[Responses to "A Review of the Book 'Minamata Disease and the Responsibility of Medical Authorities'"].

Drs. Futatsuka, Eto, and Uchino expressed their opinions in the Journal of the Japanese Society for Hygiene in the form of a review of my book, "Minamata Disease and the Responsibility of Medicine." (The reviewers translated it as "Responsibility of Medical Authorities," but for my purposes in writing this book, I believe it should be translated as "Responsibility of Medicine.") The nine major comments of the three reviewers described in this book review were reviewed from the basic perspective of toxicology, epidemiology, and neuroscience. This book review is fraught with either medical, logical, or ethical problems in all the nine points as follows: (1) the inadequate way in which exposure and health hazards are considered from the toxicological perspective, (2) problems in interpreting epidemiological information, (3) the failure to consider recent achievements in methylmercury toxicosis studies, (4) presenting the reviewers' own theories without regard to the content of my book while calling it a "book review," (5) presenting and criticizing what Takaoka does not claim as if he does, and (6) making claims that are inconsistent with the three reviewers' own views. The problems with this book review will become even clearer when you read "Minamata Disease and the Responsibility of Medicine" itself.

Hypoalgesia and recovery in methylmercury-exposed rats.

Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory impairment in the four extremities; however, the sensitivity of individual sensory modalities to MeHg has not been investigated extensively. In the present study, we performed stimulus-response behavioral experiments in MeHg-exposed rats to compare the sensitivities to pain, heat, cold, and mechanical sensations. MeHg (6.7 mg/kg/day) was orally administered to 9-week-old Wistar rats for 5 days and discontinued for 2 days, then administered daily for another 5 days. The four behavioral experiments were performed daily on each rat from the beginning of MeHg treatment for 68 days. The pain sensation decreased significantly from day 11 onwards, but recovered to control levels on day 48. Other sensory modalities were not affected by MeHg exposure. These findings suggest that the pain sensation is the sensory modality most susceptive to MeHg toxicity and that this sensitivity is reversible following discontinuation of the exposure.

Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia.

We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.

Human neurotoxicity of mercury in the Amazon: A scoping review with insights and critical considerations.

Human exposure to mercury is a major public health concern, causing neurological outcomes such as motor and visual impairment and learning disabilities. Currently, human exposure in the Amazon is among the highest in the world. A recent systematic review (doi:10.1016/j.jtemb.2018.12.001), however, highlighted the lack of high-quality studies on mercury-associated neurotoxicity. There is, therefore, a need to improve research and much to still learn about how exposure correlates with disease. In this review, we discuss studies evaluating the associations between neurological disturbances and mercury body burden in Amazonian populations, to generate recommendations for future studies. A systematic search was performed during July 2020, in Pubmed/Medline, SCOPUS and SCIELO databases with the terms (mercury*) and (Amazon*). Four inclusion criteria were used: original article (1), with Amazonian populations (2), quantifying exposure (mercury levels) (3), and evaluating neurological outcomes (4). The extracted data included characteristics (as year or origin of authorship) and details of the research (as locations and type of participants or mercury levels and neurological assessments). Thirty-four studies, most concentrated within three main river basins (Tapajós, Tocantins, and Madeira) and related to environmental exposure, were found. Mercury body burden was two to ten times higher than recommended and main neurological findings were cognitive, vision, motor, somatosensory and emotional deficits. Important insights are described that support novel approaches to researching mercury exposure and intoxication, as well as prevention and intervention strategies. As a signatory country to the Minamata Convention, Brazil has the opportunity to play a central role in improving human health and leading the research on mercury intoxication.

A scoping review of sources of mercury and its health effects among Pakistan's most vulnerable population.

Mercury and methyl mercury are poisonous to human body. In the recent times, exposure to mercury has been anthropogenic in nature. Within the past several decades, many incidences of mercury poisoning have been documented in several countries including Pakistan. Mercury has been ingested where it has been used to preserve crops, through the point and non-point source discharge into the surface water, and consequently entering the food chain. We conducted this scoping review of mercury and its health effects in Pakistan in order to raise the flag to a silent ongoing Minamata disease in the country. We conducted a systematic search of the available literature in Google Scholar, PubMed, and grey literature of unpublished theses and reports of various universities across the country. We found that in the northern Pakistan, suspended sediments were the major pathway of the riverine mercury transport. Sediments of Hunza and Gilgit River were found high in mercury concentrations. Gold mining leads to an increase in mercury concentration in soil and river waters flowing in this region. High concentrations up to 108 ng/L were found in Shimsal River. It is suspected that that high level of mercury transport may be leading to accumulation of mercury in major water bodies and lakes downstream. Occupational exposure to mercury and other heavy metals is common in an unregulated private sector of the country. Goldsmiths burn the amalgamated gold without personal protective measures. Direct exposure to the fumes of mercury leads to respiratory, dermatological, systemic and neurological ailments specific to mercury poisoning. We found good evidence of bioaccumulation of mercury in fish and fish products in Pakistan. The untreated waste water discharge is responsible to not only afflicted the fish but also the birds which feed on this fish. Further, the same untreated waste water from factories and agriculture runoffs affect vegetables grown in it. Studies looking at the biomarkers for mercury in humans have shown increased and even toxic levels of mercury among the most vulnerable populations of the country. Other sources of mercury exposure included mercury in traditional medicines and cigarette products. Though no evidence was found for its presence in drinking water, its existence in the food chain and occupational exposure pose great threat to the humans as well as animals.

Developmental exposure to methylmercury and resultant muscle mercury accumulation and adult motor deficits in mice.

Developmental methylmercury (MeHg) exposure can have lasting consequences on neural development and motor function across the lifespan. Recent evidence for MeHg targeting of myogenic pathways has drawn attention to the possibility that developing skeletal muscle plays a role in the motor deficits stemming from early life MeHg exposure. In this study we examined a potential role for muscle in influencing MeHg developmental toxicity in offspring of female mice exposed to MeHg via drinking water. Dams had access to 0, 0.5 or 5.0 ppm MeHg chloride in drinking water from two weeks prior to mating through weaning. Blood, brain and muscle tissue was harvested from dams at weaning and pups at postnatal days (PND) 6, 21 and 60 for analysis of total Hg. Muscle tissue sections were examined with histological stains. Behavioral testing of offspring was conducted at PND 60 and included locomotor activity, inverted screen, grip strength and rotarod tests to assess motor function. Total Hg (tHg) levels in dam muscles at weaning were 1.7-3-fold higher than Hg levels in blood or brain. In PND6 male and female pups, muscle and brain tHg levels were 2 to 4-fold higher than blood tHg. Brain tHg levels decreased more rapidly than muscle tHg levels between PND 6 and 21. Premised on modeling of growth dilution, brain tissue demonstrated an elimination of tHg while muscle tissue exhibited a net uptake of tHg between PND 6 and 21. Despite overall elevated Hg levels in developing muscle, no gross morphological or cytological phenotypes were observed in muscle at PND 60. At the higher MeHg dose, grip strength was reduced in both females and males at PND 60, whereas only male specific deficits were observed in locomotor activity and inverted screen tests with marginally significant deficits on rotarod. These findings highlight a potential role for developing skeletal muscle in mediating the neuromuscular insult of early life MeHg exposure.

Neuropsychological Effects of Mercury Exposure in Children and Adolescents of the Amazon Region, Brazil.

BACKGROUND: Studies with children exposed to methylmercury (MeHg) through fish consumption in the Brazilian Amazon region report that the high levels of hair Hg are associated with significant decreases in intelligence, memory, attention, and visuospatial processing. OBJECTIVE: To investigate the relationship between mercury exposure and neuropsychological functions in riverside communities of the Brazilian Amazon. METHOD: 263 participants aged 6 to 14 years old were assessed, from resettlement regions, near the Madeira river, Rondônia, Brazil. To assess the neuropsychological functions we used the following instruments: intelligence (WASI), working memory (Corsi Block-Tapping Task and Digit Span), verbal fluency (Word Generation - NEPSY II), inhibitory control (Inhibition Errors - NEPSY II), shifting (Trail Making Test) and manual motor dexterity (Grooved PegBoard Test). Socioeconomic status was obtained through household surveys. Total Hg levels were quantified hair samples (Total HgH) collected from the occipital region of the scalp and analyzed by Cold Vapor Atomic Absorption Spectrometry. RESULTS: The group in the upper quartile of Total HgH levels presented lower scores on the tasks that assessed estimated IQ, visuospatial working memory, semantic knowledge and phonological verbal fluency, when compared to the group in the lower quartile level. A regression analysis controlled for age, sex, and maternal education showed that for each increase of 10 µg/g of Total HgH, there was a decrease around half standard deviation in Verbal IQ, estimated IQ scores, semantic knowledge, phonological verbal fluency and for verbal and visuospatial working memory. CONCLUSIONS: High concentrations of Total Hg in hair were associated with a lower performance in neuropsychological functions tests. The results show that environmental exposure to Hg is associated to children and adolescents' lower neuropsychological performance in the riverine and resettled areas of the Brazilian Amazon region.

Oxidative Damage in Human Periodontal Ligament Fibroblast (hPLF) after Methylmercury Exposure.

Human exposure to mercury (Hg) is primary associated with its organic form, methylmercury (MeHg), through the ingestion of contaminated seafood. However, Hg contamination is also positively correlated with the number of dental restorations, total surface of amalgam, and organic mercury concentration in the saliva. Among the cells existing in the oral cavity, human periodontal ligament fibroblast (hPLF) cells are important cells responsible for the production of matrix and extracellular collagen, besides sustentation, renewal, repair, and tissue regeneration. In this way, the present study is aimed at investigating the potential oxidative effects caused by MeHg on hPLF. Firstly, we analyzed the cytotoxic effects of MeHg (general metabolism status, cell viability, and mercury accumulation) followed by the parameters related to oxidative stress (total antioxidant capacity, GSH levels, and DNA damage). Our results demonstrated that MeHg toxicity increased in accordance with the rise of MeHg concentration in the exposure solutions (1-7 µM) causing 100% of cell death at 7 µM MeHg exposure. The general metabolism status was firstly affected by 2 µM MeHg exposure (43.8 ± 1.7%), while a significant decrease of cell viability has arisen significantly only at 3 µM MeHg exposure (68.7 ± 1.4%). The ratio among these two analyses (named fold change) demonstrated viable hPLF with compromised cellular machinery along with the range of MeHg exposure. Subsequently, two distinct MeHg concentrations (0.3 and 3 µM) were chosen based on LC50 value (4.2 µM). hPLF exposed to these two MeHg concentrations showed an intracellular Hg accumulation as a linear-type saturation curve indicating that metal accumulated diffusively in the cells, typical for metal organic forms such as methyl. The levels of total GSH decreased 50% at exposure to 3 µM MeHg when compared to control. Finally, no alteration in the DNA integrity was observed at 0.3 µM MeHg exposure, but 3 µM MeHg caused significant damage. In conclusion, it was observed that MeHg exposure affected the general metabolism status of hPLF with no necessary decrease on the cell death. Additionally, although the oxidative imbalance in the hPLF was confirmed only at 3 µM MeHg through the increase of total GSH level and DNA damage, the lower concentration of MeHg used (0.3 µM) requires attention since the intracellular mercury accumulation may be toxic at chronic exposures.

[Mercury as a Global Pollutant and Mercury Exposure Assessment and Health Effects].

Mercury and its compounds are classified into three main groups: metallic mercury (Hg0), inorganic mercury (Hg2+), and organic mercury (methyl mercury: CH3Hg+, etc.). Metallic mercury is the only metal that is liquid at ambient temperature and normal pressure, which readily forms an amalgam with other metals. Therefore, mercury has long been used for refining various metals, and mercury amalgam has been used for dental treatment. Mercury has also been used in measuring instruments such as thermometers, barometers and blood pressure monitors, as well as electric appliances such as lighting equipment and dry batteries. Large amounts of metallic mercury are still used in other countries as a catalyst in the production of caustic soda by electrolysis. In addition, mercury compounds have been used in various chemicals such as mercurochrome, agricultural chemicals, and mildew-proofing agents. However, the use of mercury has also caused health problems for people. Minamata disease in Japan is a typical example. Also, since mercury is highly volatile, it is discharged as a product of industrial activities or derived from volcanoes, and it has been concluded on the basis of the findings of the United Nations Environment Program (UNEP) that it is circulating globally. Therefore, with the aim of establishing an internationally legally binding treaty for the regulation of mercury use to reduce risk, an intergovernmental negotiating committee was established in 2009. Japan actively contributed to this negotiation owing to its experience with Minamata disease, which led to the Convention on the regulation of mercury use being discharged as the "Minamata Convention on Mercury" and the treaty came into force on August 16, 2017. In this review, we introduce 1) the Global Mercury Assessment by UNEP; 2) mercury kinetics, exposure assessment and toxicity of different chemical forms; 3) large-scale epidemics of methylmercury poisoning; 4) methylmercury exposure assessment and health survey in whale-eating populations; 5) elemental mercury exposure assessment and health survey of mercury mine workers in China.

Hormesis of mercuric chloride-human serum albumin adduct on N9 microglial cells via the ERK/MAPKs and JAK/STAT3 signaling pathways.

Mercury chloride (HgCl2), a neurotoxicant that cannot penetrate the blood-brain barrier (BBB). Although when the BBB are got damaged by neurodegenerative disorders, the absorbed HgCl2, mainly in form of Hg (II)-serum albumin adduct (Hg-HSA) in human plasma, can penetrate BBB and affect central nervous system (CNS) cells. Current study planned to evaluate the effect of Hg-HSA on the physiological function of N9 microglial cells. At low dosage (15 ng/mL) of Hg-HAS, the observed outcomes was: promoted cell propagation, Nitric Oxide (NO) and intracellular Ca2+ levels enhancement, suppressed the release of TNF-α and IL-1ß and inhibited cell proliferation. At high dosage (15 µg/mL) we observed decline in NO and intracellular Ca2+ levels, and increment in the release of TNF-α and IL-1ß. These biphasic effects are similar to hormesis, and the hormesis, in this case, was executed through ERK/MAPKs and JAK/STAT3 signaling pathways. Study of quantum chemistry revealed that Hg2+ could form stable coordination structures in both Asp249 and Cys34 sites of HSA. Although five-coordination structure in Asp249 site is more stable than four-coordination structure in Cys34 site but four-coordination structure is formed easily in-vivo in consideration of binding-site position in spatial structure of HSA.

Determination of mercury in hair of children.

Although high or repeated exposure to different forms of Hg can have serious health consequences, the most important toxicity risk for humans is as methylmercury (MeHg) which exposure is mainly through consumption of fish. Generally, more than the 80% of Hg in hair is as MeHg, which is taken up by hair follicles as MeHg-cysteine complexes. In this context, hair samples were collected from 200 children (7 years) living in a coastal site in the North-East (A) of Italy and from 299 children (6-11 years) living in a urban area of South of Italy (B) to determine the levels of MeHg. Considering the neurotoxicity of MeHg, children were subjected to cognitive and neuropsychological tests. The hair values of Hg in the children population groups were comparable with data reported in other international surveys. On the other hand, combining results of the neurological tests with Hg levels, a possible relationship between Hg and an increase of the errors average reported in some neurological tests has been noted. Although the Hg levels were not elevated, a possible neurological influence in children, a population more susceptible than adults, might not be excluded, but the influence on neurological performances of the children could be also due to the family environment (socio economic status, educational level, etc.).

Methylmercury causes epigenetic suppression of the tyrosine hydroxylase gene in an in vitro neuronal differentiation model.

Methylmercury (MeHg) is the causative substance of Minamata disease, which is associated with various neurological disorders such as sensory disturbance and ataxia. It has been suggested low-level dietary intake of MeHg from MeHg-containing fish during gestation adversely affects the fetus. In our study, we investigated the toxicological effects of MeHg exposure on neuronal differentiation focusing on epigenetics. We used human fetal brain-derived immortalized cells (LUHMES cells) as a human neuronal differentiation model. Cell viability, neuronal, and catecholamine markers in LUHMES cells were assessed after exposure to MeHg (0-1000 nM) for 6 days (from day 2 to day 8 of neuronal differentiation). Cell viability on day 8 was not affected by exposure to 1 nM MeHg for 6 days. mRNA levels of AADC, DBH, TUJ1, and SYN1 also were unaffected by MeHg exposure. In contrast, levels of TH, the rate-limiting enzyme for dopamine synthesis, were significantly decreased after MeHg exposure. Acetylated histone H3, acetylated histone H3 lysine 9, and tri-methyl histone H3 lysine 9 levels at the TH gene promoter were not altered by MeHg exposure. However, tri-methylation of histone H3 lysine 27 levels, related to transcriptional repression, were significantly increased at the TH gene promotor after MeHg exposure. In summary, MeHg exposure during neuronal differentiation led to epigenetic changes that repressed TH gene expression. This study provides useful insights into the toxicological mechanisms underlying the effects of developmental MeHg exposure during neuronal differentiation.

Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity.

Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR). We found that 100 nM MeHg does not have any significant effect on GR activity alone, but the transactivation of gene expression by GR upon Dex (a synthetic GR agonist) administration was reduced in cells pre-treated with MeHg. Similar effects were found in transgenic zebrafish larvae expressing a GR reporter system (SR4G). Next we asked whether the effects of developmental exposure to MeHg are mediated by the effects on GR. Using a mutant zebrafish line carrying a loss-of-function mutation in the GR (grS357) we could show that the effects of developmental exposure to 2.5 nM MeHg are mitigated in absence of functional GR signaling. Taken together, our data indicate that inhibition of GR signaling may have a role in the developmental neurotoxic effects of MeHg.

Temporal trends of infant and birth outcomes in Minamata after severe methylmercury exposure.

Severe methylmercury poisoning occurred in Minamata and neighboring communities in Japan during the 1950s and 1960s, causing what is known as Minamata disease. Although an increase in stillbirths and a reduced male proportion at birth (i.e., reduced sex ratio) have been reported, no studies have evaluated the impact of exposure on an entire set of infant and birth outcomes. We therefore evaluated the temporal trends of these outcomes in the Minamata area from 1950 to 1974. We focused on the spontaneous/artificial stillbirth rate, crude fertility rate, male proportion at birth, male proportion among stillbirths, and infant mortality. We obtained the number of stillbirths, live births, and infant deaths in Minamata City and Kumamoto Prefecture (as a reference) from 1950 to 1974. After plotting annual figures for each outcome, we divided the study period into five intervals and compared them between Minamata City and Kumamoto Prefecture using the chi-squared test. We observed a slightly increased spontaneous stillbirth rate and decreased artificial stillbirth rate in Minamata City, followed by a reduced crude fertility rate. The crude fertility rates in Minamata City during the period 1955-1965 were significantly lower compared with those in Kumamoto Prefecture (p < 0.001). An increase in the male proportion among stillbirths was observed, corresponding to a reduction in the proportion of males at birth in the late 1950s. The impact on infant mortality was equivocal. These descriptive analyses demonstrate a severe regional impact of methylmercury exposure on a series of birth outcomes in the Minamata area.

Effects of Prenatal Methylmercury Exposure: From Minamata Disease to Environmental Health Studies.

Methylmercury, the causative agent of Minamata disease, can easily penetrate the brain, and adult-type Minamata disease patients showed neurological symptoms according to the brain regions where the neurons, mainly in the cerebrum and cerebellum, were damaged. In addition, fetuses are exposed to methylmercury via the placenta from maternal fish consumption, and high-level exposure to methylmercury causes damage to the brains of infants. Typical patients with fetal-type Minamata disease (i.e., serious poisoning caused by in utero exposure to methylmercury) were born during the period of severe methylmercury pollution in 1955-1959, although they showed no abnormality during gestation nor at delivery. However, they showed difficulties in head control, sitting, and walking, and showed disturbances in mental development, these symptoms that are similar to those of cerebral palsy, during the growth periods after birth. The impaired development of fetal-type Minamata disease patients was one of the most tragic and characteristic feature of Minamata disease. In this review, we first summarize 1) the effects of prenatal methylmercury exposure in Minamata disease. Then, we introduce the studies that were conducted mainly by Sakamoto et al. as follows: 2) a retrospective study on temporal and regional variations of methylmercury pollution in Minamata area using preserved umbilical cord methylmercury, 3) decline in male sex ratio observed in Minamata area, 4) characteristics of hand tremor and postural sway in fetal-type Minamata disease patients, 5) methylmercury transfer from mothers to infants during gestation and lactation (the role of placenta), 6) extrapolation studies using rat models on the effects of prenatal methylmercury exposure on the human brain, and 7) risks and benefits of fish consumption.

Methylmercury promotes prostacyclin release from cultured human brain microvascular endothelial cells via induction of cyclooxygenase-2 through activation of the EGFR-p38 MAPK pathway by inhibiting protein tyrosine phosphatase 1B activity.

Methylmercury is an environmental pollutant that exhibits neurotoxicity when ingested, primarily in the form of neuropathological lesions that localize along deep sulci and fissures, in addition to edematous and inflammatory changes in patient cerebrums. These conditions been known to give rise to a variety of ailments that have come to be collectively termed Minamata disease. Since prostaglandins I2 and E2 (PGI2 and PGE2) increase vascular permeability and contribute to the progression of inflammatory changes, we hypothesize that methylmercury induces the synthesis of these prostaglandins in brain microvascular endothelial cells and pericytes. To test this theory, human brain microvascular endothelial cells and pericytes were cultured and treated with methylmercury, after which the PGI2 and PGE2 released from endothelial cells and/or pericytes were quantified by enzyme-linked immunosorbent assay while protein and mRNA expressions in endothelial cells were analyzed by western blot analysis and real-time reverse transcription polymerase chain reaction, respectively. Experimental results indicate that methylmercury inhibits the activity of protein tyrosine phosphatase 1B, which in turn activates the epidermal growth factor receptor-p38 mitogen-activated protein kinase pathway that induces cyclooxygenase-2 expression. It was also found that the cyclic adenosine 3',5'-monophosphate pathway, which can be activated by PGI2 and PGE2, is involved in methylmercury-induced cyclooxygenase-2 expression. Since it appears that protein tyrosine phosphatase 1 B serves as a sensor protein for methylmercury in these mechanisms, it is our belief that the results of the present study may provide additional insights into the molecular mechanisms responsible for edematous and inflammatory changes in the cerebrum of patients with Minamata disease.

Secondary sex ratio in regions severely exposed to methylmercury "Minamata disease".

PURPOSE: Secondary sex ratio (i.e., male proportion at birth) is considered to function as a sentinel health indicator. Thus, examining this ratio spatially and temporally in regions with severe environmental exposure to compounds such as methylmercury may provide insight into the evolution of exposure. METHODS: We evaluated spatial and temporal distributions of the secondary sex ratio in Minamata, Japan, and neighboring areas, where severe methylmercury poisoning occurred in the 1950s and 1960s. We selected four areas exposed to methylmercury: Minamata, Ashikita, Goshonoura, and Izumi. After obtaining the number of live births, we conducted descriptive analyses by study area. RESULTS: We observed a reduction in male births in the exposed areas. In particular, a decline in the sex ratio of the Minamata area, where the first patient was officially identified in 1956, was seen around 1955. The ratio during 1955-1959 around Minamata was 0.496 [95% confidence interval (CI) 0.481-0.511]; the 95% CI did not include the value of 0.515 (the secondary sex ratio of the entire Japanese population during the study period). Declines in this ratio were also observed in other exposed areas around 1960, when acetaldehyde production (the origin of methylmercury) reached its peak. CONCLUSIONS: These analyses demonstrate that temporal and spatial distributions of the secondary sex ratio reflect the evolution of methylmercury exposure corresponding with the known history of Minamata disease.

Neuropsychological Effects of Mercury Exposure Among Dentists in Monastir City.

AIMS: The aim of this study is to assess the neuropsychological manifestations of mercury exposure in dentists. METHODS: A cross-sectional study was carried out including 64 dentists matched to a control group according to age and gender. This study protocol included a neurological evaluation, a questionnaire assessing the study groups' general characteristics and personal factors that may affect mercury urinary excretion in both groups. EUROQUEST questionnaire and Hospital Anxiety and Depression scale (HADS) were used to evaluate the neuropsychological symptoms reported during the last 12 months. In both groups, mercury impregnation was assessed by monitoring urinary mercury. RESULTS: In the exposed group, scores of neurological symptoms, memory disturbances and anxiety were found to be significantly higher than those in controls (p < 0.01). Mean scores of HAD Depression's scale were higher in the exposed group than in controls. Most of the neurotoxic manifestations were correlated to the levels of urinary mercury excretion in the exposed group. Mean levels of urinary mercury were significantly higher in the dentists group than in controls, with respective values of 21.1 ± 19.6 µg/g of creatinine and 0.05 ± 0.9 µg/g of creatinine. In nine dentists having urinary mercury levels higher than 35 µg/g of creatinine, neurological examination showed a bilateral and symmetric intentional tremor in both upper limbs. In the exposed group, the neuropsychological manifestations and levels of urinary mercury were found to be significantly correlated. CONCLUSION: Increased levels of urinary mercury observed in dentists suggest that exposure to mercury vapour emissions adversely affects dental professionals, therefore prevention measures should be strengthened, with a special medical supervision program of dentists exposed to mercury vapours should be implemented. We have also outlined some relevant patents in this article.

[Neurochemical parameters change in individuals exposed to mercury vapors].

Prospective cohort study covered individuals with preclinical and clinical stages, in early and remote periods of chronic mercurial intoxication and intact workers with length of service over 5 years. Tests included levels of serotonine, histamine, dophamine, norepinephrine, epinephrine and their metabolites (normetanephrine and metanephrine). Increased level of norepinephrine at clinical stage of mental sphere disorders was partially compensated by its transformation into normetanephrine and not associated with increase in its metabolites levels at early stage of chronic mercury intoxication. Remote period of the intoxication was characterized also by increased levels of dophamine, serotonine and histamine.