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Large numbers of individuals suffered severe neurological effects from poisoning with methyl mercury from the consumption of fish contaminated by industrial discharge in Minamata in the 1950s and 1960s and from bread made from fungicide-treated wheat in the early 1970s in Iraq. In both episodes, infants exposed in utero showed developmental delays. Data from Iraq permitted the estimation of dose-response relationships and provided evidence of greater sensitivity of the foetal brain compared to adult. Studies in a number of communities regularly consuming fish have sought to determine whether and at what level of prenatal exposure neurodevelopment defects may be detected, but the findings do not present a consistent picture. Benchmark analysis using data from Iraq and the three largest studies (New Zealand, Faroes, and Seychelles) suggest an overlap in estimated dose corresponding to a 10% increase in prevalence of adverse effects above background level. However, the Seychelles study, examining children up to 9 years of age, has not found a consistent pattern of adverse developmental effects; a possible explanation may be the presence of micronutrients in the ocean fish diet that enhance brain development and/or counter the toxic effects of methyl mercury.

This review examines the role of nutrients in child development and outlines the key nutrients identified as potentially important to neurodevelopment among high fish consumers in the Seychelles Child Development Nutrition Study (SCDNS). It describes the clinical assessment of these nutrients in the blood and breast milk samples collected from the cohort of 300 pregnant women who were recruited, at their first antenatal visit, on the SCDNS. These key nutrients include the long chain polyunsaturated fatty acids (LCPUFA), docosohexaenoic acid (DHA) and arachidonic acid (AA), both of which may affect neurodevelopment in the later stages of fetal growth. Only DHA, however, is strongly associated with fish consumption, the predominant source of the neurotoxicant methyl mercury (MeHg). Any benefits of increased selenium status on neurodevelopment are likely to accrue via detoxification of MeHg during fetal growth, while benefits of optimal iodine or thyroid status are likely to be directly related to neurodevelopment during late fetal growth. Unlike LCPUFA, Se, and I, the status of the B vitamins, folate, vitamin B12, vitamin B6, and riboflavin are unlikely to be closely related to fish consumption but the status of each of these B vitamins is likely to impinge on overall status of choline, which is expected to have direct effects on neurodevelopment both prenatally and postnatally and may also impact on MeHg toxicity. Choline status, together with the status of two other candidate nutrients, zinc and copper, which are also likely to have effects on neurodevelopment prenatally and postnatally, are expected to have some correlation with fish consumption.

ObjectiveTo assess the nutritional adequacy of Seychellois children in relation to nutrients reported to be important for cognitive development.DesignDietary intakes were assessed by 4 d weighed food diaries and analysed using dietary analysis software (WISP version 3·0; Tinuviel Software, UK). Individual nutrient intakes were adjusted to usual intakes and, in order to investigate adequacy, were compared with the UK Estimated Average Requirements for children aged 4–6 years.SettingChildren 5 years old were followed up as part of the Seychelles Child Development Nutrition Study (SCDNS), located in the high-fish-consuming population of Mahé, Republic of Seychelles.SubjectsAnalysis was carried out on a sample of 229 children (118 boys, 111 girls).ResultsChildren consumed a diet of which fortified cereal and milk products contributed the most to nutrient intakes. The majority (≥80 %) of children met requirements for several nutrients important for child development including Fe, folate and Se. Adjusted dietary intakes of Cu, Zn, iodine, niacin and vitamin A were below the Estimated Average Requirement or Recommended Nutrient Intake. Mean adjusted energy intakes (boys 4769 kJ/d (1139·84 kcal/d), girls 4759 kJ/d (1137·43 kcal/d)) were lower than the estimated energy requirement (boys 5104 kJ/d (1220 kcal/d), girls 5042 kJ/d (1205 kcal/d)) for 88 % of boys and 86 % of girls.ConclusionsNutrition was adequate for most children within the SCDNS cohort. Low intakes of some nutrients (including Zn, niacin and vitamin A) could reflect nutritional database inaccuracies, but may require further investigation. The study provides valuable information on the adequacy of intakes of nutrients which could affect the growth and development of Seychellois children.

Maternal consumption of fish during the gestational period exposes the fetus to both nutrients, especially the long-chain polyunsaturated fatty acids (LCPUFAs), believed to be beneficial for fetal brain development, as well as to the neurotoxicant methylmercury (MeHg). We recently reported that nutrients present in fish may modify MeHg neurotoxicity. Understanding the apparent interaction of MeHg exposure and nutrients present in fish is complicated by the limitations of modeling methods. In this study we fit varying coefficient function models to data from the Seychelles Child Development Nutrition Study (SCDNS) cohort to assess the association of dietary nutrients and children's development. This cohort of mother-child pairs in the Republic of Seychelles had fish consumption averaging 9 meals per week. Maternal nutritional status was assessed for five different nutritional components known to be present in fish (n-3 LCPUFA, n-6 LCPUFA, iron status, iodine status, and choline) and associated with children's neurological development. We also included prenatal MeHg exposure (measured in maternal hair). We examined two child neurodevelopmental outcomes (Bayley Scales Infant Development-II (BSID-II) Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI)), each administered at 9 and at 30 months. The varying coefficient models allow the possible interactions between each nutritional component and MeHg to be modeled as a smoothly varying function of MeHg as an effect modifier. Iron, iodine, choline, and n-6 LCPUFA had little or no observable modulation at different MeHg exposures. In contrast the n-3 LCPUFA docosahexaenoic acid (DHA) had beneficial effects on the BSID-II PDI that were reduced or absent at higher MeHg exposures. This study presents a useful modeling method that can be brought to bear on questions involving interactions between covariates, and illustrates the continuing importance of viewing fish consumption during pregnancy as a case of multiple exposures to nutrients and to MeHg. The results encourage more emphasis on a holistic view of the risks and benefits of fish consumption as it relates to infant development.

Background:Both folate and betaine are important predictors of total homocysteine (tHcy) during pregnancy. However, studies to date have only been undertaken in populations with Western dietary patterns. Objective: We investigated the predictors of tHcy in pregnant women recruited in the Seychelles, a population where access to fortifiedfoodsislimitedandwherewomenhabituallyconsumediets rich in fish, eggs, rice, and fruit. Design: Pregnant women (n 226) provided blood samples at enrollment,atweek28ofgestation,andatdelivery.Cordbloodwas obtained from a subset of participants (n 135). Results: As in other studies, maternal tHcy was lower during pregnancy than at delivery, whereas folate and vitamin B-12 status declinedsignificantlytodelivery.Despitelowmaternalfolatestatusat delivery (median: 9.0 nmol/L), with 35% of women in the deficient range(serumfolate:6.8nmol/L),cordbloodfolatestatus(median: 40.2 nmol/L) was similar to concentrations reported in Western populations. Folate was a significant predictor of tHcy at all time points (P 0.001). In contrast with previous studies, betaine was only a significant predictor of maternal tHcy (P 0.001) when the essential amino acid methionine was low. Conclusions: The current study reports 2 important findings. First, fetal requirements for folate are paramount, such that cord blood folate statusismaintained,evenwhenmaternalstatusislow.Second,betaine is a significant predictor of tHcy in pregnant women with low serum folate and low serum methionine concentrations. Am J Clin Nutr 2008;87:391–7.

Objective. The grafting of human scalp hair was used as a new application of this method to explore methyl mercury incorporation into human hair and to validate this model for mercury monitoring in hair. Methods. Human scalp grafts were transplanted to athymic BALB/c nude mice. The animals were exposed to methyl mercury either as a single dose i.p. or continuously for 4 months, using ALZET osmotic pumps. The mercury concentration in hair was determined using x-ray fluorescence (XRF) spectrometry by segmental (2 mm) analysis of a single strand, and tissue concentrations were measured by cold vapor atomic absorption analysis. Results. Human scalp hair grown in nude mice showed long-term persistence of human features including the expression of histocompatibility antigens (KAB 3, W 6/32, SF 1-1.1.1) and normal hair morphometry. The disposition of methyl mercury in nude mice followed a one-compartment model with a whole body elimination half-life of 6.7 days (elimination constant, k = 0.1/day). Autoradiographic studies revealed that methyl mercury was rapidly incorporated into areas of the hair follicle undergoing active keratinization. Methyl mercury concentrations in human hair transplanted onto nude mice were two orders of magnitude higher than in blood and attained a mean hair: blood ratio of 217 : 1, similar to ratios reported only in human studies. Conclusions. This study demonstrated that human hair grown on nude mice can record the level of exposure to methyl mercury and can serve as a valuable research tool to study mercury incorporation into human hair. Copyright © 2007 John Wiley & Sons, Ltd.

Several biological media have been used as indicators of the fetal body burden of methylmercury and the levels in the primary target tissue, the developing brain. These media include maternal hair and blood. The relative merits of these media will be considered both with regard to current knowledge of the physiology of mercury disposition in the body and also the practicality of field application with respect to sample, collection, transport, storage and processing.

Thimerosal, which releases the ethyl mercury radical as the active species, has been used as a preservative in many currently marketed vaccines throughout the world. Because of concerns that its toxicity could be similar to that of methyl mercury, it is no longer incorporated in many vaccines in the United States. There are reasons to believe, however, that the disposition and toxicity of ethyl mercury compounds, including thimerosal, may differ substantially from those of the methyl form. The current study sought to compare, in neonatal mice, the tissue concentrations, disposition and metabolism of thimerosal with that of methyl mercury. ICR mice were given single intramuscular injections of thimerosal or methyl mercury (1.4 mg Hg kg(-1)) on postnatal day 10 (PND 10). Tissue samples were collected daily on PND 11-14. Most analysed tissues demonstrated different patterns of tissue distribution and a different rate of mercury decomposition. The mean organic mercury in the brain and kidneys was significantly lower in mice treated with thimerosal than in the methyl mercury-treated group. In the brain, thimerosal-exposed mice showed a steady decrease of organic mercury levels following the initial peak, whereas in the methyl mercury-exposed mice, concentrations peaked on day 2 after exposure. In the kidneys, thimerosal-exposed mice retained significantly higher inorganic mercury levels than methyl mercury-treated mice. In the liver both organic and inorganic mercury concentrations were significantly higher in thimerosal-exposed mice than in the methyl mercury group. Ethyl mercury was incorporated into growing hair in a similar manner to methyl mercury. The data showing significant kinetic differences in tissue distribution and metabolism of mercury species challenge the assumption that ethyl mercury is toxicologically identical to methyl mercury.

Mercury is ubiquitous in the environment and therefore every human being, irrespective of age and location, is exposed to one form of mercury or another. The major source of environmental mercury is natural degassing of the earth's crust, but industrial activities can raise exposure to toxic levels directly or through the use or misuse of the liquid metals or synthesized mercurial compounds. The aim of this review is to survey differences in human exposure and in the toxicology of different forms of mercury. It covers not only symptoms and signs observed in poisoned individuals by a clinician but also subclinical effects in population studies, the final evaluation of which is the domain of statisticians.

Exposure to environmental mercury may be a factor that contributes to idiosyncratic autoimmune disease. Studies have demonstrated that inorganic, ionic mercury (i.e., Hg2+) modulates several lymphocyte signal transduction pathways, which may be a mechanism whereby Hg2+ dysregulates the immune response. The CD95/Fas apoptotic signaling pathway, which is of critical importance in regulating peripheral tolerance, is disrupted by low and environmentally relevant concentrations of Hg2+. Activation of the cysteine protease caspase-3 is a critical component of both CD95-mediated and TNF-alpha-induced apoptosis. The present work demonstrates that Hg2+ selectively disrupts death receptor mediated caspase-3 activation, where CD95-mediated caspase-3 activation is impaired in Hg2+ treated cells; whereas TNF-alpha-induced caspase-3 activation is not. Using the fluorogenic caspase-3 substrate, Ac-DEVD-7-amino-4-methyl coumarin, to measure caspase-3 enzyme activity as well as Western blotting to track processing of the caspase-3 proenzyme, we have considered the potential direct and indirect effects of Hg2+ on caspase-3. At relatively high concentrations and in a cell-free system, Hg2+ is capable of targeting the active site cysteinyl of caspase-3 resulting in enzyme inhibition. However, at more environmentally relevant exposures, Hg2+ does not gain access in appreciable quantities to the intracellular compartment where caspase-3 resides. Collectively, these data establish that Hg2+ impairs CD95-mediated apoptosis by targeting a plasma membrane proximal signaling event. By measuring the cellular Hg2+ content following various exposure conditions, we have determined that a cellular Hg2+ burden of approximately 50 ng/10(6) cells is sufficient to impair CD95-mediated caspase-3 activation. The present study furthers an understanding of the mechanism whereby relatively low and non-cytotoxic concentrations of Hg2+ may disrupt peripheral tolerance leading to sustained autoimmune disease.

Summary Introduction Exposure to methylmercury (MeHg) before birth can adversely affect children's neurodevelopment. The most common form of prenatal exposure is aternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. Methods We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The ssociation between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. Findings Mean prenatal MeHg exposure was 6·9 parts per million (SD 4·5ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure as associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conner's teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. Interpretation These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption.

The historical record of clinical cases of methyl mercury poisoning dates back to the 19th century when the first chemical synthesis occurred. The potent fungicidal properties of both methyl and the closely related ethyl mercury compound were subsequently discovered, which led to widespread agricultural application for prevention of fungal infection in seed grain. Several catastrophic outbreaks of poisoning occurred in the mid-20th century when the treated seed grain was mistakenly used to prepare homemade bread. The largest outbreak took place in rural Iraq in the early 1970s. Human poisonings also occurred in Japan due to the release of methyl mercury into bodies of fresh and ocean water. The most infamous outbreak occurred in the area of Minamata Bay: methyl mercury, which was unwittingly discharged into the ocean water, avidly accumulated in the aquatic food chain to such an extent that people who consumed fish were severely poisoned. Today, human exposure to methyl mercury occurs from consumption of fish and sea mammals. Inorganic mercury that is present in aquatic sediments is methylated by microorganisms and accumulates in the aquatic food chain. Although no cases of clinical poisoning have been reported, a number of epidemiological studies have been carried out that raise the possibility of prenatal damage. Previous studies (especially the Iraq outbreak) indicate that the prenatal stage of the life cycle is the most vulnerable. However, ongoing epidemiological studies of heavy fish consumers of the Seychelles Islands in the Indian Ocean do not reveal adverse effects. To the contrary, the results of some developmental tests that were conducted on prenatally exposed children indicate beneficial outcomes that correlate with mercury levels during pregnancy. This article discusses the potential role of micronutrients in fish as a plausible explanation for these findings.

This article discusses three examples of delay (latency) in the appearance of signs and symptoms of poisoning after exposure to methylmercury. First, a case is presented of a 150-day delay period before the clinical manifestations of brain damage after a single brief (

Mechanisms of methylmercury (MeHg) and inorganic mercury (Hg) uptake were examined in HepG2 cells, a human hepatoma-derived cell line. MeHg uptake was faster when it was present as the l -cysteine complex, as compared to the glutathione (GSH), CysGly, γ-GluCys, d -cysteine, N-acetylcysteine, l -penicillamine, or albumin complexes. Uptake of MeHg- l -cysteine was independent of Na+, stereoselective, and was inhibited by the amino acid transport system l substrates l -leucine, l -valine, and l -phenylalanine (5 mM). Moreover, [3H] l -leucine uptake was inhibited by MeHg- l -cysteine, suggesting that MeHg- l -cysteine is transported into HepG2 cells by an l -type amino acid carrier. Uptake of MeHg as the GSH complex (MeHg-SG) was dependent on the extracellular GSH concentration, and was diminished when cellular γ-glutamyl transpeptidase activity was inhibited. Inorganic mercury uptake was slower than that of MeHg, but was also sensitive to the type of thiol ligand present. These findings demonstrate that mercury uptake by HepG2 cells is dependent on the chemical structure of the mercury compound, the thiol ligand, and the activity of γ-glutamyl transpeptidase. γ-Glutamyl transpeptidase appears to play a key role in the disposition of MeHg-SG by facilitating the formation of MeHg- l -cysteine, which is readily transported into the cells on an amino acid-type carrier.

Methylmercury (MeHg) is a neurotoxicant whose high-dose effects first became known following a number of poisoning outbreaks that occurred worldwide. The primary human exposure is low dosage from fish consumption. Studies of fish-eating populations have not found a consistent pattern of association between exposures and outcomes. Therefore, examining specific areas of cognitive functioning has been suggested as an important approach to determine whether more subtle effects of MeHg exposure are present. In the Seychelles longitudinal study of prenatal and postnatal MeHg exposure from fish consumption and development, the McCarthy Scales of Children's Abilities (MSCA) were administered to children at age 66 months. No association between MeHg exposure and performance on the MSCA General Cognitive Index was identified. We analyzed these data further to determine whether associations were present on specific subscales of the MSCA. The standard MSCA subscales were analyzed. Then, more specific subscales of the MSCA were defined and analyzed utilizing a neuropsychological approach. The subscales were recombined to approximate the domains of cognitive functioning evaluated in the Faroes and New Zealand studies. Analyses of both the standard and the recombined MSCA subscales showed no adverse associations with MeHg exposure and neuropsychological endpoints. A positive association between postnatal MeHg exposure and performance on the MSCA Memory subscale was found. These findings are consistent with previous reports from the Seychelles study in that no adverse effects of MeHg exposure from fish consumption can be detected in this cohort.

Methylmercury is a neurotoxin at high exposures, and the developing fetus is particularly susceptible. Because exposure to methylmercury is primarily through fish, concern has been expressed that the consumption of fish by pregnant women could adversely affect their fetuses. The reference dose for methylmercury established by the U.S. Environmental Protection Agency was based on a benchmark analysis of data from a poisoning episode in Iraq in which mothers consumed seed grain treated with methylmercury during pregnancy. However, exposures in this study were short term and at much higher levels than those that result from fish consumption. In contrast, the Agency for Toxic Substances and Disease Registry (ATSDR) based its proposed minimal risk level on a no-observed-adverse-effect level (NOAEL) derived from neurologic testing of children in the Seychelles Islands, where fish is an important dietary staple. Because no adverse effects from mercury were seen in the Seychelles study, the ATSDR considered the mean exposure in the study to be a NOAEL. However, a mean exposure may not be a good indicator of a no-effect exposure level. To provide an alternative basis for deriving an appropriate human exposure level from the Seychelles study, we conducted a benchmark analysis on these data. Our analysis included responses from batteries of neurologic tests applied to children at 6, 19, 29, and 66 months of age. We also analyzed developmental milestones (age first walked and first talked). We explored a number of dose-response models, sets of covariates to include in the models, and definitions of background response. Our analysis also involved modeling responses expressed as both continuous and quantal data. The most reliable analyses were considered to be represented by 144 calculated lower statistical bounds on the benchmark dose (BMDLs; the lower statistical bound on maternal mercury hair level corresponding to an increase of 0.1 in the probability of an adverse response) derived from the modeling of continuous responses. The average value of the BMDL in these 144 analyses was 25 ppm mercury in maternal hair, with a range of 19 to 30 ppm. Images Figure 1

Controversy exists concerning the fetal risk associated with exposure to low-dose methylmercury from maternal fish consumption. Previous studies of the effects of acute prenatal mercury exposure identified delays in achieving developmental milestones among exposed children. This led to public health concern that prenatal low-dose exposure from fish consumption could adversely affect the fetus. We evaluated the effects of prenatal methylmercury exposure (through maternal fish consumption) on the age that children walked and first said words in the main study cohort of the Seychelles Child Development Study. We used semiparametric generalized additive models to identify nonlinearities in the relationships between prenatal exposure and developmental outcomes, after adjusting for covariates, and to evaluate their importance. Very slight delays (

Ingestion of fish or grain contaminated with methylmercury resulted in epidemics of severe neurotoxicity and death in Japan in the 1950s and 1960s1 and in Iraq in 1972.2 The World Health Organization and other organizations have warned of the dangers of methylmercury compounds to the environment and to scientific researchers.1,3–6 Dimethylmercury may be even more dangerous than methylmercury compounds. The physical properties of dimethylmercury permit transdermal absorption, and the volatility of this liquid permits toxic exposure through inhalation. Since dimethylmercury is lethal at a dose of approximately 400 mg of mercury (equivalent to a few drops, or about . . .

This article describes the health effects of the two principal forms of mercury to which humans are exposed, namely mercury vapor and methylmercury compounds. Mercury vapor is the monatomic gas that vaporizes from liquid metallic mercury. It has a long history of human exposure dating back to ancient times. The earliest life forms on this planet may have received substantial exposure and developed defense mechanisms that we inherit to this day. Severe forms of poisoning from inhalation of mercury vapor are now rare. More commonly observed in occupational exposures are subtle neurobehavioral effects and preclinical changes in biochemical markers of kidney function. Methylmercury compounds may also date back to Archean times. The methylation of inorganic mercury by methanogenic bacteria is believed to be a protective mechanism for these cells that appeared early in evolution. Unfortunately, for life forms dependent on a central nervous system, what is protective for simple cells becomes a threat to the more complex life forms. Today, the main source of human exposure is from methylation of inorganic mercury in bodies of fresh and ocean water, the ensuing bioaccumulation in the aquatic food chain, and the consumption of fish or sea mammals by humans. Methylmercury selectively damages the brain. In adult humans, damage is focal, affecting specific cell types in certain anatomical areas such as the visual cortex and the cerebellum. Prenatal exposure disrupts the normal developmental processes of the fetal brain. Indeed, the prenatal period is widely believed to be the most susceptible stage of the life cycle. At present, two large epidemiological studies are underway to determine human health risks from methylmercury in fish. J. Trace Elem. Exp. Med. 11:303–317, 1998. © 1998 Wiley-Liss, Inc.

The major physical forms of mercury to which humans are exposed are mercury vapor, Hg0, and methylmercury compounds, Ch3HgX. Mercury vapor emitted from both natural and anthropogenic sources is globally distributed in the atmosphere. It is returned as a water-soluble form in precipitation and finds its way into bodies of fresh and ocean water. Land run-off also accounts for further input into lakes and oceans. Inorganic mercury, present in water sediments, is subject to bacterial conversion to methylmercury compounds that are bioaccumulated in the aquatic food chain to reach the highest concentration in predatory fish. Human exposure to mercury vapor is from dental amalgam and industries using mercury. Methylmercury compounds are found exclusively in seafood and freshwater fish. The health effects of mercury vapor have been known since ancient times. Severe exposure results in a triad of symptoms, erethism, tremor, and gingivitis. Today, we are concerned with more subtle effects such as preclinical changes in kidney function and behavioral and cognitive changes associated with effects on the central nervous system. Methylmercury is a neurological poison affecting primarily brain tissue. In adults, brain damage is focal affecting the function of such areas as the cerebellum (ataxia) and the visual cortex (constricted visual fields). Methylmercury also at high doses can cause severe damage to the developing brain. Today the chief concern is with the more subtle effects arising from prenatal exposure such as delayed development and cognitive changes in children.

To reach its target tissue, methylmercury must traverse brain capillary endothelial cells, the site of the blood-brain barrier. Methylmercury uptake from blood plasma into these cells is mediated in part by an amino acid carrier that transports the methylmercury-L-cysteine complex; however, the mechanism by which it is released from the endothelial cells into brain interstitial space is unknown. Using bovine brain capillary endothelial cells in culture, the present study examined the hypothesis that methylmercury is transported out of these cells as a glutathione (GSH) complex. GSH concentration in cultured bovine brain capillary endothelial cells was 13.1 +/- 3.3 nmol/mg protein. Depletion of intracellular GSH in [203Hg]methylmercury-preloaded cells by exposure to 1-chloro-2,4-dinitrobenzene or diethyl maleate decreased the rate of [203Hg]methylmercury efflux. Incubation of [203Hg]methylmercury-preloaded cells with high concentrations of S-methylglutathione, S-ethylglutathione, S-butylglutathione, and sulfobromophthalein-glutathione inhibited [203Hg]methylmercury efflux. The GSH analogs gamma-glutamylglycylglycine and ophthalmic acid also inhibited [203Hg]methylmercury efflux, but to a lesser degree than the glutathione S-conjugates, whereas L-leucine, L-methionine, and L-alanine had no effect. Efflux was not affected by depletion of intracellular ATP with 2-deoxyglucose or antimycin A. These results indicate that complexation with GSH and subsequent transport of the complex by an ATP-independent mechanism may be involved in the transport of methylmercury out of brain capillary endothelial cells.

In order to establish guidelines for exposure of astronauts to iodine, used as a water disinfectant in space, we studied the usefulness of hair, saliva, and urine for biological monitoring in humans and in the human hair/nude mouse model. The monitoring of iodine in patients that received 150 mCi of Na131I (carrier-free) showed similar patterns of elimination for blood, saliva, and urine. The mean correlation coefficient (r) between iodine elimination for blood/saliva was 0.99, for blood/urine, 0.95, and for saliva/urine, 0.97. The absolute value of iodine concentrations in urine revealed marked variability, which was corrected by adjusting for creatinine levels. The autoradiographic studies of human hair demonstrated that iodine is rapidly incorporated into external layers of the hair root and can be removed easily during washing. These data were confirmed after iodine exposure using the human hair/nude mouse model. Hair does not provide satisfactory information about exposure due to unstable incorporation of iodine. The most useful medium for biological monitoring of astronauts exposed to high doses of iodine in drinking water is urine, when adjusted for creatinine, and saliva, if quantitative evaluation of flow rate is provided. Images Figure 1. Figure 2. Figure 3. Figure 4.

Both terrestrial and aquatic food chains are capable of accumulating certain environmental contaminants to toxic concentrations. This article focuses on the aquatic food chain because we have less control over contaminant entry into this chain than we have for the terrestrial chain. In general, at least three special properties are required for a contaminant to bioaccumulate in an aquatic food chain: 1) a high octanol-water partition coefficient, 2) chemical and metabolic stability in water and in organisms in the food chain, and 3) a low toxicity to organisms in the chain so that the chain is not broken by loss of an intermediate species. Few of the thousands of chemicals produced by human industry meet these requirements. In terms of organic chemicals, the best known examples of bioaccumulation in aquatic food chains are the polychlorinated biphenyls (PCBs), dioxins, and organochlorine pesticides such as dichlorodiphenyltrichloroethane (DDT). Few examples exist of bioaccumulation of metal compounds. Methylmercury is arguably the most dramatic and best documented example of high bioaccumulation.

Metals have been mined and used since ancient times. The industrial era has seen a sharp increase in both the amounts and variety of metals that find applications in industry. The inadvertent release of metals, such as from fossil fuel consumption, also adds to the global burden. A number of catastrophic outbreaks have alerted us to the occupational and environmental health risks. Life on this planet has evolved in the presence of metals. Cells learned to make use of the more abundant metals in the Archean oceans as an integral component in their structure and function. Today, we inherit these as the essential metals. At the same time, evolving life must have developed means of coping with the potentially toxic actions of metals. The appearance of oxygen in the atmosphere in the Precambrian period also resulted in cells both using and developing protective mechanisms against what must have been a highly toxic, reactive gas. Atmospheric oxygen must have increased the solubility of many metals as insoluble metal sulfides were oxidized to the more soluble sulfates. It may be no coincidence that the protective mechanisms for oxygen are also used to protect against a number of toxic metals. Selected examples are given on the role of evolution in metal toxicology, specifically, examples where the normal function of essential metals is deranged by competition with nonessential metals. Examples are also given of protective mechanisms that involve enzymes or cofactors involved in the oxygen defense system.

Rat pheochromocytoma PC12 cell sublines with increasing resistance to methylmercury (MeHg) were isolated by exposure to MeHg in two sequential steps. The strongest resistance (PC12/TM) among the clones obtained by the first cloning was characterized. PC12/TM cells exhibited about an 8- to 10-fold increase in resistance compared with parent PC12 cells on the bases of the concentration required for 50% inhibition of growth and colony-forming activity. PC12/TM cells accumulated smaller amounts of MeHg (one-half to one-fifth) than parent PC12 cells. This reduced MeHg accumulation in PC12/TM cells resulted from the slow uptake and rapid efflux. A close correlation between reduced MeHg accumulation and MeHg resistance was found among seven sublines of PC12 cells with different sensitivity to MeHg. The reduced retention of MeHg in PC12 sublines was also well correlated with the sensitivity to MeHg. Phenol-3,6-dibromophthalein disulfonate inhibited MeHg efflux from PC12/TM cells and increased its accumulation. These results suggest that efflux of MeHg from PC12/TM cells is associated with glutathione.

In the past, methylmercury compounds were manufactured as fungicides or appeared as unwanted byproducts of the chemical industry, but today the methylation of inorganic mercury in aquatic sediments and soils is the predominant if not the sole source of methylmercury. This form of mercury is bioaccumulated to a high degree in aquatic food chains to attain its highest concentrations in edible tissues in long-lived predatory fish living in both fresh and ocean waters. It is well absorbed from the diet and distributes within a few days to all tissues in the body. It crosses without hindrance the blood-brain and placental barriers to reach its principal target tissue, the brain. It is eliminated chiefly in the feces after conversion to inorganic mercury. The biological half-time of methylmercury in human tissues is about 50 days, but there is wide individual variation. Adult poisoning is characterized by focal damage to discrete anatomical areas of the brain such as the visual cortex and granule layer of the cerebellum. A latent period of weeks or months may ensue before the appearance of signs and symptoms of poisoning. The latter manifest themselves as paresthesia, ataxia, constriction of the visual fields, and hearing loss. The prenatal period is the most sensitive stage of the life cycle to methylmercury. Prenatally poisoned infants exhibit a range of effects from severe cerebral palsy to subtle developmental delays. Methylmercury is believed to inhibit those processes in the brain specially involved in development and growth such as neuronal cell division and migration.

Methylmercury is among the most potentially toxic species to which human populations are exposed, both at high levels through poisonings and at lower levels through consumption of fish and other seafood. However, the molecular mechanisms of methylmercury toxicity in humans remain poorly understood. We used synchrotron X-ray absorption spectroscopy (XAS) to study mercury chemical forms in human brain tissue. Individuals poisoned with high levels of methylmercury species showed elevated cortical selenium with significant proportions of nanoparticulate mercuric selenide plus some inorganic mercury and methylmercury bound to organic sulfur. Individuals with a lifetime of high fish consumption showed much lower levels of mercuric selenide and methylmercury cysteineate. Mercury exposure did not perturb organic selenium levels. These results elucidate a key detoxification pathway in the central nervous system and provide new insights into the appropriate methods for biological monitoring.

Umbilical cord blood from 1,023 consecutive births in the Faroe Islands showed a median blood-mercury concentration of 121 nmol/l (24.2 micrograms/l); 250 of those samples (25.1%) had blood-mercury concentrations that exceeded 200 nmol/l (40 micrograms/l). Maternal hair mercury concentrations showed a median of 22.5 nmol/g (4.5 micrograms/g), and 130 samples (12.7%) contained concentrations that exceeded 50 nmol/g (10 micrograms/g). Frequent ingestion of whale meat dinners during pregnancy and, to a much lesser degree, frequent consumption of fish, and increased parity or age were associated with high mercury concentrations in cord blood and hair. Blood-mercury levels were slightly lower if the mother had occasionally ingested alcoholic beverages. Mercury in blood correlated moderately with blood selenium (median, 1.40 mumol/l). Increased selenium concentrations were associated with intake of whale meat, alcohol abstention, delivery after term, and high parity. Lead in cord blood was low (median, 82 nmol/l), particularly if the mothers had frequently had fish for dinner and had abstained from smoking.

The mechanism by which methylmercury (MeHg) crosses the blood-brain barrier was examined in the rat. Previous studies demonstrated that intravenous injection of L-cysteine with MeHg accelerates MeHg uptake into brain. Since the complex of MeHg with L-cysteine is structurally similar to L-methionine, a substrate for the L (leucine-preferring) amino acid transport system, this carrier may be involved in MeHg uptake. To examine this hypothesis, the rapid carotid infusion technique was used in the anesthetized rat. The concentration dependence of 203Hg uptake into brain after injection of Me203Hg-L-cysteine complex was nonlinear, exhibiting characteristics of saturable transport (apparent Michaelis constant 0.39 mM, vmax 33 nmol.min-1.g-1). A slower, nonsaturable uptake was seen after MeHg-L-cysteine uptake was inhibited by methionine and the amino acid analogue 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), an L system substrate, but not by alpha-methylaminoisobutyric acid, an alanine-preferring system substrate. Furthermore, L-[14C]methionine transport was inhibited by MeHg-L-cysteine but not by MeHgCl. There was a significant amount of uptake of 203Hg when injected as Me203Hg-glutathione, and this was inhibited by L-methionine and BCH but not D-methionine. S-ethylglutathione also inhibited 203Hg uptake after administration as Me203Hg-glutathione but had no effect on Me203Hg-L-cysteine uptake. These results suggest that MeHg may enter the brain as a cysteine complex via the L system and that plasma MeHg-glutathione serves as a source of MeHg-cysteine.

Background Fish is an important source of nutrition worldwide. Fish contain both the neurotoxin methyl mercury (MeHg) and nutrients important for brain development. The developing brain appears to be most sensitive to MeHg toxicity and mothers who consume fish during pregnancy expose their fetus prenatally. Although brain development is most dramatic during fetal life, it continues for years postnatally and additional exposure can occur when a mother breast feeds or the child consumes fish. This raises the possibility that MeHg might influence brain development after birth and thus adversely affect children's developmental outcomes. We reviewed postnatal MeHg exposure and the associations that have been published to determine the issues associated with it and then carried out a series of analyses involving alternative metrics of postnatal MeHg exposure in the Seychelles Child Development Study (SCDS) Main Cohort. Methods The SCDS is a prospective longitudinal evaluation of prenatal MeHg exposure from fish consumption. The Main Cohort includes 779 subjects on whom recent postnatal exposure data were collected at the 6-, 19-, 29-, 66-, and 107-month evaluations. We examined the association of recent postnatal MeHg exposure with multiple 66- and 107-month outcomes and then used three types of alternative postnatal exposure metrics to examine their association with the children's intelligence quotient (IQ) at 107 months of age. Results Recent postnatal exposure at 107 months of age was adversely associated with four endpoints, three in females only. One alternative postnatal metric was beneficially associated with 9-year IQ in males only. Conclusions We found several associations between postnatal MeHg biomarkers and children's developmental endpoints. However, as has been the case with prenatal MeHg exposure in the SCDS Main Cohort study, no consistent pattern of associations emerged to support a causal relationship.

Fish contain nutrients that promote optimal brain growth and development but also contain methylmercury (MeHg) that can have toxic effects. The present study tested the hypothesis that the intake of selected nutrients in fish or measures of maternal nutritional status may represent important confounders when estimating the effects of prenatal methylmercury exposure on child development. The study took place in the Republic of Seychelles, an Indian Ocean archipelago where fish consumption is high. A longitudinal cohort study design was used. A total of 300 mothers were enrolled early in pregnancy. Nutrients considered to be important for brain development were measured during pregnancy along with prenatal MeHg exposure. The children were evaluated periodically to age 30 months. There were 229 children with complete outcome and covariate data for analysis. The primary endpoint was the Bayley Scales of Infant Development-II (BSID-II), administered at 9 and 30 months of age. Combinations of four secondary measures of infant cognition and memory were also given at 5, 9 and 25 months. Cohort mothers consumed an average of 537 g of fish (nine meals containing fish) per week. The average prenatal MeHg exposure was 5.9 ppm in maternal hair. The primary analysis examined the associations between MeHg, maternal nutritional measures and children's scores on the BSID-II and showed an adverse association between MeHg and the mean Psychomotor Developmental Index (PDI) score at 30 months. Secondary analyses of the association between the PDI and only MeHg alone or nutritional factors alone showed only a borderline significant association between MeHg and the PDI at 30 months and no associations with nutritional factors. One experimental measure at 5 months of age was positively associated with iodine status, but not prenatal MeHg exposure. These findings suggest a possible confounding role of maternal nutrition in studies examining associations between prenatal MeHg exposures and developmental outcomes in children.

Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.

Information on the status of long-chain polyunsaturated fatty acids (LCPUFAs) in pregnancy and breast milk in very high fish-eating populations is limited. The aim of this study was to examine dietary intake and changes in fatty acid status in a population of pregnant women in the Republic of Seychelles. Serum docosahexaenoic acid (DHA) decreased significantly between 28-week gestation and delivery (n=196). DHA status did not correlate significantly with length of gestation and was not associated with self-reported fish intake, which was high at 527 g/week. In breast milk, the ratio of DHA to arachidonic acid (AA) was consistent with those observed in other high fish-eating populations. Overall the data suggest that high exposure to LCPUFAs from habitual fish consumption does not prevent the documented decrease in LCPUFA status in pregnancy that occurs as a result of foetal accretion in the third trimester of pregnancy.

Human health risks from methylmercury in fish are evaluated in terms of dose-response relationships for both adult and prenatal human exposures. Specifically, information has become available from three independent epidemiological studies indicating that methylmercury levels in the mother during pregnancy predict the probability of adverse effects in her offspring. The mercury levels in the mother are measured as concentration in head hair which in turn is an excellent predictor of blood concentration. The adverse effects in the offspring take the form of psychomotor retardation. These dose-response relations along with a one-compartment kinetic model for methylmercury accumulation in humans will be used to estimate minimum toxic daily intakes; these are, for nonpregnant adults, 4,300 ng Hg/kg body weight/d and about 600 to 1,100 ng Hg/kg/d for pregnant adults. These values assume continuous exposure until the individual has attained steady state balance with respect to the body burden of methylmercury. This will take up to one year in most cases.

Introduction Prenatal exposure to organic methylmercury (MeHg) from seafood consumption has been reported to increase children's blood pressure (BP). A report from the Faroe Islands noted significantly increased diastolic and systolic BP in 7-year-old children as prenatal MeHg exposure increased. The Faroese diet includes sea mammals that contain MeHg, cadmium, and other pollutants. We examined this relationship in the Seychelles Islands to determine if it was present in a society exposed primarily to MeHg from consuming ocean fish. Methods We obtained BP at ages 12 and 15 years on children with known prenatal MeHg exposure enrolled in the Seychelles Child Development Study (SCDS). We examined the association between prenatal MeHg exposure and BP using longitudinal models and linear regression adjusted for relevant covariates. Results Blood pressure at both ages was associated with BMI, height and maternal hypertension during pregnancy as expected. No association between prenatal MeHg exposure and BP was present in girls at either age or in either sex at age 12 years. At age 15 years diastolic BP in boys increased with increasing prenatal MeHg exposure, while systolic BP was unaffected. Summary It is unclear whether the association between prenatal MeHg exposure and diastolic BP seen in 15-year-old boys is of biological significance or if it is a chance finding. However, the finding is intriguing and deserves further study.

Today the most widespread human exposures to mercury are to mercury vapor emitted from amalgam tooth fillings, to ethylmercury as a preservative in vaccines, and to methylmercury in edible tissues of fish. This review will focus on the mechanisms of transport of these three species of mercury. All three species are freely moveable throughout the body. Inhaled vapor in view of its physical properties as an uncharged atomic gas is believed to be transported by passive diffusion. Methylmercury and ethylmercury also move freely in the body. Methylmercury, and presumably its closely related chemical cousin ethylmercury, cross cell membranes as complexes with small molecular weight thiol compounds, entering the cell in part as a cysteine complex on the large neutral amino acid carriers and exiting the cell in part as a complex with reduced glutathione on endogenous carriers. The implications of these mechanisms with regard to biological monitoring are discussed.

N-Acetylcysteine (NAC) is a sulfhydryl-containing compound that produces a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned mice, but the molecular mechanism for this effect is poorly defined. MeHg readily binds to NAC to form the MeHg-NAC complex, and recent studies indicate that this complex is an excellent substrate for the basolateral organic anion transporter (Oat)-1, Oat1/Slc22a6, thus potentially explaining the uptake from blood into the renal tubular cells. The present study tested the hypothesis that intracellular MeHg is subsequently transported across the apical membrane of the cells into the tubular fluid as a MeHg-NAC complex using the multidrug resistance-associated protein-2 (Mrp2/Abcc2). NAC markedly stimulated urinary [(14)C]MeHg excretion in wild-type Wistar rats, and a second dose of NAC was as effective as the first dose in stimulating MeHg excretion. In contrast with the normal Wistar rats, NAC was much less effective at stimulating urinary MeHg excretion in the Mrp2-deficient (TR-) Wistar rats. The TR- rats excreted only approximately 30% of the MeHg excreted by the wild-type animals. To directly test whether MeHg-NAC is a substrate for Mrp2, studies were carried out in plasma membrane vesicles isolated from livers of TR- and control Wistar rats. Transport of MeHg-NAC was lower in vesicles prepared from TR- rats, whereas transport of MeHg-cysteine was similar in control and TR- rats. These results indicate that Mrp2 is involved in urinary MeHg excretion after NAC administration and suggest that the transported molecule is most likely the MeHg-NAC complex.

The chapter first describes the main sources of exposure through air, food, and water but also points to unusual sources such as medical implants. Special attention is given to the processes of lun ...

This review covers the toxicology of mercury and its compounds. Special attention is paid to those forms of mercury of current public health concern. Human exposure to the vapor of metallic mercury dates back to antiquity but continues today in occupational settings and from dental amalgam. Health risks from methylmercury in edible tissues of fish have been the subject of several large epidemiological investigations and continue to be the subject of intense debate. Ethylmercury in the form of a preservative, thimerosal, added to certain vaccines, is the most recent form of mercury that has become a public health concern. The review leads to general discussion of evolutionary aspects of mercury, protective and toxic mechanisms, and ends on a note that mercury is still an "element of mystery."

Thimerosal is a preservative that has been used in manufacturing vaccines since the 1930s. Reports have indicated that infants can receive ethylmercury (in the form of thimerosal) at or above the U.S. Environmental Protection Agency guidelines for methylmercury exposure, depending on the exact vaccinations, schedule, and size of the infant. In this study we compared the systemic disposition and brain distribution of total and inorganic mercury in infant monkeys after thimerosal exposure with those exposed to MeHg. Monkeys were exposed to MeHg (via oral gavage) or vaccines containing thimerosal (via intramuscular injection) at birth and 1, 2, and 3 weeks of age. Total blood Hg levels were determined 2, 4, and 7 days after each exposure. Total and inorganic brain Hg levels were assessed 2, 4, 7, or 28 days after the last exposure. The initial and terminal half-life of Hg in blood after thimerosal exposure was 2.1 and 8.6 days, respectively, which are significantly shorter than the elimination half-life of Hg after MeHg exposure at 21.5 days. Brain concentrations of total Hg were significantly lower by approximately 3-fold for the thimerosal-exposed monkeys when compared with the MeHg infants, whereas the average brain-to-blood concentration ratio was slightly higher for the thimerosal-exposed monkeys (3.5 +/- 0.5 vs. 2.5 +/- 0.3). A higher percentage of the total Hg in the brain was in the form of inorganic Hg for the thimerosal-exposed monkeys (34% vs. 7%). The results indicate that MeHg is not a suitable reference for risk assessment from exposure to thimerosal-derived Hg. Knowledge of the toxicokinetics and developmental toxicity of thimerosal is needed to afford a meaningful assessment of the developmental effects of thimerosal-containing vaccines.

ercury has been used commercially and medically for centuries. In the past it was a common constituent of many medications. It is still used in hospitals in thermometers and blood-pressure cuffs and commercially in batteries, switches, and fluorescent light bulbs. Large quantities of metallic mercury are employed as electrodes in the electrolytic production of chlorine and sodium hydroxide from saline. These uses still give rise to accidental and occupational exposures. 1 Today, however, exposure of the general population comes from three major sources: fish consumption, dental amalgams, and vaccines. Each has its own characteristic form of mercury and distinctive toxicologic profile and clinical symptoms. Dental amalgams emit mercury vapor that is inhaled and absorbed into the bloodstream. Dentists and anyone with an amalgam filling are exposed to this form of mercury. Liquid metallic mercury (quicksilver) still finds its way into homes, causing a risk of poisoning from the vapor and creating major cleanup costs. Humans are also exposed to two distinct but related organic forms, methyl mercury (CH 3 Hg + ) and ethyl mercury (CH 3 CH 2 Hg + ). Fish are the main if not the only source of methyl mercury, since it is no longer used as a fungicide. In many countries, babies are exposed to ethyl mercury through vaccination, since this form is the active ingredient of the preservative thimerosal used in vaccines. Whereas removal of certain forms of mercury, such as that in blood-pressure cuffs, will not cause increased health risks, removal of each of the three major sources described in this article entails health risks and thus poses a dilemma to the health professional. Exposure to mercury from dental amalgams and fish consumption has been a concern for decades, but the possible risk associated with thimerosal is a much newer concern. These fears have been heightened by a recent recommendation by the Environmental Protection Agency (EPA) that the allowable or safe daily intake of methyl mercury be reduced from 0.5 µg of mercury per kilogram of body weight per day, the threshold established by the World Health Organization in 1978, 2 to 0.1 µg of mercury per kilogram per day. 3 Table 1 summarizes the clinical toxicologic features of mercury vapor and methyl and ethyl mercury. It also includes data on inorganic divalent mercury, since this is believed to be the toxic species produced in tissues after inhalation of the vapor. 5 It is also responsible for kidney damage after exposure to ethyl mercury, since ethyl mercury is rapidly converted to the inorganic form. 13 Inorganic mercury as both mercuric and mercurous salts was also the chief cause of acrodynia, a childhood disease that is now mainly of historical interest. 14 The clinical symptoms of acrodynia consist of painful, red, swollen fingers and toes in association with photophobia, irritability, asthenia, and hypertension. It is believed to be a hypersensitivity reaction. m

Methylmercury (MeHg) readily crosses cell membrane barriers to reach its target tissue, the brain. Although it is generally assumed that this rapid transport is due to simple diffusion, recent studies have demonstrated that MeHg is transported as a hydrophilic complex, and possibly as an L-cysteine complex on the ubiquitous L-type large neutral amino acid transporters (LATs). To test this hypothesis, studies were carried out in Xenopus laevis oocytes expressing two of the major L-type carriers in humans, LAT1-4F2 heavy chain (4F2hc) and LAT2-4F2hc. Oocytes expressing LAT1-4F2hc or LAT2-4F2hc demonstrated enhanced uptake of [(14)C]MeHg when administered as the L-cysteine or D,L-homocysteine complexes, but not when administered as the D-cysteine, N -acetyl-L-cysteine, penicillamine or GSH complexes. Kinetic analysis of transport indicated that the apparent affinities ( K (m)) of MeHg-L-cysteine uptake by LAT1 and LAT2 (98+/-8 and 64+/-8 microM respectively) were comparable with those for methionine (99+/-9 and 161+/-11 microM), whereas the V (max) values were higher for MeHg-L-cysteine, indicating that it may be a better substrate than the endogenous amino acid. Uptake and efflux of [(3)H]methionine and [(14)C]MeHg-L-cysteine were trans -stimulated by leucine and phenylalanine, but not by glutamate, indicating that MeHg-L-cysteine is both a cis - and trans -substrate. In addition, [(3)H]methionine efflux was trans -stimulated by leucine and phenylalanine even in the presence of an inwardly directed methionine gradient, demonstrating concentrative transport by both LAT1 and LAT2. The present results describe a major molecular mechanism by which MeHg is transported across cell membranes and indicate that metal complexes may form a novel class of substrates for amino acid carriers. These transport proteins may therefore participate in metal ion homoeostasis and toxicity.

The three modern "faces" of mercury are our perceptions of risk from the exposure of billions of people to methyl mercury in fish, mercury vapor from amalgam tooth fillings, and ethyl mercury in the form of thimerosal added as an antiseptic to widely used vaccines. In this article I review human exposure to and the toxicology of each of these three species of mercury. Mechanisms of action are discussed where possible. Key gaps in our current knowledge are identified from the points of view both of risk assessment and of mechanisms of action.