile sample was collected and sent out for blinded analysis. Urinary porphyrins from twenty-four children, 2-13 years of age, diagnosed with autism or PDD-NOS were compared to their ATEC scores as well as their scores in the specific domains (Speech/Language, Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) assessed by ATEC. Their urinary porphyrin samples were evaluated at Laboratoire Philippe Auguste (which is an ISO-approved clinical laboratory). The results of the study indicated that the participants' overall ATEC scores and their scores on each of the ATEC subscales (Speech/Language, Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) were linearly related to urinary porphyrins associated with mercury toxicity. The results show an association between the apparent level of mercury toxicity as measured by recognized urinary porphyrin biomarkers of mercury toxicity and the magnitude of the specific hallmark features of autism as assessed by ATEC.

[Is there a link between the mercury release of amalgam fillings and the results of psychological questionnaires?]. / Gibt es Zusammenhänge zwischen der Quecksilberbelastung durch Amalgamfüllungen und Ergebnissen testpsychoIogischer Fragebogen-Untersuchungen?

Amalgam as a dental filling material shows excellent material property. It is fast, easy and economical to implement. Evidence for the release of mercury (Hg) from amalgam fillings was given in a number of studies. Mercury release from amalgam dental fillings is often claimed to be a possible cause of unspecific chronic symptoms such as chronic fatigue, headache and migraine. The present study explored relationships between the mercury release from amalgam fillings and the results of psychological questionnaires. The urine of 126 men and women in the age range of 16 to 76 years was examined. 45 participants did not present any amalgam restorations. The mercury released into the urine was measured by using cold-vapour AAS. The results of the study show that chronic mercury exposure, in the low concentration range, is not linked with chronic subjective symptoms.

Mercury as a serious health hazard for children in gold mining areas.

In many developing countries, mercury is used to extract gold from ore in small-scale mining areas. Exposure through mercury in these small-scale mining communities is a serious health hazard, especially to the children living and working there. Many children begin working with immediate contact to mercury from the very early age of seven. In Indonesia and Zimbabwe, 166 children were clinically examined for mercury. The mercury concentration in the blood, urine, and hair was analyzed. Compared to the control groups, the exposed children showed typical symptoms of mercury intoxication, such as ataxia. The children working with mercury had high levels of this substance in the various biomonitors. The exposure derives mainly from the liquid mercury used to bind gold, forming an amalgam. The amalgam is heated and the smelting amalgam releases mercury vapor plus the wanted gold. Mercury vapor in contrast to liquid mercury is highly toxic. This elemental, vaporized mercury is the main form of exposure. Since in over 50 countries children live in small-scale gold mining areas and are exposed in a similar way to mercury, immediate action is needed to reduce this severe chemical health hazard for children. Child labor with hazardous substances such as mercury must be stopped.

Biomarkers of exposure and effect as indicators of the interference of selenomethionine on methylmercury toxicity.

The present study was conducted to clarify the interference of selenomethionine (SeMet) on methylmercury (MeHg) toxicity through the evaluation of changes in biomarkers of exposure and effect in rats exposed to MeHg and co-exposed to MeHg and SeMet. Male Wistar rats received two intraperitoneally (i.p.) administrations, either MeHg (1.5mg/kg body weight), SeMet alone (1mg/kg body weight) or combined MeHg and SeMet, followed by 3 weeks of rat urine collection and neurobehavioural assays. The effects of different administrations were investigated by the quantification of total mercury in kidney and brain, analysis of urinary porphyrins, determination of hepatic GSH and evaluation of motor activity functions (rearing and ambulation). MeHg exposure resulted in a significant increase of urinary porphyrins during the 3 weeks of rat urine collection, where as it caused a significant decrease in motor activity only at the first day after cessation of rat exposure. Additionally, SeMet co-exposure was able to normalize the porphyrins excretion, and a tendency to restore rat motor activity was observed, on the first day after cessation of exposure. Brain and kidney mercury levels increased significantly in rats exposed to MeHg; however, in co-exposed rats to SeMet no significant changes in Hg levels were found as compared to rats exposed to MeHg alone. Hence, the present study shows that urinary porphyrins are sensitive and persistent indicators of MeHg toxicity and demonstrates for the first time that SeMet reduces its formation. Finally, these results confirm that the mechanism of interaction between SeMet and MeHg cannot be explained by the reduction of Hg levels in target organs and suggestions are made to clarify the interference of SeMet on MeHg toxicity.

Neurocognitive screening of mercury-exposed children of Andean gold miners.

Performance on Raven's Coloured Progressive Matrices (RCPM) test of visual-spatial reasoning was used to evaluate the effects of mercury (Hg) exposure on 73 Andean children aged 5 to 11 years (mean: 8.4) living in the Nambija and Portovelo gold mining areas of Ecuador, where Hg is widely used in amalgamation. Mean levels of Hg found in blood (Hg(B)), urine (Hg(U)), and hair (Hg(H)) samples were 5.1 microg/L (SD: 2.4; range: 1-10 microg/L), 13.3 microg/L (SD: 25.9; range: 1-166 microg/L), and 8.5 microg/g (SD: 22.8; range: 1-135 microg/g), respectively. Of the children in the Nambija area 67-84.9% had abnormal RCPM standard scores (i.e., < or = 25%tile), depending on the test norm used in the data analysis. Higher standard scores for Peruvian (t = 4.77; p = < 0.0001) and Puerto Rican (t = 4.51; p = < 0.0001) norms than for U.S. norms suggested a linguistic influence. No difference was found between Peruvian and Puerto Rican norms (t = 0.832; p = < 0.408), which showed a significant positive correlation (r = 0.915, p = < 0.0001). Children with abnormal Hg(B) and Hg(H) levels had significantly lower scores on the RCPM subtest B than did children with nontoxic Hg levels (t = -2.16; p = < 0.034). These results suggest that a substantial number of Hg-exposed children in the Nambija study area have neurocognitive deficits in visual-spatial reasoning.

Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through fish consumption.

In order to assess early neurotoxic effects associated with relatively low levels of mercury absorbed through fish eating, two groups of 22 adult male subjects, habitual consumers of tuna fish, and 22 controls were examined using a cross-sectional field study. The assessment included neurobehavioral tests of vigilance and psychomotor function, hand tremor measurements and serum prolactin assessment. Mercury in urine (U-Hg) and serum prolactin (sPRL) were measured in all exposed subjects and controls, whereas measurements of the organic component of mercury in blood (O-Hg) were available for only 10 exposed and six controls. U-Hg was significant higher among exposed subjects (median 6.5 microg/g of creatinine, range 1.8-21.5) than controls (median 1.5 microg/g of creatinine, range 0.5-5.3). The median values of O-Hg were 41.5 microg/l among the tuna fish eaters and 2.6 microg/l in the control group. Both U-Hg and O-Hg were significantly correlated with the quantity of fish consumed per week. Significant differences in sPRL were found between exposed (12.6 ng/ml) and controls (9.1 ng/ml). Individual sPRL were significantly correlated with both U-Hg and O-Hg levels. The neurobehavioral performance of subjects who consumed tuna fish regularly was significantly worse on color word reaction time, digit symbol reaction time and finger tapping speed (FT). After considering the education level and other covariates, the multiple stepwise regression analysis indicated that O-Hg concentration was most significantly associated with individual performance on these tests, accounting for about 65% of the variance in test scores.