Address correspondence to H.M. Chan, CINE, McGill University, 21,1111 Lakeshore Rd., Ste-Anne-de-Bellevue, Quebec, H9X 3V9, Canada. Telephone: (514) 398-7765. Fax: (514) 398-1020. E-mail: chan@agradm.lan.mcgill.ca

Received 26 May 1999; accepted 2 August 1999.

Introduction

The Risk of Organic Mercury in the Diet
Methyl mercury (MeHg) intoxication has been a public health problem for many decades (1). Consideration of the role of environmental factors in determining susceptibility to MeHg toxicity has recently been renewed by evidence from epidemiologic studies in the Amazon (2), the Republic of the Seychelles (3), and the Faroe Islands (4). Although many of these populations have been exposed to similar doses of MeHg through the consumption of fish and seafood, some populations have experienced subsequent neurotoxic effects, whereas others have not (5). Growing awareness of the use of nutrition to maintain optimum health emphasizes the relevance of considering the way that nutritional factors may affect heavy metal toxicity. There are many reviews on human susceptibility to toxic heavy metals (e.g., 6-10). However, most reviews do not give enough attention to nutritional factors that might influence human response to heavy metal intoxication. This review focuses on nutrition as a potential modifier of MeHg toxicity. Reviews of the pharmacology and chemistry of mercury (Hg) compounds have been presented elsewhere (1,11).

Since the epidemic MeHg poisoning from contaminated fish consumption in Minamata, Japan, in the late 1950s (12,13), MeHg has been one of the most dramatic and best-documented examples of the bioaccumulation of toxins in the environment, particularly in the aquatic food chain (14). The neurologic symptoms induced by MeHg in the Minamata epidemic are still being observed 22 years after consumption of contaminated fish (15). MeHg attains its highest concentrations in edible tissues of long-lived predatory fish. It is an example of a toxic compound that is well absorbed from the diet despite having no demonstrated biologic requirement in humans (9), and the diet serves as the main source of exposure in human populations (1).

Daily intake of MeHg depends on its concentration in foodstuffs and on the dietary habits of the consumer. With increasing naturally present inorganic Hg in the hydrosphere and biosphere due to acid rain and industrial mining activities and the subsequent biomethylation of this Hg, the global exposure to MeHg in the 21st century is expected to increase (16). MeHg has been implicated as a neurotoxicant, a mutagen, and a teratogen in biologic organisms (17). Therefore, MeHg toxicity is becoming a global environmental health concern.

Currently, the Food and Agriculture Organization/World Health Organization (FAO/WHO) provisional tolerable weekly intake is defined as 3.3 µg/kg/week or 200 µg/week for adults and breast-fed infants, based on prevention of parathesia in adults and older children (1). Moreover, the fetus is particularly sensitive to MeHg even at levels that result in few, if any, signs of maternal clinical illness or toxicity. High levels of pre-natal MeHg exposure can result in cerebral palsy, mental retardation, low birth weight, and early sensorimotor dysfunction (18). Therefore, scientists have focused on the re-evaluation of reference doses for MeHg in view of its prenatal developmental effects, infant exposure, and the important objective of establishing the lowest level effects for human exposure (19-23).

Recently, results of two large controlled longitudinal studies of effects of prenatal Hg exposure from seafood consumption on child neurodevelopment have been published (24,25). These studies are considered references by many regulatory agencies because they use low-dose chronic exposure and state-of-the-art methodologies for measuring developmental effects. The first study was conducted in the Republic of Seychelles, an archipelago in the Indian Ocean, where 85% of the population daily consumes ocean fish (3,24). A cohort of 711 mother-child pairs was studied. The mean maternal hair total Hg level was 6.8 ppm and the mean child hair total Hg level at 66 months of age was 6.5 ppm. No adverse outcomes at 66 months were associated with either prenatal or postnatal MeHg exposure. The second study was conducted on a cohort of 1,022 consecutive singleton births during 1986 and 1987 in the Faroe Islands (4,25). At approximately 7 years of age, 917 of the children underwent detailed neurobehavioral examination. Clinical examination and neurophysiologic testing did not reveal any clear-cut Hg-related abnormalities. However, when a subsample of 112 children whose mothers had a hair Hg concentration of 10-20 ppm was compared to a subsample of children whose mothers had exposures below 3 ppm, mild decrements were observed, especially in the domains of motor function, language, and memory (25).

In response to this recently available epidemiologic data, Health Canada has proposed a provisional no observable adverse effect level of 10 ppm Hg in maternal hair (26). When converted to an equivalent daily intake from food and using a 5-fold uncertainty factor to account for interindividual variability, the provisional tolerable daily intake for women of reproductive age and infants was revised to 0.2 µg/kg body weight (bw)/day (26). The U. S. Environmental Protection Agency (U.S.EPA) took a similar approach and set the reference dose for MeHg at 0.1 µg/kg bw/day, using an uncertainty factor of 10 (27). Under these guidelines, the maximum weekly MeHg intake for a woman of average body weight (65 kg) should be less than 91 µg (Health Canada) or 45.5 µg (U.S. EPA). Assuming the average MeHg concentration in fish is 0.5 µg/g, a woman can only consume between half a fish (100 g) to a whole fish meal (200 g) per week. It is clear that a significant portion of the population, particularly the families of fishermen and aboriginal people, are exposed to MeHg beyond these guideline levels. The risk of dietary exposure to MeHg among the general public has to be better characterized.

Epidemiologic Evidence for Dietary Effects on MeHg Toxicity
An extensive review of epidemiologic data relating Hg exposure through the diet to nutritional parameters is presented in Table 1 (see Appendix for all tables). Fish and marine products are generally regarded as the major sources of MeHg exposure among the general public. Data collected by the Joint United National Environment Program (UNEP)/FAO/WHO Food Contamination Monitoring Program revealed that the MeHg contribution from fish and fish products varied from 20 to 85% among different populations and that drinking water, cereals, vegetables, and meat could also be significant contributors to MeHg burden (46,47). In addition, dietary practices such as chewing hard-boiled eggs, which decreased mercury vapor (Hg⁰) release from dental amalgams (48), or chewing gum, which increased the release of Hg⁰ from dental amalgams (40), may modify individual exposures to Hg. Thus, the conclusion that fish are a major contributor to the total intake of Hg is not necessarily justified for every population and is highly dependent on dietary habits (46,47).

Epidemiologic studies have been conducted on the exposure of humans to Hg through fish and marine mammal consumption in different geographical areas: the Seychelles (21,24), the Canadian North (49,50), the Amazon (2), the Faroe Islands (25), Papua New Guinea (51), and Sweden (52). There are inconsistencies in the toxic dose; for example, the populations in the Amazon appear to be more sensitive (53). It has been suggested that dietary practice may be a significant factor affecting the susceptibility to MeHg on the basis of the observation that more whale meat is consumed in the Faroe Islands and more fish in the Seychelles (5). The duration and timing of exposure are also critical factors. For example, effects of prenatal exposure were more significant than the effects of exposure through breast-feeding in mice (54).

Of all nutrients, selenium (Se), because of protective effects observed in animal studies, has received the most attention as a potential protector against MeHg toxicity in populations consuming seafood (55). Moreover, the main sources of Hg in the diet, such as fish and marine mammals, are also rich sources of Se (56). Thus, Se has been the main nutritional factor considered by epidemiologic and clinical studies to date (Table 1). Dewailly (28) and Grandjean et al. (32) reported a correlation between Se and Hg in the serum or plasma, but other researchers did not observe such a correlation (34,45). No epidemiologic studies, however, have shown a correlation between Se intake and the occurrence or absence of symptoms for MeHg intoxication. Inconsistencies were also observed in the protective effects seen in animal studies (57). The role of Se remains to be confirmed in MeHg intoxication.

Macronutrient intakes such as fat intake have also been correlated with MeHg toxicity. Meltzer et al. (36) observed a positive correlation between dietary Hg and low-density lipoprotein cholesterol. Unsaturated fatty acids were also correlated with Hg exposure in populations frequently consuming seafood and fish (28,42), but there was no evidence of beneficial or antagonistic effects (Table 1). Other diet-related conditions with symptoms similar to those of MeHg may exacerbate its intoxication. Farkas (30) suggested that thiamine deficiency in Northern Canadian Indians may often be concurrent with MeHg exposure and that the neurotoxicity symptoms may be additive. Alcoholism and the occurrence of fetal alcohol syndrome are also diet-related confounders of the symptoms of MeHg toxicity (58). Since most studies did not collect sufficient detailed dietary information, it is unclear how dietary modifications, besides decreased consumption of Hg-containing foods, can affect the risk of MeHg toxicity.

Roles for Nutrition in MeHg Toxicity
Even though there is little evidence of nutrient effects at the population level, there is plenty of evidence that nutrients interact with the metabolism of Hg at the physiologic level. Nutrients can affect bioavailability, toxico-dynamics, and transport to target organs, and influence the immunologic, biochemical, or cytologic functional responses to Hg. However, as in the limited understanding of the mechanisms of MeHg toxicity (17,59,60), the overall mechanisms of modification of MeHg toxicity by nutrients are not well understood. Review articles in this area of nutritional toxicology are scant; most focus on the modification of MeHg toxicity by Se (57,61-63), vitamin C (64-66), vitamin E (64,65), and essential minerals (7,67). Examples of foods, macronutrients, vitamins, minerals and other food-related compounds that cause alterations in the metabolism of Hg are summarized in Tables 2, 3, and 4.

Foods such as fish, milk, meat, and wheat bran (Table 2); minerals such as Se, zinc (Zn), copper (Cu), and magnesium (Mg) (Table 3); and vitamins such as vitamin C, vitamin E, and vitamin B complex (Table 4) have been implicated in the alteration of Hg metabolism. However, evidence for protective or antagonistic effects is often complex and highly dependent on metabolic conditions. With the exception of Se and vitamin E, evidence for other nutrients is derived mainly from results of one or two studies. Moreover, nutritional considerations in many of these studies were not the main objective of the study. To address the conflicting results of the recent epidemiologic studies, principal investigators of these studies and other experts in Hg toxicology were invited to participate in a workshop titled the "Scientific Issues Relevant to Assessment of Health Effects from Exposure to MeHg" held by the National Institute of Environmental Health Sciences in North Carolina (November 18-20, 1998) (154). Among other conclusions, it was agreed that dietary factors may affect MeHg toxicity, but due to inadequate data there is a need for an extensive review of factors that might influence chronic MeHg toxicity. In response, this review provides an overview of our current understanding of how dietary factors affect MeHg toxicity.

Nutrition-Mercury Interactions

Studies on the interactions of nutrients and MeHg fall into two major categories: effects of nutrients on Hg metabolism and effects of Hg on nutrient metabolism. Both types of interactions will be addressed. Most information is currently derived from animal research and thus implications for human populations consuming mixed diets can only be speculative at this time.

Absorption of MeHg
Studies on the effects of nutrients on MeHg absorption are summarized in Table 5. Such studies are few, and the inconsistent animal model, dose, and route of exposure make comparison of studies difficult. MeHg is absorbed throughout the intestine and absorption is possible through most biologic membranes (158). Up to 90% of MeHg is quickly absorbed across the intestinal membrane and binds in vivo to proteins (158,159) such as albumin and other sulfur-containing proteins (104,160). MeHg recycles through the enterophepatic system in adults (159,161) and is excreted primarily in the feces (88). It has been suggested that nutritional factors influence the reabsorption rate of MeHg rather than its primary absorption (96). Several nutrients such as wheat bran may decrease the toxic effects of MeHg by inhibiting MeHg reabsorption in the gut after enterohepatic circulation. Wheat bran fiber (30% of diet) has been shown to alter the demethlyation rate of MeHg by intestinal flora in mice and thus influence the reabsorption and the excretion rate of Hg (78). Antibiotic treatment removed the differential effect of diet on Hg elimination in mice fed 0.6 mg Hg/kg body weight as methyl mercury chloride (MeHgCl) (88). It was also suggested that the speciation of Hg in some fish, such as tuna, may be less toxic to fish consumers than other fish or foods containing other forms of Hg (55), but it is unknown if this effect is due to decreased bioavailability of MeHg. An important factor not adequately addressed is the effect of pH on absorption of biologic forms of MeHg, although Endo et al. (162) observed that alkalinity of the bile promoted the absorption of mercuric mercury (Hg²⁺) in rats.

Foods such as milk may also promote the absorption of MeHg (Table 5). Landry et al. (85) showed that a milk diet in mice enhanced the reabsorption of MeHg after enterohepatic circulation. They suggested that this was due to decreased demethylation of MeHg, as inorganic forms of Hg are less readily absorbed (85). It is likely that diet affects the absorption of organic and inorganic Hg by a combination of different mechanisms. For instance, the inhibition of Hg²⁺ absorption by a milk diet, unlike MeHg absorption, is thought to be due to its association with the milk triglycerides (86) rather than metabolism by intestinal flora. In addition, removal of the cecum decreased the excretion of Hg after exposure to Hg²⁺ in mice (163), but the significance of bowel resection to MeHg exposure in humans is not known.

The effects of MeHg on nutritional metabolism can be deleterious (Table 5). Mykkanen and Metsaniitty (98) studied the effect of MeHg on the absorption of Se and selenomethionine (Se-Met) in the duodenum of leghorn chicks and concluded that Hg reduced the transfer of selenite from the intestine to the body but not the transfer of Se-Met. This study suggested that the form of Se is a critical factor in the regulation of Se-Hg interactions. MeHg, not Hg²⁺, is implicated in altering chloride (Cl^-) secretion in enterocytes (133), but Hg²⁺ such as that from MeHg demethylation also influences the absorption of nutrients. Mykkanen and Metsaniitty (98) suggested that a Se-Hg²⁺ complex may reduce the absorption of Se. The binding of Hg²⁺ to transmembrane thiol groups was implicated in the inhibition of the sugar-sodium (Na⁺) phlorizin-sensitive cotransport system, and thus inhibition of the absorption of galactose in rats (113). Interestingly, cysteine (Cys) treatment post-Hg²⁺ exposure reversed this type of inhibition (113). Iturri and Nunez (164) observed that Hg²⁺ had no effect on the uptake of ferrous and ferric ions in mouse intestine.

Metabolism, Compartmentalization, and Kinetics
Nutrients have been shown to modulate the toxicokinetics and dynamics of MeHg metabolism. The following sections elaborate on the effects of nutrients on transport, distribution, and retention of MeHg, and the overall effects of MeHg on the metabolism of protein, carbohydrate, lipids, and other metabolites.

Nutrient effects on transport, distribution and retention of MeHg. Foods and Macronutrients. In mice, MeHg is transported in blood, bound to serum proteins such as albumin and mercaptoalbumin (104), as stable conjugates to major organs such as kidney, liver, and brain, and also to the placenta and fetus in pregnancy. A significant fraction of MeHg, however, remains in erythrocytes and epithelial tissues (165). Although it is unknown whether certain foods could inhibit MeHg toxicity by influencing its transport, l-leucine, l-methionine, and 2-amino-2-norborane carboxylic acid may inhibit the uptake of MeHg through amino acid transport system l (166).

Cys is implicated as one nutrient that may increase MeHg neurotoxicity (Table 5). Studies with cultured calf brain capillary endothelial cells, an in vitro model of the blood-brain barrier, suggest that MeHg is transported to the brain as an l-Cys complex by amino acid transport system l (167), but MeHg may enter organs by any one of several transport systems, including the facilitated d-glucose transport system and the Cl^- ion transport system (93). Equilibrium constants of mercurials favor a link with thiol ligands (57). Association of MeHg with thiol compounds of small molecular weight promotes transport of MeHg both into and out of cells, providing access to specific membrane carriers through mimicry of natural substrates (57). For example, the observed MeHg-Cys complex was similar to Met, and the structure of two glutathione (GSH) molecules bound to Hg was similar to oxidized GSH (168,169).

Conversely, MeHg can also disturb nutrient transport such as the exchange of Met and Se through the blood-brain barrier (170). In pregnancy, Hg²⁺ can alter fetal uptake of nutrients such as Se, vitamin B₁₂, and Zn in mice (171), chickens (98), and humans (172,173). Hg²⁺ inhibited the Na⁺-dependent l-alanine transport and l-lysine transport across human placenta (172), and Urbach et al. (173) showed that transfer of amino acids, but not glucose, across the placenta was affected. It is unknown whether competition occurs between serum protein-transported nutrients such as Cu and MeHg.

Hojbjerg et al. (111,174) and Rowland et al. (78,88,175) showed that diet composition affects the distribution of MeHg and its toxicity. Retention of Hg by various organs has been the prime concern of most studies on nutrient-Hg interactions (Tables 6-8). Whole-body Hg retention, organ Hg distribution and mortality rate are usually measured. Most studies, however, report effects of acute Hg exposure by injection rather than the more relevant chronic dietary exposure.

Seafood has received attention as a possible modifier of MeHg distribution in a way that protects organisms exposed to MeHg through the consumption of seafood. Eaton et al. (181) showed that cats receiving MeHg naturally in seal liver developed no signs of neurologic abnormalities after 90 days, unlike cats consuming beef liver with added MeHgCl. Thrower and Andrewartha (182) also reported that in rats, consumption of shark flesh naturally containing Hg and Se resulted in stimulated activities of GSH peroxidase, whereas Torula yeast diets with added Hg and Se did not. Ganther and Sunde (183) observed that MeHg exposure from a diet of tuna fish prolonged survival of Japanese quail compared to corn and soy diets containing similar levels of MeHg. Ohi et al. (72), however, also observed that Se in tuna fish was approximately half as efficient as selenite in the prevention of neurologic symptoms of MeHg exposure in rats.

The percentage of fiber in the diet also affects the retention of Hg. Rowland et al. (78) examined the effects of pectin, wheat bran, and cellulose compared to fiber-free diets on the toxicity of MeHg in mice and found that these alterations in the diet altered the ability of microflora to demethylate MeHg and thus affected the reabsorption rate of MeHg. As discussed earlier, wheat bran increased the excretion of Hg after MeHg exposure (78).

Protein level in the diet also affected the metabolism of MeHg; adequate protein intake prolongs survival after oral doses of MeHg (69,87,89,257). Specific amino acids such as Cys may detoxify MeHg by preventing inhibition of enzymes such as carnitine acyltransferase (108). However, Cys can act as a carrier for MeHg across the blood-brain barrier and thus alter Hg distribution by increasing Hg levels in the brain and increasing neurotoxicity (76,82).

Certain phytochemicals found in the diet reportedly protect against MeHg toxicity. Bala et al. (75) found that -linoleic acid reduced aberrations and sister chromatid exchanges caused by MeHg exposure in lymphocyte cultures. Tree barks containing tannins have been used industrially to decontaminate Hg in industrial sludge by adsorption (194). In addition, Cha (73) reported that rats consuming raw garlic as 6.7% of their diet decreased Hg accumulation in liver, kidneys, bone, and testes after exposure to 4 ppm MeHgCl in their drinking water for 12 weeks.

Foods such as milk and coconut oil appear to increase the retention of MeHg in organisms. Kostial et al. (258,259) suggested that milk diets may reduce Hg²⁺ retention compared to solid food diets in suckling rats. It is not clear how milk pre- and post-treatments affect the survival of laboratory animals of different ages exposed to MeHg or how this might be significant for human infants exposed to MeHg.

Increased coconut oil in the diet (5-50%) increased the whole-body retention of Hg in mice receiving single injections of 5 µmol MeHgCl, whereas increased cod liver oil in the diet (5-50%) did not affect the retention of MeHg (111). Mortality increased in Japanese quail with 15 ppm MeHgCl in their diet as the percentage of linoleic acid increased (84). However, these effects were only observed in birds that had not been receiving linoleic acid in their diets since hatching (83). It was shown that long-chain fatty acids interact with Hg in vitro (260), but how these interactions affect the toxicity of MeHg is unknown. Kling and Soares (84) suggested that increased levels of polyunsaturated fatty acids in the diet may increase susceptibility to Hg poisoning, but no results were presented to support this hypothesis.

Total Hg levels in mouse brain increased with a low-protein diet and the increase was further enhanced by sulfur amino acid supplementation (69). Hepatic, renal, blood, and plasma Hg levels also increased with a sulfur amino acid supplement to inadequate protein diets, likely because of changes in the neutral amino acid transport that altered the biochemical fate of MeHg (69). The one commonly consumed nonfood known to alter MeHg detoxification is alcohol. Ethanol appears to enhance the toxic effects and the mortality of MeHg (185-187). It enhances toxicity to the kidney by reducing activities of amino acid transferases and creatine phosphokinases (79,188).

Minerals. Adequate intakes of Se and Zn may delay MeHg toxicity. Se has been suggested to counteract the toxicity of several heavy metals, including cadmium, Hg²⁺, MeHg, thallium, and silver (63). The protective effect of Se against MeHg intoxication is less dramatic than that against sublimate intoxication (57), and Se in food at best delays but does not prevent MeHg intoxication (57). For both inorganic and organic Hg, Se has been implicated in the formation of the Hg-Se complexes GSH-Se-Hg and bis(methylmercuric) selenide, respectively (115,237,249,261). The protective effect of Se against MeHg toxicity does not appear to involve Hg absorption in the intestine or excretion of Hg in the urine or feces; Se also does not appear to affect the rate of MeHg demethylation (57). Sumino et al. (201) suggested that Se modifies the form of MeHg, thus altering its distribution by freeing MeHg from blood proteins.

The chemical speciation of Se is also an important factor. Nielsen and Andersen (97) observed that Se-Met, compared to selenite, fed to mice (3 µg/mL in drinking water) only slightly affected the toxicokinetics of MeHgCl in offspring. HgCl₂ given to rats caused a decrease in GSH reductase activity and -glutamyl Cys synthetase in the kidney (262). This decrease in enzyme activity was blocked if rats were given Se after Hg exposure (2:1 ratio of Hg to Se). Chmielnicka (263) reported that when selenite and Hg²⁺ were given jointly, the rise in urinary excretions of endogenous Cu²⁺ and Zn²⁺ due to Hg exposure were decreased. Several theories have been proposed for the protective effect of Se, including delayed onset of Hg toxicity, decreased severity of effects of inorganic or organic Hg, and the formation of an inert Hg-Se complex (10,264).

Studies on the effects of Zn²⁺ on Hg exposure have focused mainly on inorganic Hg rather than organic mercury. It is thought that Zn²⁺ may reduce lipid peroxidation by increasing the activities of enzymes such as GSH peroxidase to ameliorate signs of neurotoxicity (125,265). Zn²⁺ induction of metallothionein (MT) in rat astrocytes was protective of alterations in sodium and potassium ion flux due to MeHg exposure (225).

Iron appears to enhance MeHg toxicity. LeBel et al. (266) showed that the iron chelator deferoxamine inhibited MeHg-induced excess oxygen reactive species formation. Peckham and Choi (267) also observed that MeHg exposure to fetal mouse astrocytes disrupted ferritin along cell membranes.

Vitamins. It is well established that active oxygen species (superoxide radical, hydroxyl radical, singlet oxygen, peroxides) are produced during the metabolism of MeHg (114,268,269). Vitamins E and C may modify MeHg toxicity due to their antioxidant properties. Vitamin E protected against neurotoxic effects such as ataxia, paralysis of hind limbs, and necrosis in brain in rat and hamster (143,270). Vitamin E alleviated toxicity due to organic Hg toxicity but not Hg²⁺ toxicity in Japanese quail (84). There is also some evidence that the protective effect provided by vitamin E extends from the parent to offspring (208). Vitamin E inhibited MeHg toxicity in a number of in vitro studies (144,145,251).

Studies of vitamin C treatment after exposure to MeHg showed contradictory results. Vijayalakshmi et al. (180) and Bapu et al. (127) examined the effects of vitamin C treatment after subcutaneous injections of MeHgCl for 7 days in mice and found improvements in recoveries of enzymes activities of - and ß-galactosidases and glycosidases. However, the recovery of enzymes was not complete and was organ dependent, thus highlighting a general problem in therapy of MeHg toxicity. A treatment that provides a beneficial decrease in the Hg burden in an organ such as the liver or the kidney may increase the Hg burden in another organ, such as the brain, stimulating symptoms of neurotoxicity (103). For example, exposure to vitamin C enhanced MeHg toxicity in cultured mouse neuroblastoma cells (251). In humans, Calabrese et al. (44) observed no change in Hg body burden of humans as measured by hair Hg after supplementation with ascorbic acid for 3 months.

Vitamin A was protective in cell culture (255) but enhanced MeHg toxicity in in vivo studies with rats (148). It is unknown if these effects are related to antioxidant/pro-oxidant activity of vitamin A or to some other factor of metabolism.

Several B vitamins have been implicated in the amelioration of MeHg toxicity, possibly because of their role in overall health and repair in organisms (103). Vitamin B₁₂ has received the most attention because of its biologic role in methylation metabolism. For example, Met synthetase is inhibited by MeHg in rat organs, except liver (95), likely due to its nature as a sulfhydryl enzyme. No study has examined how this might affect B₁₂ metabolism and folate metabolism in which Met synthethase plays a role (271), or how folate and B₁₂ supplementation affect MeHg toxicity symptoms. Zorn and Smith (147) studied the effect of folate, vitamin B₁₂ and ascorbate on Hg²⁺ methylation in guinea pigs. They concluded that doses of these vitamins can increase MeHg in the liver and in hair, and the combination of the vitamin C with vitamin B₁₂ can increase MeHg in the brain.

Combined nutrient effects. Information on how combinations of nutrients influence MeHg metabolism is scant, but several combinations of nutrients have been examined (Table 9). The protective effects of Se and vitamin E appear to be additive at low Se concentrations (202,204), possibly because of the interaction between vitamin E and Se antioxidant mechanisms. Met competed with Hg for Cys-mediated transport across the blood-brain barrier (82), and the availability of other amino acids also affected this transport (257). There also appears to be a relationship between vitamin E and vitamin A effects on MeHg toxicity (148).

Effect of MeHg on protein metabolism. Mercury exposure results in inhibition of protein synthesis due to inactivation of enzymes, such as the inhibition of several aspartate and alanine amino acid transferases observed in fish exposed to Hg²⁺ (277). However, protein synthesis in the mitochondria appears to be stimulated in mice exposed to MeHg (100).

Induction of GSH with a Cys precursor (1 mmol l-2-oxothiazolidine-4-carboxylic acid) reduced MeHgCl-induced amino acid release from astrocytes (278). A general pattern of GSH enzyme (GSH reductase and GSH peroxidase) induction was observed in both liver and kidney of mice after dietary exposure to MeHg and sodium selenite (224). Buthionine, a specific inhibitor of GSH, reduced cystine-enhanced MeHg toxicity, suggesting that cystine may enhance MeHg toxicity indirectly by stimulating the synthesis of cellular GSH (279).

Effect of MeHg on lipid, carbohydrate, and energy metabolism. Mercury affects both lipid and carbohydrate metabolism. MeHg exposure decreased the incorporation of ¹⁴C glucose in the brains of suckling rats (280). Janik (281) also showed that rats fed MeHgCl more than 3 weeks had altered levels of glycogen and lactic acid in their hearts and livers and Das and Scott (282) showed that offspring of mice injected with MeHgCl had abnormal glycogen deposits in their alveolar tubules. Rana and Sharma (283) showed that many enzymes in carbohydrate metabolism are inhibited by exposure to Hg²⁺, including glucose-6-phosphatase, amylase, maltase, and lactase. Varghese et al. (106) reported that carbohydrate metabolism in crabs exposed to Hg²⁺ switched toward glycolysis and caused an initial increase in blood sugar levels upon exposure. Exposure to Hg also decreased the glycogen content in liver, muscle, brain, and kidney in fish (103).

Hg exposure can alter lipid profiles and fatty acid and cholesterol production (284-287). MeHg decreased triglycerides in the central nervous system of rats (102), possibly due to alterations in Mg²⁺, adenosine triphosphate (ATP), or acetyl coenzyme A levels. MeHg, on the other hand, increased the levels of tocopherol in rat serum, possibly due to increased serum lipid levels (254). Kasuya (77) reported that the phospholipids sphingomyelin and phosphatidyl serine of cellular membranes prevented some of the toxic effects of organic Hg compounds in tissue culture. Hg²⁺ inhibited hepatic fatty acid synthetase and the stimulated mitochondrial fatty acid elongation in chickens (110,152). Other enzymes of lipid metabolism such as lipase (283) and carnitine acetyltransferase in the human placenta (108) were also inhibited. George (288) also reported that Hg affected fat cell response to insulin in vitro.

Perturbation of essential mineral metabolism by MeHg. Methyl mercury perturbs the metabolism of Zn, Cu, Mn, Cr, Ni, Fe (manganese, chromium, nickel, iron), and Se (127). Abdulla and Chmielnicka (289) suggested the analysis of elemental composition of body tissues and fluids be used as an indicator of the effect of MeHg on nutritional and pathologic status of humans. For example, Cu concentration in the kidney could be used an indicator of renal toxicity due to MeHg exposure. Bjorkman et al. (290) found that Se levels in the brain occipital pole and thalamus were lower in monkeys exposed to 50 µg MeHg/day for up to 18 months. Hg vapor can induce MT formation, which alters blood levels of metallic cations such as Cu²⁺ and Zn²⁺ (291), possibly due to the dissociation and mobilization of Cu²⁺ and Zn²⁺ from MT (292). Manganese is also mobilized from tissues (127), possibly due to the denaturation of enzymes that use it as a cofactor.

Interaction of MeHg with electrolytes. Mercury affects sodium and potassium ion channels, and some end points of Hg toxicity can be protected by pharmacologic ion-channel blockers (225). Some of these effects may be due to the inhibition of Na⁺/K⁺-ATPases (136,293).

Ca²⁺ metabolism was also perturbed by Hg, resulting in increased Ca²⁺ permeability and altered Ca²⁺ metabolism in muscle tissue (294,295). Sakamota et al. (296) observed that Ca²⁺-channel blockers prevented a decrease in body weight and other neurologic symptoms in rats. Hg also affected Cl^- channels in rats (297).

Excretion of MeHg
Methyl mercury is normally excreted in bile as a GSH complex in rats (298), and it has been observed that some thiols can increase biliary excretion of MeHg (299-301). Nutrients can also influence the excretion of Hg after exposure to MeHg (Table 10). Rowland et al. (78,88) concluded that dietary fiber such as wheat bran increased the demethylation rate of MeHg by intestinal flora and increased the fecal excretion of Hg. Se may reduce (199) or increase (302) the excretion of Hg.

Nutritional factors may also decrease the excretion of Hg after MeHg exposure. A low-protein diet (7.5%) decreased the amount of Hg being excreted into the urine (68). Gregus et al. (139) found that injections of lipoic acid decreased MeHg excretion by competing for GSH. Interestingly, Hg²⁺ excretion into the bile was increased by the same treatment of lipoic acid.

Public Health Considerations

Problems Induced by Nutrient Deficiency
The health implications for human populations consuming MeHg through a mixed diet remain speculative. Loss of appetite, decreased food intake, decreased water intake, and loss of body weight are side effects associated with MeHg exposure (303,304). The implications of diet modification on these parameters, however, have not been examined in humans. Nutrient deficiencies may develop as a result of anorexia and may also develop in cases of chronic Hg intake. Yonemoto et al. (233) showed that MeHg exposure could stimulate the formation of toxic, volatile dimethylselenide, which causes loss of Se by exhalation. MeHg may also be associated with an increased requirement for vitamins E and B₁ (103) and vitamin C (149). Inorganic Hg has also been shown to alter the levels of nutrients such as vitamins C and E in the kidney (124).

Few studies have examined the effects of malnutrition on the metabolism and toxicity of Hg, but malnutrition in general has a deleterious effect. Inadequate protein increased MeHg-induced mortality in mice (69), and Met deficiency during MeHgCl exposure caused an increase in serum prostaglandins (192). Yamini and Sleight (305) reported that vitamin C deficiency in guinea pigs promoted toxicity of MeHg, and Nishikido et al. (229) found that Se deficiency exacerbated MeHg fetal lethality in mouse.

Is There a Case for Nutritional Therapy?
Current chelation therapies for the treatment of MeHg intoxication are thiol derivatives (306). Choices have included 2,3-dimercaptopropane-1-sulfonate (307) and N-acetylcysteine (308). However, an efficient and effective therapy that can be used for long-term chronic MeHg exposure in fish-eating populations is not available.

The search for therapies in chronic MeHg intoxication has led to the suggestion that vitamins or other dietary modifications may enhance the detoxification of MeHg. Megadoses of vitamin B₁₂, folic acid, or amino acids can affect Hg uptake and methylation, though sometimes not in a positive way. Zorn and Smith (147) reported that vitamin B₁₂ administered alone or with folic acid increased methylation of Hg²⁺, resulting in increased MeHg levels in the liver. Megadoses of vitamin B₁₂ administered with vitamin C after exposure to Hg²⁺ increased MeHg levels in the brain (147). The enhancement of Hg²⁺ toxicity by vitamin C treatment led to the suggestion that megadoses of vitamin C should be contraindicated among populations with high Hg exposure (150). Some researchers have suggested that certain types of fish should be preferred because of their high Se content (309), but others warn of the toxicity with high levels of Se (205). Another suggestion was to detoxify food containing Hg by food processing. For instance, Aizpurua et al. (176) used cysteine (0.5%) solution to remove Hg from shark muscle but concluded that the method was too inefficient to be of practical purpose.

The effect of cooking and preparation method on the concentrations of MeHg in seafood and fish has been examined (310-312), but these effects are minor compared to factors such as fish age and size.

It is important to encourage collaborations among toxicologists, nutritionists, and public health officials in risk assessment and risk management. Emphasis should be given to assessing overall dietary quality and identifying alternative food sources for replacing the nutrients provided by fish and seafood in the diet. Both the risks and the nutritional and sociocultural benefits of consuming these foods should be assessed before drastic interventions to discourage people from consumption are implemented. For example, among the aboriginal populations, the traditionally consumed fish and seafood often provide a rich source of nutrients such as protein, Fe, vitamins, and Ca²⁺ that may be less easy to obtain in expensive store-bought foods (313). Country foods are cheap, reliable sources of foods with high-quality protein, minerals, and vitamins (314). Increased physical activity that occurs during the procurement of these foods reduces the risk of diabetes, obesity, and loss of fitness (315). There is a continuing need for education among fish- and seafood-consuming populations. Fear or lack of understanding of contamination in animal and fish foods may lead to a drastic shift away from the traditional diet and may result in increased consumption of high-carbohydrate diets associated with health risks such as diabetes and obesity (316). Often only a slight modification in eating patterns or partial restriction of highly MeHg-contaminated foods for individuals identified with high exposure may decrease MeHg intake significantly. It may not be necessary to recommend complete removal of a food from a diet (50,315-318). The relationships between MeHg and trophic level or fish size can be explained so that the species with less MeHg can be promoted (319). The public must also be aware of the increased sensitivity of young children and women of childbearing age, especially pregnant women and nursing mothers, to MeHg. Moreover, it has been concluded that exposure to MeHg through breast milk does not outweigh the benefit of infant weight gain produced by breast-feeding (320). Therefore, continuation of breast-feeding is recommended despite the risk of MeHg exposure to the infant during lactation.

Conclusion

A wide variety of foods and nutrients alter MeHg metabolism, but the mechanisms of interaction often remain speculative. More studies designed specifically to address the role of nutrition in the metabolism and detoxification of MeHg are needed. Such studies must expand the understanding of the biologic mechanisms and the toxicokinetics to aid in making interspecies comparisons. In addition, hypotheses about the effect of nutrients on MeHg have sometimes been made on the basis of studies using inorganic Hg; these hypotheses should also be tested during chronic dietary exposure to MeHg.

Clarification of the effects of specific dietary lipids on MeHg toxicity is needed and is relevant for defining MeHg exposure in seafood-consuming communities with high intakes of polyunsaturated fatty acids and -3 fatty acids (33,321). In addition, understanding of how dietary supplementation of cofactors and coenzymes for enzymes that are inhibited by MeHg might alter MeHg toxicity is very limited and requires the focus of well-designed studies. Another interesting area not yet been explored is the effect of herbal foods and phytochemical agents on MeHg intoxication.

We hope that this review will stimulate interest and consideration of nutritional parameters in studies of MeHg intoxication and lead to further studies addressing mechanistic hypotheses. Currently, the epidemiologic links between exposure to MeHg and beneficial or detrimental effects of diet have not been established, but it is clear that dietary factors need to be better addressed in future epidemiologic and clinical studies. Emphasis should be given to assessing overall dietary quality, with appropriate recommendations, as needed, to reduce MeHg exposure.

Appendix

(The Appendix contains tables 1-10 in a 193 K pdf file.) Individual tables can be reached through the following links.
Table 1 (97 K)
Table 2 (97 K)
Tables 3-4 (97 K)
Table 5 (97 K)
Table 6 (97 K)
Table 7 (97 K)
Table 8 (97 K)
Table 9 (97 K)
Table 10 (97 K)

For further information on viewing pdf files, please go here.

REFERENCES AND NOTES

1. World Health Organization. Methyl mercury. Environ Health Crit 101:144 (1990).

2. Lodenius M, Malm O. Mercury in the Amazon. Rev Environ Contam Toxicol 157:25-52 (1998).

3. Myers GJ, Davidson PW, Shamlaye CF, Axtell C, Cernichiari E, Choisy O, Choi A, Cox C, Clarkson TW. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles Child Development Study. Neurotoxicology 18:819-830 (1997).

4. Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, Murata K, Sorensen N, Dahl R, Jorgensen PJ. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 19:417-428 (1997).

5. Myers GJ, Davidson PW. Prenatal methylmercury exposure and children - neurologic, developmental and behavioural research. Environ Health Perspect 106(suppl 3):841-847 (1998).

6. Chan HM. Metal accumulation and detoxification in humans. In: Metal Metabolism in Aquatic Environments (Langston WJ, Bebianno MJ, eds). London:Chapman and Hall, 1998;415-438.

7. Chowdhury BA, Chandra RK. Biological and health implications of toxic heavy metal and essential trace element interactions. Prog Food Nutr Sci 11:55-113 (1987).

8. Clarkson TW. Human toxicology of mercury. J Trace Elem Exp Med 11:303-317 (1995).

9. Gochfeld M. Factors influencing susceptibility to metals. Environ Health Perspect 105(suppl 4):817-822 (1997).

10. Goyer RA. Toxic and essential metal interactions. Ann Rev Nutr 17:37-50 (1997).

11. Suzuki T, Imura N, Clarkson TW. Advances in Mercury Toxicology. New York:Plenum Press, 1991.

12. Tsubaki T, Irukayama K. Minamata Disease: Methylmercury Poisoning in Minamata and Niigata, Japan. Amsterdam:Elsevier, 1977.

13. Weiss B. Long ago and far away: a retrospective on the implications of Minamata. Neurotoxicology 17:257-263 (1996).

14. Boudou A, Ribeyre F. Mercury in the food web: accumulation and transfer mechanisms. Metal Ions Biol Syst 34:289-319 (1997).

15. Harada M, Nakanishi J, Konuma S, Ohno K, Kimura T, Yamaguchi H, Tsuruta K, Kizaki T, Ookawara T, Ohno H. The present mercury contents of scalp hair and clinical symptoms in inhabitants of the Minamata. Environ Res 77:160-164 (1998).

16. Fitzgerald WF, Clarkson TW. Mercury and monomethylmercury: present and future concerns. Environ Health Perspect 96:159-166 (1991).

17. Leonard A, Jacquet P, Lauwerys RR. Mutagenicity and teratogenicity of mercury compounds. Mutat Res Rev Gen Toxicol 114:1-18 (1983).

18. Gilbert SG, Grant-Webster K. Neurobehavioral effects of developmental methylmercury exposure. Environ Health Perspect 103(suppl 6):135-142 (1995).

19. Clarkson T. Methylmercury. Fundam Appl Toxicol 16:20-21 (1991).

20. Foldspang A, Hansen JC. Dietary intake of methylmercury as a correlate of gestational length and birth weight among newborns in Greenland. Am J Epidemiol 132:310-317 (1990).

21. Marsh DO, Clarkson TW, Myers GJ, Davidson PW, Cox C, Cernichiari E, Tanner MA, Lednar W, Shamlaye C, Choisy O. The Seychelles study of fetal methylmercury exposure and child development: introduction. Neurotoxicology 16:583-596 (1995).

22. Ratcliffe HE, Swanson GM, Fischer LJ. Human exposure to mercury - a critical assessment of evidence of adverse health effects. J Toxicol Environ Health 49:221-270 (1996).

23. Stern AH. Re-evaluation of the reference dose for methylmercury and assessment of current exposure levels. Risk Anal 13:355-364 (1993).

24. Davidson PW, Myers GJ, Cox C, Axtell C, Shamlaye C, Sloanereeves J, Cernichiari E, Needham L, Choi A, Wang YN, et al. Effects of prenatal and postnatal methyl mercury exposure from fish consumption on neurodevelopment - outcomes at 66 months of age in the Seychelles child development study. JAMA 280(8):701-707 (1998).

25. Grandjean P, Weihe P, White RF, Debes F. Cognitive performance of children prenatally exposed to safe levels of methyl mercury. Environ Res 77:165-172 (1998).

26. Feeley MM, Lo MT. Risk assessment for mercury in Health Canada - development of the provisional tolerable daily intake (pTDI) value. In: Mercury in Eastern Canada and the Northeast States. Proceedings of the Conference, 21-23 September 1998, Fredericton, New Brunswick. New Brunswick, Ontario, Canada: Ecological Monitoring and Assessment Network, 1999;32.

27. Rice G, Mahaffey K, Lyon B. Predicting exposure: US EPA Mercury Report to Congress. In: Mercury in Eastern Canada and the Northeast States. Proceedings of the Conference, 21-23 September 1998, Fredericton, New Brunswick. New Brunswick, Ontario, Canada:Ecological Monitoring and Assessment Network, 1999;32.

28. Dewailly E. Evaluation of prenatal exposure to organochlorines and heavy metals in Nunavik newborns 1993-1996. In: Environmental Studies No 74: Synopsis of Research Conducted under the 1995-1997 Northern Contaminants Program (Jensen J, ed). Ottawa, Canada:Indian and Northern Affairs Canada, 1997;293.

29. Wheatley MA, Wheatley B. The effect of eating habits on mercury levels among Inuit residents of Sugluk, PQ. Inuit Stud 5:27-43 (1981).

30. Farkas CS. Commentary: potential for and implications of thiamine deficiency in northern Canadian Indian populations affected by mercury contamination. Ecol Food Nutr 8:11-20 (1979).

31. Grandjean P. Reference intervals for trace elements in blood: significance of risk factors. Scan J Clin Lab Invest 52(4):321-337 (1992).

32. Grandjean P, Weihe P, Jorgensen PJ, Clarkson T, Cernichiari E, Videro T. Impact of maternal seafood diet on fetal exposure to mercury, selenium, and lead. Arch Environ Health 47:185-195 (1992).

33. Anttolainen M, Valsta LM, Alfthan G, Kleemola P, Salminen I, Tamminen M. Effect of extreme fish consumption on dietary and plasma antioxidant levels and fatty acid composition. Eur J Clin Nutr 50:741-746 (1996).

34. Hansen JC, Kromann N, Wulf HC, Alboge K. Selenium and its interrelation with mercury in wholeblood and hair in an East Greenlandic population. Sci Total Environ 38:33-40 (1984).

35. Wormworth J. Toxins and tradition: the impact of food-chain contamination on the Inuit of northern Quebec. Canada Med Assoc J 152:1237-1240 (1995).

36. Meltzer HM, Mundal HH, Alexander J, Bibow K, Ydersbond TA. Does dietary arsenic and mercury affect cutaneous bleeding time and blood lipids in humans? Biol Trace Elem Res 46:135-153 (1994).

37. Futatsuka M, Ueda A, Yasutake R, Nomura S. Estimation of daily dietary intake of methyl mercury in Minamata district. Kumamoto Med J 35:23-33 (1982).

38. Tamashiro H, Arakaki M, Akagi H, Futatsuka M, Higa K. Mortality and life-table in Minamata disease. Jpn J Public Health 30:403-412 (1983).

39. Tsuda M, Hasunuma R, Kawanishi Y, Okazaki I. Urinary concentrations of heavy metals in healthy Japanese under 20 years of age: a comparison between concentrations expressed in terms of creatinine and of selenium. Tokai J Exp Clin Med 20:53-64 (1995).

40. Sallsten G, Thoren J, Barregard L, Schutz A, Skarping G. Long-term use of nicotine chewing gum and mercury exposure from dental amalgam fillings. J Dental Res 75:594-598 (1996).

41. Turan B, Delilbasi E, Dalay N, Sert S, Afrasyap L, Sayal A. Serum selenium and glutathione-peroxidase activities and their interaction with toxic metals in dialysis and renal transplantation patients. Biol Trace Elem Res 33:95-102 (1992).

42. Svensson BG, Schutz A, Nilsson A, Akesson I, Akesson B, Skerfving S. Fish as a source of exposure to mercury and selenium. Sci Total Environ 126:61-74 (1992).

43. Oskarsson A, Schultz A, Skerfving S, Hallen IP, Ohlin B, Lagerkvist BJ. Total and inorganic mercury in breast milk in relation to fish consumption and amalgam in lactating women. Arch Environ Health 51:234-241 (1996).

44. Calabrese EJ, Stoddard A, Leonard DA, Dinardi SR. The effects of vitamin C supplementation on blood and hair levels of cadmium, lead, and mercury. Ann NY Acad Sci 498:347-353 (1987).

45. Alexander J, Thomassen Y, Aaseth J. Increased urinary excretion of selenium among workers exposed to elemental mercury vapor. J Appl Toxicol 3:143-145 (1983).

46. Galal-Gorchev H. Dietary intake of pesticide residues: cadmium, mercury, and lead. Food Addit Contam 8:793-806 (1991).

47. Galal-Gorchev H. Dietary intake, levels in food and estimated intake of lead, cadmium, and mercury. Food Addit Contam 10:115-128 (1993).

48. Aronsson AM, Lind B, Nylander M, Nordberg M. Dental amalgam and mercury. Biol Metals 2:25-30 (1989).

49. Muckle G, Dewailly E, Ayotte P. Prenatal exposure of Canadian children to polychlorinated biphenyls and mercury. Can J Publ ic Health 89:S20-S25 (1998).

50. Wheatley B, Paradis S. Exposure of Canadian aboriginal peoples to methylmercury. Water Air Soil Pollut 80:3-11 (1995).

51. Suzuki T. Mercury in human ecology. In: Advances in Mercury Toxicology (Suzuki T, Imura N, Clarkson TW, eds). New York:Plenum Press, 1991;459-483.

52. Skerfving S. Mercury in women exposed to methylmercury through fish consumption, and in their newborn babies and breast milk. Bull Environ Contam Toxicol 41:475-482 (1988).

53. Lebel J, Mergler D, Lucotte M, Amorim M, Dolbec J, Miranda D, Arantes G, Rheault I, Pichet P. Evidence of early nervous system dysfunction in Amazonian populations exposed to low-levels of methylmercury. Neurotoxicology 17:157-167 (1996).

54. Nielsen JB, Andersen O. A comparison of the lactational and transplacental deposition of mercury in offspring from methylmercury-exposed mice. Effect of seleno-l-methionine. Toxicol Lett 76:165-171 (1995).

55. Ganther HE, Goudie C, Sunde ML, Kopecky MJ, Wagner P, Oh SH, Hoekstra WG. Selenium: relation to decreased toxicity to methyl mercury added to diets containing tuna. Science 175:1122-1124 (1972).

56. Cuvin-Aralar MLA, Furness RW. Mercury and selenium interaction: a review. Ecotoxicol Environ Saf 21:348-364 (1991).

57. Magos L. Overview on the protection given by selenium against mercurials. In: Advances in Mercury Toxicology (Suzuki T, Imura N, Clarkson TW, eds). New York:Plenum Press, 1991;289-297.

58. Grandjean P, Weihe P. Neurobehavioral effects of intrauterine mercury exposure: potential sources of bias. Environ Res 61:176-183 (1993).

59. Atchison WD, Hare MF. Mechanisms of methyl mercury-induced neurotoxicity. FASEB J 8:622-629 (1994).

60. Sarafian T, Verity MA. Oxidative mechanisms underlying methyl mercury neurotoxicity. Int J Dev Neurosci 9:147-153 (1991).

61. Chmielnicka J, Komsta-Szumska E, Zareba G. Effect of interaction between ⁶⁵Zn, mercury and selenium in rats (retention, metallothionein, endogenous copper). Arch Toxicol 53:165-175 (1983).

62. Imura N, Naganuma A. Mode of modifying action of selenite on toxicity and behavior of mercury and other metals. Nutr Res (suppl 1):499-507 (1985).

63. Whanger PD. Selenium in the treatment of heavy metal poisoning and chemical carcinogenesis. J Trace Elem Electrol Health Dis 6:209-221 (1992).

64. Calabrese EJ. Nutrition and Environmental Health, Vol 1. New York:John Wiley and Sons, 1980;94-519.

65. Levander OA, Cheng L. Micronutrient Interactions, Vitamins, Minerals, and Hazardous Elements. Ann NY Acad Sci 355:1-372 (1980).

66. Solomons NW, Viteri FE. Biological interaction of ascorbic acid and mineral nutrients [iron, selenium, copper, nickel, manganese, zinc, cobalt, cadmium, mercury, vitamin C]. Adv Chem Ser 200:551-569 (1982).

67. Peraza MA, Ayalafierro F, Barber DS, Casarez E, Rael LT. Effects of micronutrients on metal toxicity. Environ Health Perspect 106(suppl 1):203-216 (1998).

68. Sharma DC. Biochemical basis of the toxicity of mercury. Med Hypotheses 23:259-263 (1987).

69. Adachi T, Yasutake A, Hirayama K. Influence of dietary protein and sulfer amino acids on the fate of methyl mercury in mice. Toxicology 93:225-234 (1994).

70. Stillings BR, Lagally H, Bauersfeld P, Soares J. Effect of cystine, selenium and fish protein on the toxicity and metabolism of methylmercury in rats. Toxicol Appl Pharmacol 30:243-254 (1974).

71. El-Begearmi MM, Ganther HE, Sunde ML. Dietary interaction between methylmercury, selenium, arsenic, and sulfur amino acids in Japanese quail. Poult Sci 61:272-279 (1982).

72. Ohi G, Nishigaki S, Seki H, Tamura Y, Maki T, Konno H, Ochiai S, Yamada H, Shimamura Y, Mizoguchi I, et al. Efficacy of selenium in tuna and selenite in modifying methylmercury intoxication. Environ Res 12:49-58 (1976).

73. Cha C. A study on the effect of garlic to the heavy metal poisoning of rat. J Korean Med Sci 2:213-223 (1987).

74. Alexander J, Aaseth J. Organ distribution and cellular uptake of methyl mercury in the rat as influenced by the intra- and extracellular glutathione concentration. Biochem Pharmacol 31:685-690 (1982).

75. Bala KVCS, Sridevi K, Rao KP. Inhibition of methyl mercury chloride-induced chromosomal damage by -linolenic acid. Food Chem Toxicol 31:431-434 (1993).

76. Aschner M, Clarkson TW. Mercury 203 distribution in pregnant and nonpregnant rats following systemic infusions with thiol-containing amino acids. Teratology 36:321-328 (1987).

77. Kasuya M. Effects of inorganic, aryl, alkyl and other mercury compounds on the outgrowth of cells and fibers from dorsal root ganglia in tissue culture. Toxicol App Pharmacol 23:136-146 (1972).

78. Rowland IR, Mallett AK, Flynn J, Hargreaves RJ. The effect of various dietary fibres on tissue concentration and chemical form of mercury after methylmercury exposure in mice. Arch Toxicol 59:94-98 (1986).

79. McNeil SI, Bhatnagar MK, Turner CJ. Combined toxicity of ethanol and methylmercury in rat. Toxicology 53:345-363 (1988).

80. Dunn JD, Clarkson TW, Magos L. Ethanol reveals novel mercury detoxification step in tissues. Science 213:1123-1125 (1981).

81. Zalups RK, Lash LH. Binding of mercury in renal brush-border and basolateral membrane-vesicles-implication of a cysteine conjugate of mercury involved in the luminal uptake of inorganic mercury in the kidney. Biochem Pharmacol 53:1889-1900 (1997).

82. Aschner M, Clarkson TW. Uptake of methylmercury in the rat brain: effects of amino acids. Brain Res 462:31-39 (1988).

83. Kim P, Choi BH. Selective inhibition of glutamate uptake by mercury in cultured mouse astrocytes. Yonsei Med J 36:299-305 (1995).

84. Kling LJ, Soares JH. The effect of vitamin E and dietary linoleic acid on mercury toxicity. Nutr Rep Int 24:39-45 (1981).

85. Landry TD, Doherty RA, Gates AH. Effects of three diets on mercury excretion after methylmercury administration. Bull Environ Contam Toxicol 22:151-8 (1979).

86. Jugo S. Metabolism of toxic heavy metals in growing organisms: a review. Environ Res 13:36-46 (1977).

87. Adachi T, Yasutake A, Hirayama K. Influence of dietary protein levels on the fate of methylmercury and glutathione metabolism in mice. Toxicology 72:17-26 (1992).

88. Rowland IR, Robinson RD, Doherty RA. Effects of diet on mercury metabolism and excretion in mice given methylmercury: role of gut flora. Arch Environ Health 39:401-408 (1984).

89. Adachi T, Yasutake A, Eto K, Hirayama K. Influence of dietary protein levels on the acute toxicity of methylmercury in mice. Toxicology 112:11-17 (1996).

90. Farkas CS. Strong tea and mercury in relation to the nutritional status of northern Canadian Indians [Abstract]. J Can Diet Assoc 38:248 (1977).

91. Richardson RJ, Wilder AC, Murphy SD. Uptake of mercury and mercury-amino acid complexes by rat renal cortex slices. Proc Soc Exp Biol Med 150:303-307 (1975).

92. Hirayama K. Effect of amino acids on brain uptake of methyl mercury. Toxicol Appl Pharmacol 55:318-323 (1980).

93. Wu G. Screening of potential transport systems for methyl mercury uptake in rat erythrocytes at 5 degrees by use of inhibitors and substrates. Pharmacol Toxicol 77:169-176 (1995).

94. Wu G. No involvement of system N, System Y⁺ and the oligopeptide-H⁺ transport system in the uptake of methylmercury in rat erythrocytes. J Appl Toxicol 18:55-61 (1998).

95. Smith JR, Smith JG. Effects of methylmercury in vitro on methionine synthase activity in various rat tissues. Bull Environ Contam Toxicol 45:649-654 (1990).

96. Yannai S, Sachs KM. Absorption and accumulation of cadmium, lead and mercury from foods by rats. Food Chem Toxicol 31:351-355 (1993).

97. Nielsen JB, Andersen O. The toxicokinetics of mercury in mice offspring after maternal exposure to methylmercury--effect of selenomethionine. Toxicology 74:233-241 (1992).

98. Mykkanen HM, Metsaniitty L. Selenium-mercury interaction during intestinal absorption of ⁷⁵Se compounds in chicks. J Nutr 117:1453-1458 (1987).

99. Zalups RK, Barfuss DW. Small aliphatic dicarboxylic acids inhibit renal uptake of administered mercury. Toxicol Appl Pharmacol 148:183-193 (1998).

100. Kuznetsov DA. Paradoxical effect of methyl mercury on mitochondrial protein synthesis in mouse brain tissue. Neurochem Res 12:751-753 (1987).

101. Thomas DJ, Smith JC. Effects of coadministered low-molecular-weight thiol compounds on short-term distribution of methyl mercury in the rat. Toxicol Appl Pharmacol 62:104-110 (1982).

102. Sood PP, Vinay SD. Therapeutic abilities of thiol compounds in the restoration of methylmercury-inhibited cholesterol and triglycerides of the rat's central nervous system. Arch Environ Contam Toxicol 21:212-217 (1991).

103. Bapu C, Vijaylakshmi K, Sood PP. Comparison of monothiols and vitamin therapy administered alone or in combinations during methyl mercury poisoning. Bull Environ Contam Toxicol 52:182-189 (1994).

104. Yasutake A, Hirayama K, Inoue M. Interaction of methylmercury compounds with albumin. Arch Toxicol 64:639-643 (1990).

105. Srivastava DK. Comparative effects of copper, cadmium and mercury on tissue glycogen of the catfish, Heteropneustes fossils (Bloch). Toxicol Lett 11:135-139 (1982).

106. Varghese G, Naik PS, Katdare M. Respiratory responses and blood sugar level of the crab, Barytelphusa cunicularis (Westwood), exposed to mercury, copper and zinc. Ind J Expl Biol 30:308-312 (1992).

107. Babcan J, Sevc J. Mercury (Hg II) in systems with natural organic matter. Ekol-Bratislava 13:199-205 (1994).

108. Shoaf AR, Jarmer S, Harbison RD. Heavy metal inhibition of carnitine acetyltransferase activity in human placental syncytiotrophoblast: possible site of action of HgCl₂, CH₃HgCl, and CdCl₂ Terat og Carcinog Mutagen 6:351-360 (1986).

109. Nakada S, Imura N. Uptake of methylmercury and inorganic mercury by mouse glioma and mouse neuroblastoma cells. Neurotoxicology 3:249-258 (1982).

110. Donaldson WE. Mercury inhibition of avian fatty acid synthetase complex. Chem-Biol Interact 11:343-350 (1975).

111. Hojbjerg S, Nielsen JB, Anderson O. Effects of dietary lipids on whole-body retention and organ distribution of organic and inorganic mercury in mice. Food Chem Toxicol 30:703-708 (1992).

112. Rodriguez-Yoldi MJ, Lluch M, Ponz F. Action of mercury on sugar transport across rat small intestine, in vivo. Revista Espanola Fisiolog 43:239-244 (1987).

113. Lugea A, Barber A, Ponz F. Inhibition of d-galactose and l-phenylalanine transport by HgCl₂ in rat intestine in vitro. Revista Espanola Fisiolog 50:167-173 (1994).

114. Yee S, Choi BH. Oxidative stress in neurotoxic effects of methylmercury poisoning. Neurotoxicology 17:18-26 (1996).

115. Naganuma A, Imura N. Changes in in vitro interaction profiles of mercuric mercury and selenite in rabbit blood under various reaction conditions. J Pharmacobio-Dyn 6:331-339 (1983).

116. Naganuma A, Imura N. Species difference in biliary excretion of methylmercury. Biochem Pharmacol 33:679-682 (1984).

117. Morimoto K, Iijima S, Koizumi A. Selenite prevents the induction of sister-chromatid exchanges by methylmercury and mercuric chloride in human whole-blood cultures. Mutat Res 102:183-192 (1982).

118. Kling LJ, Soares JH. Vitamin E deficiency in the Japanese quail. Poult Sci 59:2352-2354 (1980).

119. Stoewsand GS, Bache CA, Lisk DJ. Dietary selenium protection of methylmercury intoxication of Japanese quail. Bull Environ Contam Toxicol 11:152-156 (1974).

120. Balthrop JE, Braddon SA. Effects of selenium and methyl mercury upon glutathione and glutathione S-transferase in mice. Arch Environ Contam Toxicol 14:197-202 (1985).

121. Caurant F, Navarro M, Amiard JC. Mercury in pilot whales: possible limits to the detoxification. Sci Total Environ 186:95-104 (1996).

122. Chen RW, Lacy VL, Whanger PD. Effect of selenium on methyl mercury binding to subcellular soluble protein in rat tissue. Res Comm Chem Pathol Pharmacol 12:297-308 (1975).

123. Magos L, Clarkson TW, Sparrow S, Hudson AR. Comparison of the protection given by selenite, selenomethionine and biological selenium against the renotoxicity of mercury. Arch Toxicol 60:422-426 (1987).

124. Fukino H, Hirai M, Hsueh YM, Yamane Y. Effect of zinc pretreatment on mercuric chloride-induced lipid peroxidation in the rat kidney. Toxicol Appl Pharmacol 73(3):395-401 (1984).

125. Fukino H, Hirai M, Hsueh YM, Moriyasu S, Yamane Y. Mechanism of protection by zinc against mercuric chloride toxicity in rats: effects of zinc and mercury on glutathionine metabolism. J Toxicol Environ Health 19:75-89 (1986).

126. Kumagai Y, Hommatakeda S, Shinyashiki M., Shimojo N. Alterations in superoxide dismutase isozymes by methylmercury. Appl Organ Chem 11:635-643 (1997).

127. Bapu C, Purohit RC, Sood PP. Fluctuation of trace elements during methylmercury toxication and chelation therapy. Human Exp Toxicol 13:815-823 (1994).

128. Lee W, Swinehart JH, Crowe JH. The effects of copper(II), mercury(II) and iron(III) onprimary amines and divalent cation losses from and glycine incorporation into the gills of the bivalve mollusc, Mytilus californianus. Molec Physiol 3:79-87 (1983).

129. Bodgen JD, Kemp FW, Troiano RA, Jortner BS, Timpone C, Giuliani D. Elevated renal copper from mercury exposure. In: Trace Substances in Environmental Health: Proceedings of University of Missouri's Annual Conference (13th), University of Missouri. Columbia, MO:University of Missouri, 1979;353-359.

130. Chetty CS, Rajanna S, Hall E, Yallapragada PR, Rajanna B. In vitro and in vivo effects of lead, methyl mercury and mercury on inositol 1,4,5-triphosphate and 1,3,4,5-tetrakisphosphate receptor bindings in rat brain. Toxicol Lett 87:11-17 (1996).

131. Kostial K, Kargacin B, Simonovic I. Iodine in diet increases mercury absorption in rats. J Appl Toxicol 2:215-216 (1982).

132. Liu X, Nordberg GF, Jin T. Increased urinary excretion of zinc and copper by mercuric chloride injection in rats. Biometals 5:17-22 (1992).

133. Bohme M, Diener M, Rummel W. Chloride secretion induced by mercury and cadmium: action sites and mechanisms. Toxicol Appl Pharmacol 114:295-301 (1992).

134. Siegel BZ, Siegel SM, Correa T, Dagan C, Galvez G, LeeLoy L, Padua A, Yaeger E. The protection of invertebrates, fish, and vascular plants against inorganic mercury poisoning by sulfur and selenium derivatives. Arch Environ Contam Toxicol 20:241-246 (1991).

135. Komsta-Szumska E, Chmielnicka J. Effect of zinc, cadmium or copper on mercury distribution in rat tissues. Toxicol Lett 17:349-354 (1983).

136. Anner BM, Moosmayer M, Imesch E. Mercury blocks Na-K-ATPase by a ligand-dependent and reversible mechanism. Am J Physiol 262:F830-F836 (1992).

137. Aschner M, Vitarella D, Allen JW, Conklin DR, Cowan KS. Methylmercury-induced astrocytic swelling is associated with activation of the Na⁺/H⁺ anti-porter, and is fully reversed by amiloride. Brain Res 799:207-214 (1998).

138. Wang X, Horisberger JD. Mercury binding site on Na⁺/K⁽⁺⁾-ATPase: a cysteine in the first transmembrane segment. Mol Pharmacol 50(3):687-691 (1996).

139. Gregus Z, Stein AF, Varga F, Klaassen CD. Effect of lipoic acid on biliary excretion of glutathione and metals. Toxicol Appl Pharmacol 114:88-96 (1992).

140. Leskova GE. Protective effect of lipoic acid amide in experimental mercurialism. Gig Tr Prof Zalbol 6:27-30 (1979).

141. Kling LJ, Soares JH. Effect of mercury and vitamin E on tissue gluthione peroxidase activity and thiobarbituric acid values. Poult Sci 61:1762-1765 (1982).

142. Kling LJ, Soares JH, Haltman WA. Effect of vitamin E and synthetic antioxidants on the survival rate of mercury-poisoned Japanese quail. Poult Sci 66:325-331 (1987).

143. Chang LW, Gilbert M, Sprecher J. Modification of methylmercury neurotoxicity by vitamin E. Environ Res 17:356-366 (1978).

144. Kasuya M. Effect of vitamin E on the toxicity of alkyl mercurials on nervous tissue in culture. Toxicol Appl Pharmacol 32:347-354 (1975).

145. Park ST, Lim KT, Chung YT, Kim SU. Methylmercury-induced neurotoxicity in cerebral neuron culture is blocked by antioxidiants and NMDA receptor antagonists. Neurotoxicology 17(1):37-46 (1996).

146. Andersen HR, Andersen O. Effects of dietary -tocopherol and ß-carotene on lipid peroxidation induced by methyl mercuric chloride in mice. Pharmacol Toxicol 73:192-201 (1993).

147. Zorn NE, Smith JT. A relationship between vitamin B₁₂, folic acid, ascorbic acid and mercury uptake and methylation. Life Sci 47:167-173 (1990).

148. Welsh SO. Contrasting effects of vitamins A and E on mercury poisoning [Abstract]. Fed Proc 36:1146 (1977).

149. Blackstone S, Hurley RJ, Hughes RE. Some inter-relationships between vitamin C (l-ascorbic acid) and mercury in the guinea-pig. Food Cosmet 12:511-516 (1974).

150. Murray DR, Hughes RE. The influence of dietary ascorbic acid on the concentration of mercury in guinea-pig tissues. Proc Nutr Soc 35:118A-119A (1976).

151. Worker NA, Migicovsky BB. Effect of vitamin D on the utilation of zinc, cadmium and mercury in the chick. J Nutr 75:222-224 (1961).

152. Donaldson WE. Biotin deficiency and lipogenesis in chicks: paradoxical stimulation of lipogenesis by dietary mercury. Nutr Rep Int 23:95-101 (1981).

153. Matts RL, Schatz JR, Hurst R, Kagen R. Toxic heavy metal ions activate theheme-regulated eukaryotic initiation factor-2 alpha kinase by inhibiting the capacity of hemin-supplemented reticulocyte lysates to reduce disulfide bonds. J Biol Chem 266:12695-12702 (1991).

154. U.S. National Toxicology Program. Scientfific issues relevant to assessment of net health effects from exposure to methylmercury. Research Triangle Park, NC:National Institute of Environmental Health Sciences, 1999.

155. Yannai S, Mokady S, Sachs K, Berk Z. The safety of several algae grown on wastewater as a feedstuff for broilers. Archiv Hydrobiologie Beiheft 11:139-149 (1978).

156. Welsh SO, Soares JH. The bioavailability of mercury in the tissue of hens fed methyl mercury chloride [Abstract]. Fed Proc 33:660 (1974).

157. Ohi G, Nishigaki S, Seki H, Tamura Y, Maki T, Maeda H, Ochiai S, Yamada H, Shimamura Y, Yagyu H. Interaction of dietary methylmercury and selenium on accumulation and retention of these substances in rat organs. Toxicol Appl Pharmacol 32:527-533 (1975).

158. Clarkson TW. The pharmacology of mercury compounds. Ann Rev Pharmacol 12:375-406 (1972).

159. Norseth T, Clarkson TW. Intestinal transport of 203Hg-labeled methyl mercury chloride. Role of biotransformation in rats. Arch Environ Health 22:568-577 (1971).

160. Cambar J, Boudou A, Hocquellet P, Faugere JG. Mercury fixation in different subfractions of human serum albumin separated by polyacrylamide gel electrophoresis. Eur J Toxicol Environ Hyg 8:201-204 (1975).

161. Norseth T. Biliary excretion and intestinal reabsorption of mercury in the rat after injection of methyl mercuric chloride. Acta Pharmacol Toxicol 33:280-288 (1973).

162. Endo T, Nakaya S, Kimura R, Murata T. Gastrointestinal absorption of inorganic mercuric compounds in vivo and in situ. Toxicol Appl Pharmacol 74:223-229 (1984).

163. Seko Y, Miura T, Takahashi M. Reduced decomposition and faecal excretion of methyl mercury in caecum-resected mice. Acta Pharmacol Toxicol 50:117-120 (1982).

164. Iturri S, Nunez MT. Effect of copper, cadmium, mercury, manganese and lead on Fe²⁺ and Fe³⁺ absorption in perfused mouse intestine. Digestion 59:671-675 (1998).

165. Norseth T, Clarkson TW. Studies on the biotransformation of ²⁰³Hg-labeled methyl mercury chloride in rats. Arch Environ Health 21:717-727 (1970).

166. Mokrzan EM, Kerper LE, Ballatori N, Clarkson TW. Methylmercury-thiol uptake into cultured brain capillary endothelial cells on amino acid system l. J Pharmacol Exp Ther 272:1277-1284 (1995).

167. Aschner M, Aschner JL. Mercury neurotoxicity: mechanisms of blood-brain barrier transport. Neurosci Biobehav Rev 14:169-176 (1990).

168. Magos L. Physiology and toxicology of mercury. Metal Ions Biol Sys 34:321-370 (1997).

169. Clarkson TW. Molecular and ionic mimicry of toxic metals. Ann Rev Pharmacol Toxicol 33:545-571 (1993).

170. Steinwall O, Olsson Y. Impairment of the blood-brain barrier in mercury poisoning. Acta Neurol Scand 45:351-361 (1969).

171. Danielsson BR, Dencker L, Khayat A, Orsen I. Fetotoxicity of inorganic mercury in the mouse: distribution and effects on nutrient uptake by placenta and fetus. Biol Res Preg Perinatol 5:102-109 (1984).

172. Iioka H, Moriyama I, Itoh K, Hino K, Okamura Y, Itani Y, Katoh Y, Ichijo M. The role of glutathione on placental amino acid transport (using microvillous membrane vesicles) [in Japanese]. Nippon Sanka Fujinka Gakkai Zasshi - Acta Obstetrica et Gynaecologica Japonica 39:2133-2136 (1987).

173. Urbach J, Boadi W, Brandes JM, Kerner H, Yannai S. Effect of inorganic mercury on in vitro placental nutrient transfer and oxygen consumption. Reprod Toxicol 6:69-75 (1992).

174. Hojbjerg SG. The effect of nutritional factors on absorption, retention and excretion or oranic and inorganic mercury in mice and rats [Abstract]. Danish Med Bull 43:376 (1996).

175. Rowland I. The influence of the gut microflora on food toxicity. Proc Nutr Soc 40:67-74 (1981).

176. Aizpurua ICM, Tenuta A, Sakuma AM, Zenebon O. Use of cysteine to remove mercury from shark muscle. Int J Food Sci Tech 32:333-337 (1997).

177. Welsh SO, Soares JH, Stillings BR, Lagally H. Effects of mercury and selenium on serum transaminase levels of quail, hens and rats. Nutr Rep Int 8:419-429 (1973).

178. Hirayama K. Effects of combined administration of thiol compounds and methylmercury chloride on mercury distribution in rats. Biochem Pharmacol 34:2030-2032 (1985).

179. Ohi G, Nishigaki S, Seki H, Tamura Y, Maki T, Minowa K, Shimamura Y, Mizoguchi I, Inaba Y, Takizawa Y, et al. The protective potency of marine animal meat against the neurotoxicity of methylmercury: its relationship with the organ distribution of mercury and selenium in the rat. Food Cosmet Toxicol 18:139-145 (1980).

180. Vijayalakshmi K, Bapu C, PP Sood. Differential effects of methylmercury, thiols and vitamins on galactosidases of nervous and non-nervous tissues. Bull Environ Contam Toxicol 49:71-77 (1992).

181. Eaton RDP, Secord DC, Hewitt P. An experimental assessment of the toxic potential of mercury in ringed seal liver [from Canadian waters] for adult laboratory cats. Toxicol Appl Pharmacol 55:514-521 (1980).

182. Thrower SJ, Andrewartha KA. Glutathione peroxidase response in tissues of rats fed diets containing fish protein concentrate prepared from shark flesh of known mercury and selenium contents. Bull Environ Contam Toxicol 26:77-84 (1981).

183. Ganther HE, Sunde ML. Effect of tuna fish and selenium on the toxicity of methylmercury: a progress report. J Food Sci 39:1-15 (1974).

184. Takahashi H, Shibuya K, Fukushima Y. A study of the factors influencing toxicity of methylmercury [in Japanese]. Kumamota University Medical School Toxciol Rep 11:15-16 (1978).

185. Rumbeiha WK, Gentry PA, Bhatnagar MK. The effects of administering methylmercury in combination with ethanol in the rat. Vet Human Toxicol 34:21-25 (1992).

186. Tamashiro H, Arakaki M, Akagi H, Murao K, Hirayama K, Smolensky MH. Effects of ethanol on methyl mercury toxicity in rats. J Toxicol Environ Health 18:595-605 (1986).

187. Turner CJ, Bhatnagar MK, Yamashiro S. Ethanol potentiation of methyl mercury toxicity: a preliminary report. J Toxicol Environ Health 7:665-668 (1981).

188. Turner CJ, Bhatnagar MK, Speisky H. Effect of subchronic administration of ethanol and methylmercury in combination on the tissue distribution of mercury in rats. Can J Physiol Pharmacol 68:1558-1562 (1990).

189. Brookes N, Kristt DA. Inhibition of amino acid transport and protein synthesis by HgCl₂ and methylmercury in astrocytes: selectivity and reversibility. J Neurochem 53:1228-1237 (1989).

190. Bienvenue E, Boudou A, Desmazes JP, Gavach C, Georgescauld D, Sandeaux J, Seta P. Transport of mercury compounds across bimolecular lipid membranes: effect of lipid composition, pH and chloride concentration. Chem-Biol Interact 48:91-101 (1984).

191. Kronrad L, Petrbokova I, Vavrejn B. A comparison of the distribution of mercury and cadmium complexes with cysteine in rats and mice. Radiobiol-Radiother 14:569-575 (1973).

192. Meydani M, Meydani SN, Hathcock JN. Effects of dietary methionine, methylmercury, and atrazine on ex-vivo synthesis of prostaglandin E₁ and thromboxane B₂. Prostaglandins Leukotr Med 14:267-278 (1984).

193. Gage JC. Mechanisms for the biodegradation of organic mercury compounds: the action of ascorbate and of soluble proteins. Toxicol Appl Pharmacol 32:225-238 (1975).

194. Gaballah I, Kilbertus G. Recovery of heavy metal ions through decontamination of synthetic solutions and industrial effluents using modified barks. J Geochem Explor 62:241-286 (1998).

195. Rai LC, Gaur JP, Kumar HD. Protective effects of certain environmental factors on the toxicity of zinc mercury, and methylmercury to Chlorella vulgaris. Environ Res 25:250-259 (1981).

196. Kuznetsov DA, Zavijalov NV, Govorkov AV, Sibileva TM. Methyl mercury-induced nonselective blocking of phosphorylation processes as a possible cause of protein synthesis inhibition in vitro and in vivo. Toxicol Lett 36:153-160 (1987).

197. Sell JL, Horani FG. Influence of selenium on toxicity and metabolism of methylmercury in chicks and quail. Nutr Rep Int 14:439-447 (1976).

198. Goldsmith RH, Soares JH. Barbiturate potentiation in mercury poisoning. Bull Environ Contam Toxicol 13(6):737-740 (1975).

199. Komsta-Szumska E, Reuhl KR, Miller DR. Effect of selenium on distribution, demethylation, and excretion of methylmercury by the guinea pig. J Toxicol Environ Health 12:775-785 (1983).

200. Kleinschuster SJ, Yoneyama M, Sharma. A cell aggregation model for the protective effect of selenium and vitamin E on methylmercury toxicity. Toxicology 26:1-9 (1983).

201. Sumino K, Yamamoto R, Kitamura SA. Role of selenium against methyl mercury toxicity. Nature 268:73-74 (1977).

202. Kasuya M. Effect of selenium on the toxicity of methylmercury on nervous tissue in culture. Toxicol Appl Pharmacol 35:11-20 (1976).

203. Kling LJ, Soares JH. Mercury metabolism in Japanese quail. II: The effects of dietary mercury and selenium on blood and liver glutathione peroxidase activity and selenium concentration. Poult Sci 57:1286-1292 (1978).

204. Welsh SO, Soares JH. Effects of selenium and vitamin E on methyl mercury toxicity in the Japanese quail [Abstract]l. Fed Proc 34:913 (1975).

205. El-Begearmi MM, Sunde ML, Ganther HE. A mutual protective effect of mercury and selenium in Japanese quail. Poult Sci 56:313-322 (1977).

206. El-Begearmi MM, Goudie C, Ganther HE, Sunde ML. Attempts to quantitate the protective effects of selenium against mercury toxicity using Japanese quail [Abstract]. Fed Proc 32:886 (1973).

207. Welsh SO, Soares JH. Serum transaminase levels and the interacting effects of selenium and vitamin E in mercury toxicity [Abstract]. Fed Proc 32:261 (1973).

208. El-Begearmi MM, Ganther HE, Sunde ML. Vitamin E decreases methylmercury toxicity [Abstract]. Poult Sci 55:2033 (1976).

209. Hoffman DJ, Heinz GH. Effects of mercury and selenium on glutathione metabolism and oxidative stress in mallard ducks. Environ Toxicol Chem 17:161-166 (1998).

210. Heinz GH, Hoffman DJ. Methylmercury chlroide and selenomethionine interactions on health and reproduction in mallards. Environ Toxicol Chem 17:139-145 (1998).

211. Klaverkamp JF, Macdonald WA, Lillie WR, Lutz A. Joint toxicity of mercury and selenium in salmonid eggs. Arch Environ Contam Toxicol 12:415-419 (1983).

212. Nuutinen S, Kukkonen JVK. The effect of selenium and organic material in lake sediments on the bioaccumulation of methylmercury by Lumbriculus variegatus (oligochaeta). Biogeochemistry 40:267-278 (1998).

213. Froseth JA, Piper RC, Carlson JR. Relationship of dietary selenium and oral methylmercury to blood and tissue selenium and mercury concentration and deficiency-toxicity signs in swine [Abstract]. Fed Proc 33:660 (1974).

214. Pedersen TV, Block M, Part P. Effect of selenium on the uptake of methyl mercury across perfused gills of rainbow trout Oncorhynchus mykiss. Aquat Toxicol 40:361-373 (1998).

215. Thomas DJ, Smith JC. Effects of co-administered sodium selenite on short-term distribution of methyl mercury in the rat. Environ Res 34:287-294 (1984).

216. Johnson SL. MNS Thesis. Ithaca, NY:Cornell Univerisity,1972.

217. Chang LW, Suber R. Protective effect of selenium on methyl mercury toxicity: a possible mechanism. Bull Environ Contam Toxicol 29:285-289 (1982).

218. Iwata H, Okamoto H, Ohsawa Y. Effect of selenium on methylmercury poisoning. Res Comm Chem Pathol Pharmacol 5:673-680 (1973).

219. Masukawa T, Kito H, Hayashi M, Iwata H. Formation and possible role of bis(methylmercuric) selenide in rats treated with methylmercury and selenite. Biochem Pharmacol 31:75-78 (1982).

220. Potter S, Matrone G. Effects of selenium on methylmercury poisoning. Res Comm Chem Pathol Pharmacol 5:673-680 (1974).

221. Potter S, Matrone G. Effect of selenite on the toxicity of dietary methyl mercury and mercuric chloride in the rat. J Nutr 104:638-647 (1974).

222. Mochizuki Y, Kobayashi T, Doi R. In vitro effects of mercury-selenium compounds on enzymes.Toxicol Lett 14:201-206 (1982).

223. Yamamoto R, Suzuki T. Decreased membrane fragility of mouse erythrocytes by small dose of methylmercury and its restoration by coadministered selenite. Tohoku J Exp Med 137:297-303 (1982).

224. Di Simplicio P, Gorelli M, Vignani R, Leonzio C. The differential modulation of the enzymes of glutathione metabolism: indication of overlapping effects of toxicity and repair in mouse liver and kidney after dietary treatment with methyl mercury and sodium selenite. Biol Trace Elem Res 36:167-181 (1993).

225. Aschner M, Conklin DR, Yao CP, Allen JW, Tan KH. Induction of astrocyte metallothioneins (MTS) by zinc confers resistance against the acute cytotoxic effects of methyl mercury on cell swelling, Na⁺ uptake and K⁺ release. Brain Res 813:254-261 (1998b).

226. Sakaizumi M, Egami N. Enhancement of mercury compound toxicity to the embryos of Oryzias latipes by halogens. In: Radiation Effects on Aquatic Organisms (Egami N, ed). Baltimore:University Park Press, 1980;73-77.

227. Komsta-Szumska E, Miller DR. A kinetic analysis of the interaction between methyl mercury and selenium. Toxicology 33:229-238 (1984).

228. Di Simplicio P, Leonzio C. Effects of selenium and mercury on glutathione and glutathione-dependent enzymes in experimental quail. Bull Environ Contam Toxicol 42:15-21 (1989).

229. Nishikido N, Furuyashiki K, Naganuma A, Suzuki T, Imura N. Maternal selenium deficiency enhances the fetolethal toxicity of methyl mercury. Toxicol Appl Pharmacol 88:322-328 (1987).

230. Aschner M, Rising L, Mullaney KJ. Differential sensitivity of neonatal rat astrocyte cultures to mercuric chloride (MC) and methylmercury (MeHg): studies on K+ and amino acid transport and metallothionein (MT) induction. Neurotoxicology 17:107-116 (1996).

231. Krone CA, Robisch PA, Tilbury KL, Stein JE, Mackey EA, Becker PR, O'Hara TM, Philo LM. Elements in liver tissues of bowhead whales (Balaena mysticetus). Marine Mamm Sci 15:123-142 (1999).

232. Cappon CJ, Smith JC. Chemical form and distribution of mercury and selenium in eggs from chickens fed mercury-contaminated grain. Bull Environ Contam Toxicol 26:472-478 (1981).

233. Yanemoto J, Webb M, Magos L. Methylmercury stimulates the exhalation of volatile selenium and potentiates the toxicity of selenite. Toxicol Lett 24(1):7-14 (1985).

234. Sharma DC, Davis PS. Effect of sodium selenite and selenomethionine on the accumulation and acute toxicity of mercuric and methylmercuric chloride in the goldfish (Carassius auratus). Indian J Exp Biol 18:82-84 (1980).

235. Bjorkman L, Palm B, Nylander M, Nordberg M. Mercury and selenium distribution in human kidney cortex. Biol Trace Elem Res 40:255-265 (1994).

236. Suzuki KT, Sasakura C, Yoneda S. Binding sites for the (Hg-Se) complex on selenoprotein P Biochim Biophys Acta - Prot Struct Molec Enz 1429:102-112 (1998).

237. Naganuma A, Imura N. Bis(methylmercuric) selenide as a reaction product from rabbit blood. Res Comm Chem Pathol Pharmacol 27:163-173 (1980).

238. Iwata H, Masukawa T, Kito H, Hayashi M. Involvement of tissue sulfhydryls in the formation of a complex of methylmercury with selenium. Biochem Pharmacol 30:3159-3163 (1981).

239. Kling LJ, Soares JH. Mercury metabolism in Japanese quail. I: The effect of dietary mercury and selenium on their tissue distribution. Poult Sci 57:1279-1285 (1978).

240. Naganuma A, Nakajima E, Shigehara E, Tanaka M, Imura N. Mercury distribution in mouse brain after i.v. administration of bis(methylmercuric) selenide. Toxicol Lett 15:175-179 (1983).

241. Moller-Madsen B, Danscher G. Localization of mercury in CNS of the rat. IV: The effect of selenium on orally administered organic and inorganic mercury. Toxicol Appl Pharmacol 108:457-473 (1991).

242. Prohaska JR, Ganther HE. Interactions between selenium and methylmercury in rat brain. Chem-Biol Interact 16:155-167 (1977).

243. Fang S. Interaction of selenium and mercury in the rat. Chem-Biol Interact 17:25-40 (1977).

244. Johnson SL, Pond WG. Inorganic vs organic mercury toxicity in growing rats. Protection by dietary Se but not Zn. Nutr Rep Int 9:135-147 (1974).

245. Komiya K, Kawauchi S. Properties of the mercury and selenium complex formed in rat plasma in vivo. J Pharmcobio-Dyn 4:545-551 (1981).

246. Magos L, Webb M. Effect of selenium on the brain uptake of methylmercury. Arch Toxicol 38:201-207 (1977).

247. Wagner PA. Studies on the interaction of selenium with silver and methylmercury in the rat. PhD Thesis. Madison, WI:University of Wisconsin, 1975.

248. Seppanen K, Laatikainen R, Salonen JT, Kantola M, Lotjonen S, Harri M, Nurminen L, Kaikkonen J, Nyyssonen K. Mercury-binding capacity of organic and inorganic selenium in rat blood and liver. Biol Trace Elem Res 65:197-210 (1998).

249. Magos L, Webb M, Hudson AR. Complex formation between selenium and methyl mercury. Chem-Biol Interact 28:359-362 (1979).

250. Sharma DC, Davis PS, Sharma PK. Studies in search of modifiers of the toxicity of mercurials and speculations on its biochemical mechanism. Biochem Pharmacol 30(22):3105-3107 (1981).

251. Prasad KN, Ramanjujam M. Vitamin E and vitamin C alter the effect of methyl mercuric chloride on neuroblastoma and glioma cells in culture. Environ Res 21:343-349 (1980).

252. Welsh SO. The protective effect of vitamin E and N,N´-diphenyl-p-phenylenediamine (DPPD) against methyl mercury toxicity in the rat. J Nutr 109:1673-1681 (1979).

253. Chang LW, Dudley AW, Dudley MA, Ganther HE, Sunde ML. Modification of the neurotoxic effects of methylmercury by selenium. In: Neurotoxicology (Roizin L, Shiraki H, Greevie N, eds). New York:Raven Press, 1977;275-282.

254. Welsh SO. Influence of vitamin E on mercury poisoning in rats [Abstract]. Fed Proc 35:761 (1976).

255. Kasuya M. [Abstract] Jap J Hyg 30:61 (1976).

256. Sharma DC, Davis PS, Sharma PK. Effect of ascorbic acid on biotransformation and modification of the toxicity of mercurials in goldfish (Carassius auratus). Experientia 38:565-567 (1982).

257. Adachi T, Hirayama K. Dietary protein levels cause different effects of methionine supplement on the fate of methyl mercury in mice. Jpn J Toxic Environ Health 44:226-232 (1998).

258. Kostial K, Kargacin B, Landeka M. Influence of dietary ingredients on the body retention of strontium, cadmium and mercury in suckling rats. Toxicol Lett 23:163-168 (1984).

259. Kostial K, Rabar I, Ciganovic M, Simonovic I. Effect of milk on mercury absorption and gut retention in rats. Bull Environ Conxicol 23:566-571 (1979).

260. Kriznaric D, Cosovic B, Kozarac Z. The adsorption and interaction of long-chain fatty acids and heavy metals at the mercury electrode/sodium chloride solution interface. Mar Chem 14:17-29 (1983).

261. Magos L, Clarkson TW, Hudson AR. Differences in the effects of selenite and biological selenium on the chemical form and distribution of mercury after the simultaneous administration of HgCl₂ and selenium to rats. J Pharmacol Exp Ther 228:478-483 (1984).

262. Maines MD. Modulating factors that determine interindividual differences in response to metals. In: Risk Assessment of Essential Metals, Vol 1 (Mertz W, Abernathy CO, Olin SS, eds). Washington DC:Int Life Sci, 1994;21-24.

263. Chmielnicka J. Experimental study of interactions between selenium, zinc and copper. In: Proceedings of the Selenium-Tellurium Development Association International Symposium, Brussels, Belgium. Brussels, 1994;171-172.

264. Carmicheal NG, Squibb KS, Engel DW, Fowler BA. Metals in the molluscan kidney: uptake and subcellular distribution of 109Cd, ⁵⁴Mn and ⁶⁵Zn by the clam, Mercenaria mercenaria. Comp Biochem Physiol 65:203-206 (1980).

265. Gale TF. The amelioration of mercury-induced embryotoxic effects by simultaneous treatment with zinc. Environ Res 35:405-412 (1984).

266. LeBel CP, Ali SF, Bondy SC. Deferoxamine inhibits methyl mercury-induced increases in reactive oxygen species formation in rat brain. Toxicol Appl Pharmacol 112:161-165 (1992).

267. Peckham NH, Choi BH. Surface charge alterations in mouse fetal astrocytes due to methyl mercury: an ultrastructural study with cationized ferritin. Exp Molec Pathol 44:230-234 (1986).

268. Ali SF, LeBel CP, Bondy SC. Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity. Neurotoxicology 13:637-648 (1992).

269. Sarafian TA, Bredsen DE, Verity MA. Cellular resistance to methylmercury. Neurotoxicity 17:27-36 (1996).

270. Chang LW, Gilbert M, Sprecher J. Morphological evidence on the protective effects of vitamin E against methylmercury toxicity in the nervous system [Abstract]. Fed Proc 36:404 (1977).

271. Bender DA. B-vitamins in the nervous system. Neurochem Int 6:297-321 (1984).

272. Iwata H, Masukawa T, Kito H, Hayashi M. Degradation of methylmercury by selenium. Life Sci 31:859-866 (1982).

273. Ohi G, Susumu N, Seki H, Tamura Y, Maki T, Konno H, Ochiai S, Yamada H, Shimamura Y, Mizoguchi I, et al. Efficacy of selenium in tuna and selenite in modifying methylmercury intoxication. Environ Res 12:49-58 (1976).

274. Welsh SO, Soares JH. The protective effect of vitamin E and selenium against methyl mercury toxicity in the Japanese quail. Nutr Rep Int 13:43-51 (1976).

275. Sorg O, Schilter B, Honegger P, Monnettschudi F. Increased vulnerability of neurones and glial cells to low concentrations of methylmercury in a prooxidant situation. Acta Neuropathol 96:621-627 (1998).

276. Nielsen JB, Andersen O. Transplacental passage and fetal deposition of mercury after low-level exposure to methylmercury--effect of seleno-l-methionine. J Trace Elem Electrol Health Dis 6:227-232 (1992b).

277. Gill TS, Tewari H, Pande J. Use of the fish enzyme system in monitoring water quality: effects of mercury on tissue enzymes. Comp Biochem Physiol C 97:287-292 (1990).

278. Aschner M, Mullaney KJ, Wagoner D, Lash LH, Kimelberg HK. Intracellular glutathione (GSH) levels modulate mercuric chloride (MC)-and methylmercuric chloride (MeHgCl)-induced amino acid release neonatal rat primary astrocytes cultures. Brain Res 664:133-140 (1994).

279. Spindle A. Matsumoto N. Enhancement of methylmercury toxicity by l-cystine in cultured mouse blastocysts. Reprod Toxicol 1:279-284 (1987).

280. Menon NK, Lopez RR. The effects of mild congenital methylmercury intoxication on the metabolism of 3-hydroxybutyrate and glucose in the brains of suckling rats. Neurotoxicology 6:55-61 (1985).

281. Janik A. The toxic effect of methylmercuric chloride on the organism in light of research on the hematopoietic system and metabolism of carbohydrates and lipids in heart and liver [in Polish]. Folia Med Cracoviensia 32:319-332 (1991).

282. Das RM, Scott JE. Perinatal lung development following maternal exposure to methylmercuric chloride. Ped Pulmonol 17:11-21 (1994).

283. Rana SV, Sharma R. Co-enzyme effects of inorganic mercury in the liver of a freshwater fish Channa punctatus. J Appl Toxicol 2:275-277 (1982).

284. Bano Y, Hasan M. Mercury induced time-dependent alterations in lipid profiles and lipid peroxidation in different body organs of cat-fish Heteropneustes fossilis. J Environ Sci Health [B]: 24:145-166 (1989).

285. Cloez I, Dumont O, Piciotti M, Bourre JM. Alterations of lipid synthesis in the normal and dysmyelinating trembler mouse sciatic nerve by heavy metals (Hg, Pb, Mn, Cu, Ni). Toxicology 46:65-71 (1987).

286. Salminen K. Alterations of rat brain lipids in methyl mercury intoxication. Acta Vet Scand 16:76-83 (1975).

287. Thaxton P, Parkhurst CR, Cogburn LA, Young PS. Adrenal function in chickens experiencing mercury toxicity. Poult Sci 54:578-584 (1975).

288. George JM. Effect of mercury on response of isolated fat cells to insulin and lipolytic hormones. Endocrinology 89:1489-1498 (1971).

289. Abdulla M, Chmielnicka J. New aspects on the distribution and metabolism of essential trace elements after dietary exposure to toxic metals. Biol Trace Elem Res 23:25-53 (1989).

290. Bjorkman L, Mottet K, Nylander M, Vahter M, Lind B, Friberg L. Selenium concentrations in brain after exposure to methylmercury: relations between the inorganic mercury fraction and selenium. Arch Toxicol 69:228-234 (1995).

291. Falnoga I, Kregar I, Skreblin M, Tusek-Znidaric M, Stegnar P. Interactions of mercury in rat brain. Biol Trace Elem Res 37:71-83 (1993).

292. Webb M, Cain K. Functions of metallothioneins. Biochem Pharmacol 31:137-142 (1982).

293. Anner BM, Moosmayer M. Mercury inhibits Na-K-ATPase primarily at the cytoplasmic side. Am J Physiol 262:F843-F848 (1992).

294. Abramson JJ, Trimm JL, Weden L, Salama G. Heavy metals induce rapid calcium release from sarcoplasmic reticulum vesicles isolated from skeletal muscle. Proc Natl Acad Sci 80:1526-1530 (1983).

295. Atchison WD, Joshi U, Thornburg JE. Irreversible suppression of calcium entry into nerve terminals by methylmercury. J Pharmacol Exp Ther 238:618-624 (1986).

296. Sakamoto M, Ikegami N, Nakano A. Protective effects of Ca²⁺ channel blockers against methyl mercury toxicity. Pharmacol Toxicol 78:193-199 (1996).

297. Arakawa O, Nakahiro M, Narahashi T. Mercury modulation of GABA-activated chloride channels and non-specific cation channels in rat dorsal root ganglion neurons. Brain Res 551:58-63 (1991).

298. Refsvik T, Norseth T. Methyl mercuric compounds in rat bile. Acta Pharmacol Toxicol 36:67-78 (1975).

299. Cikrt M, Tichy M. Effect of some chelating agents on the biliary excretion of mercury in the organism. J Hyg Epidemiol Microbiol Immunol 24:346-355 (1980).

300. Magos L, Clarkson TW, Allen J. The interrelationship between non-protein bound thiols and the biliary excretion of methyl mercury. Biochem Pharmacol 27:2203-2208 (1978).

301. Refsvik T. The influence of some thiols on biliary excretion of methyl mercury. The influence of some thiols on biliary excretion of methyl mercury. Acta Pharmacol Toxicol 52:22-29 (1983).

302. Rubenstein DA, Soares JH. The effect of selenium on the biliary excretion and tissue deposition of two forms of mercury in the broiler chick. Poult Sci 58:1289-1298 (1979).

303. Magos L. Neurotoxicity, anorexia and the preferential choice of antidote in methylmercury intoxicated rats. Neurobehav Toxicol Teratol 4:643-646 (1982).

304. Thayer RH, Donaldson WE. Mercury inhibition of fatty acid synthesis in chicks. Chemico-Biol Interact 11:235-243 (1975).

305. Yamini B, Sleight SD. Effects of ascorbic acid deficiency on methyl mercury dicyandiamide toxicosis in guinea pigs. J Environ Pathol Toxicol Oncol 5:139-150 (1984).

306. Aaseth J. Recent advances in the therapy of metal poisonings with chelating agents. Human Toxicol 2:257-272 (1983).

307. Zalups RK, Parks LD, Cannon VT, Barfuss DW. Mechanisms of action of 2,3-dimercaptopropane-1-sulfonate and the transport, disposition, and toxicity of inorganic mercury in isolated perfused segments of rabbit proximal tubules. Molec Pharmacol 54:353-363 (1998).

308. Ballatori N, Lieberman MW, Wang W. N-Acetyl-cysteine as an antidote in methyl mercury poisoning. Environ Health Perspect 106:267-271 (1998).

309. Freeman HG, Shum G, Uthe JF. The selenium in swordfish in relation to total mercury content. J Environ Sci Health Part A 13:235-240 (1978).

310. Armbruster G, Gutenmann WH, Lisk DJ. The effects of six methods of cooking on residues of mercury in striped bass. Nutr Rep Int 37:123-126 (1988).

311. D'Arrigo V. Influence of the cooking method on mercury content in fish products. Industrie Alimentari 18:127-129 (1979).

312. Gutenmann WH, Lisk DJ. Higher average mercury concentration in fish fillets after skinning and fat removal. J Food Saf 11:99-103 (1991).

313. Kinloch D, Kuhnlein H, Muir DCG. Inuit foods and diet: a preliminary assessment of benefits and risks. Sci Total Environ 122:247-248 (1992).

314. Receveur O, Boulay M and Kuhnlein HV. Decreasing traditional food use affects diet quality for adult Dene/Metis in 16 communities of the Canadian Northwest Territories. J Nutr 127:2179-2186 (1997).

315. Trevisan R, Vedovato M, Tiengo A. The epidemiology of diabetes mellitus. Nephrol Dial Transplant 13 (suppl 8):2-5 (1998).

316. Shah M, Garg A. High-fat and high-carbohydrate diets and energy balance. Diabetes Care 19:1142-1152 (1996).

317. Wheatley MA. The importance of social and cultural effects of mercury on aboriginal peoples. Neurotoxicology 17(1):251-256 (1996).

318. Dumont C, Kosatsky T. Bush food contamination and public health policy. Arctic Med Res (suppl 1):699-703 (1991).

319. Burger J, Sanchez J, Gochfeld M. Fishing, consumption and risk perception in fisherfolk along an East Coast estuary. Environ Res 77:25-35 (1998).

320. Johnson BL, Hicks HE, Jones DE, Cibulas W, Wargo A, Derosa CT. Public health implications of persistent toxic substances in the Great Lakes and St. Lawrence Basins. J Great Lakes Res 24:698-722 (1998).

321. Dewailly E. Cord Blood Study. In: Environmental Studies, No 73 (Murray JL, Shearer RG, Han SL, eds). Ottawa, Canada:Minister of Public Works and Government Services Canada, 1996;283-994.

---

Last Updated: February 16, 2000