Environmental Medicine, Part 3: Long-Term Effects of Chronic Low-Dose Mercury Exposure

Mercury is ubiquitous in the environment, and in our mouths in the form of "silver" amalgams. Once introduced to the body through food or vapor, mercury is rapidly absorbed and accumulates in several tissues, leading to increased oxidative damage, mitochondrial dysfunction, and cell death. Mercury primarily affects neurological tissue, resulting in numerous neurological symptoms, and also affects the kidneys and the immune system. It causes increased production of free radicals and decreases the availability of antioxidants. It also has devastating effects on the glutathione content of the body, giving rise to the possibility of increased retention of other environmental toxins. Fortunately, effective tests are available to help distinguish those individuals who are excessively burdened with mercury, and to monitor them during treatment. Therapies for assisting the reduction of a mercury load include the use of 2,3dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propanesulfonic acid (DMPS). Additional supplementation to assist in the removal of mercury and to reduce its adverse effects is discussed. (Altern Med Rev 2000;5(3):209-223) Methylmercury Sources Mercury is ubiquitous in the environment due to constant off-gassing of mercury from the earth's crust. This mercury enters waterways, where it is methylated by algae and bacteria. Methylmercury makes its way through the food chain into fish and shellfish, and ultimately into humans. Additional mercury, released from industrial sources into the atmosphere, also is converted in waterways into methylmercury. Because of mercury contamination, 40 states now have warnings on some of their waterways. Warnings of unacceptably high mercury levels in fish have been issued for nearly 15 percent of the nation's lake acres and five percent of its river and stream miles. In the Pacific Northwest, the most recent finding of high mercury levels is in the sediment of the Spokane River in Washington State. The mercury contamination came from its headwaters – Lake Coeur d'Alene, in northern Idaho. The contamination of this lake with mercury, as well as zinc, lead, cadmium, arsenic, and antimony is believed to have come from more than a century of mining operations in northern Idaho's Silver Valley. The United States Geological Survey has estimated the bed of Lake Coeur d'Alene contains about 70 million metric tons of contaminated sediment. In 1999, the U.S. Environmental Protection Agency (EPA) directed utilities to measure the amount of mercury released by coal-burning power plants. Mercury is also released into the environment by oil burning, from its use as a fungicide (often applied to seeds), from outdoor paint (mercury was banned in indoor paint in 1990), and from processes involving chlorine manufacture and use. Waste mercury is released into the atmosphere by cremations (with estimates that a single crematorium releases more than 5,400 kg of mercury per year). A significant amount of elemental mercury is also released into the environment from wastewater from dental offices. In King County, Washington, mercury contaminates the sludge from wastewater treatment sites which is often sold as fertilizer. Gold mining in the Amazon Basin utilizes mercury to capture gold particles as amalgam, resulting in widespread mercury pollution in the Amazon River and its human and animal inhabitants. Fish absorb methylmercury from water passing over their gills and as they feed on aquatic organisms. Methylmercury accumulates in fish, and ultimately in humans as it travels up the food chain. Methylmercury binds tightly to fish proteins, and its presence in consumed fish is not appreciably reduced by cooking. The half-life of methylmercury in fish is two years, which is two-to-five times greater than the half-life of inorganic mercury. Nearly all fish contain trace amounts of methylmercury. Fish living in areas of high pollution, such as the Great Lakes, have higher levels of mercury and other pollutants. Methyl-mercury levels for most fish range from less that 0.01 ppm to 0.5 ppm. Usually only large predator fish, such as shark and swordfish, are found to contain tissue levels of methylmercury that reach the U.S. Food and Drug Administration (FDA) limit – 1 ppm – for human consumption. Certain species of very large tuna, typically sold as tuna steaks or sushi, can have levels of 1 ppm or greater. Canned tuna is usually composed of smaller species of tuna such as skipjack and albacore, which typically have much lower levels, averaging about 0.17 ppm. In the Seychelles Islands in the western Indian Ocean, the larger fish – kingfish, becune, carangue, balo, and bonita – all exceeded the 1 ppm level. More than half of the dogtooth tuna recently sampled there also exceeded the FDA limit, with some sampled fish reaching levels of 3.3 and 4.4 ppm. While the level of methylmercury in skipjack tuna from those waters ranged only from 0.02-0.44 ppm, the average concentration of methylmercury in most commercial fish is less than 0.3 ppm. Sport fish from the Great Lakes average from a low of 0.11 ppm in Lake Michigan and 0.19 ppm in Lake Huron, to between 0.24-0.58 ppm in Lake Erie and 0.48-0.88 ppm in Lake St. Clair. Perch from Lake St. Clair had the high mark of 0.88 ppm, while those from Lake Erie averaged 0.24 ppm. In Lake Erie, the high mercury-containing fish were walleye, white bass, and smallmouth bass. Whales also have a very high mercury content. In the FDA's Total Diet Survey, mercury was found in 100 percent (16/16) of canned tuna samples (avg. 0.277 ppm), frozen cod/haddock fillets (avg. 0.132 ppm), canned mushrooms (avg. 0.0298 ppm), and shrimp (avg. 0.0281 ppm). Mercury was found in 15/16 samples of fish sticks (avg. 0.0254 ppm) and crisped rice cereal (avg. 0.0044 ppm). Methylmercury is efficiently absorbed into the body (more than 95-percent absorption from food) and crosses both the blood-brain barrier and the placental barrier. It is known to be a potent neurotoxin and teratogen. Its biological half-life in humans is about 70 days. Methylmercury is present in the breast milk of lactating mothers who consume a mainly seafood diet. The mercury concentration in the milk of these women ranges from 2.45 μg/liter in women of the Faroe Islands, who eat meat and blubber of the pilot whale, to 3 μg/liter in Sweden and 7.6 μg/liter in coastal Alaska (where they consume whale). Major methylmercury poisoning incidents occurred in Minamata Bay (1953-1960) and Niigata (1965) in Japan after industrial dumping of mercury led to chronic mercury poisoning in people whose primary source of food was seafood from those waters. Another poisoning episode occurred in Iraq in the fall and winter of 19711972. In this situation, wheat treated with alkyl mercury as a fungicide and intended for seed was instead ground into flour for bread. This contamination resulted in more than 6,000 individuals being hospitalized and 459 deaths. Elemental Mercury Sources Silver "amalgam" dental fillings typically weigh between 1.5-2.0 g, with approximately 50 percent of the material being elemental mercury. When no chewing occurs, individuals with amalgam fillings on occlusal surfaces have been found to have oral levels of mercury vapor nine times greater than those without amalgams. Upon chewing, the same individuals had a six-fold increase in oral elemental mercury levels, resulting in a 54-times greater level of mercury vapor in their oral cavities than persons without amalgams. Serial measurements of these individuals found mercury concentrations remained elevated during 30 minutes of continuous chewing, and then declined slowly over 90 minutes after chewing ceased. Based on the relatively small size of the trial (35 subjects), the researchers concluded individuals with 1-4 occlusal amalgams would be exposed to an average daily dose of 8 μg elemental mercury; those with 12 or more occlusal amalgams were estimated to receive 29 μg per day, and the average of all 35 subjects was estimated at 20 μg per day. Individual cases have been published showing urinary mercury excretion to be 23-60 μg/Hg/day (2554 μg/g creatinine) indicating a daily intake as high as 100 μg. In these individuals, bruxism and gum chewing were noted as probable causes of the high mercury output, which fell back to normal levels with amalgam removal. Higher levels of mercury release from dental amalgams have also been found with tooth brushing and after consuming hot drinks. Mercury vapor is highly lipid soluble and enters the blood from both the lungs and oral mucosa. It traverses cell membranes (including the blood-brain and placental barriers), rapidly partitions between plasma and red blood cells, and becomes widely distributed. As much as 40 percent of mercury vapor is excreted through the feces. Once in the cell, elemental mercury is oxidized by catalase-hydrogen peroxide and becomes divalent Hg2+, which then combines covalently with sulfhydryl groups in molecules such as hemoglobin, reduced glutathione, and cysteine residues in proteins. Thus, individuals exposed to mercury have been found to have lower levels of reduced glutathione. Blood mercury concentrations have been positively correlated with the number and surface area of amalgam restorations, and are significantly higher in individuals with amalgams than those without. Amalgams are also associated with higher urinary mercury output, as well as higher levels in breast milk, although not hair. When examining the association between mercury presence and breast milk it was found the total and inorganic mercury levels in blood and milk did correlate with the number of amalgam fillings. In this study, when seafood was not the main dietary staple, there was no association found between dietary methylmercury intake and milk levels. Exposure of the breastfed infant to mercury from the mother's amalgams was calculated up to 0.3μg/kg (one-half of the tolerable daily intake for adults recommended by the World Health Organization). Animal models have demonstrated that mercury from dental amalgams concentrates in the kidney, liver, gastrointestinal tract, and jaw. The choroid plexus, an important part of the blood-brain barrier, acts as a sink for mercury and other heavy metals. It has also been shown that mercury is selectively concentrated in the human brain in the medial basal nucleus, amygdala, and hippocampus regions (all of which are involved with memory function), in the granular layer of the cerebellum, and in sensory neurons of the dorsal root ganglia. Mercury has also been shown to be taken up by the retina and in granule cells of layer IV in the visual cortex, which can cause a reversible impairment of color perception. Other Mercury Exposure Sources Historically, mercury was used to treat syphilis and other infective diseases. Mercury is still used today in some medicines as a preservative, being present in this form in various vaccinations. Mercury poisoning has occurred from mercury in abandoned industrial sites. In Texarkana, Arkansas, teenagers found two pints of mercury in an abandoned neon sign plant, resulting in one hospitalization and seven homes being evacuated by the EPA. A more serious incident occurred in New Jersey in 1995, where a five-story factory building used to manufacture mercury vapor lamps in the 1930s was converted into condominium apartments. When residents reported finding standing pools of mercury on the countertops and floors, local health agencies were contacted. Air mercury levels were found to range from 5 μg/m3 to 888 μg/m3 (over visible pools of mercury on the floor). Sixty-nine percent of the residents had urinary mercury levels greater than 20 μg/l. Comparisons of urine at the time of evacuation from the building and 10 weeks later showed no significant differences. Former residents with the highest urinary mercury levels exhibited the most errors on a test of fine motor function, and reported the most somatic and psychological symptoms. In another residential poisoning, mercury vapor was spread by the use of the family vacuum cleaner, which had been used to clean up mercury from a broken thermometer. Continued use of the vacuum cleaner spread mercury droplets throughout the house. A two-year-old girl developed nephrotic syndrome and her three-year-old brother had significant neurological problems. Mercury poisoning has also been found in persons living proximal to an inactive mercury mine in California, and in individuals from several states using Crema de Belleza-Manning facial cream. This cream was found to contain 6-10 percent mercury, while the facial cream Nutrapeil Cremaning Plus was found to have 9.7 percent mercury. Adverse Effects on the Body Cellular and Nutritional Alterations Mercury has the ability to cause changes at the cellular level, which has been seen in platelets and erythrocytes. These cells have been used as surrogate markers for mercury damage of neurological tissue. The addition of methylmercury to whole blood can cause a dramatic dissolution of microtubules in platelets and red blood cells – an effect more pronounced in erythrocytes than platelets – which is consistent with the known sequestration of methylmercury in erythrocytes. This effect on microtubules has also been found in the brain, and results in disruption of the cell cycle. This disruption can cause apoptosis (programmed cell death) in both neuronal and non-neuronal cells. Mercury causes apoptosis in monocytes and decreases phagocytic activity. In one study, the percentage of cells undergoing apoptosis was dependent on the mercury content of the medium, regardless of the form of mercury. Methylmercury chloride exposure caused a decrease in the mitochondrial transmembrane potential within one hour of exposure, leading to altered mitochondrial function. Methylmercury can also cause increased lymphocyte apoptosis. This mechanism includes a depletion of glutathione (GSH) content, which predisposes the cell to oxidative damage, while activating death-signaling pathways. On examination of synovial tissue, it was found that mercury (as well as cadmium and lead) caused a decrease in DNA content and an increase in collagenase-resistant protein formation, leading to increased risk for reduced joint function and decreased ability to repair joint damage. Mercury is bound by selenium in the body, which can actually counteract mercuric chloride and methylmercury toxicity. This appears to result in a reduced amount of available selenium, which compounds the oxidative burden on the body. Mercury decreases GSH levels in the body, which occurs by several mechanisms. Mercury binds irreversibly to GSH, causing the loss of up to two GSH molecules per molecule of mercury. The GSH-Hg-GSH complex is excreted via the bile into the feces. Part of the irreversible loss of GSH is due to the inhibition of GSH reductase by mercury, which is used to "recycle" oxidized GSH and return GSH to the pool of available antioxidants. At the same time, mercury also inhibits GSH synthetase, so a lesser amount of new GSH is created. Since mercury promotes formation of hydrogen peroxide, lipid peroxides, and hydroxyl radicals, it is evident that mercury sets up a scenario for a serious imbalance in the oxidative/antioxidant ratio of the body. Mercury's heavy oxidative toll on the body has been postulated to be a cause of increased rates of fatal myocardial infarctions and other forms of cardiovascular disease. These interactions clearly show an increased need for selenium, glutathione, and vitamin E (which have been shown to reduce methyl-mercury toxicity). Mercury-Induced Neurotoxicity Mercury in both organic and inorganic forms is neurotoxic. Methylmercury accumulates in the brain and becomes associated with mitochondria, endoplasmic reticulum, golgi complex, nuclear envelopes, and lysosomes. In nerve fibers methylmercury is localized primarily in myelin sheaths, where it leads to demyelination, and in mitochondria. Pathologic examination of patients with methylmercury poisoning indicates the cerebellar cortex is prominently affected, with granule cells being more susceptible than Purkinje cells. Typically, glial cells are spared direct damage, although reactive gliosis may occur. Toxicity from mercury probably does not result from action on a single target. Instead, because of its highly reactive nature, a complex series of many unrelated (and some interrelated) effects may occur more or less simultaneously, initiating a sequence of additional events that ultimately lead to cell death. The adverse affect of mercury on GSH has secondary effects on the levels of Na+, K+ and Mg++ ATPases, all of which are dependent on sulfhydryl compounds. These enzymes, all critical for proper functioning of nervous and other tissues, are all inhibited by various mercurial compounds. Injection of GSH in animals exposed to methylmercury resulted in the recovery of N+, K+, and Mg++ ATPases. In the absence of nutrients to counteract this action, the inhibition of these ATPases results in neurotoxic swelling and destruction of astrocytes. Astrocytes are the primary cells responsible for homeostatic control of synaptic pH, Na/K, and glutamate. Mercury is also known to inhibit synaptic uptake of dopamine, serotonin, and norepinephrine. Mercury apparently has a higher binding affinity for serotonin binding sites. Mercury has also been reported to cause an increase in evoked acetylcholine release followed by a sudden and complete blockade. Prolonged exposure to methylmercury results in an up-regulation of muscarinic cholinergic receptors in the hippocampus and cerebellum, and on circulating lymphocytes. It also affects the release of neurotransmitters from presynaptic nerve terminals. This may be due to its ability to change the intracellular concentration of Ca2+ by disrupting regulation of Ca2+ from intracellular pools and increasing the permeability of plasma membranes to Ca2+. While there is undoubtedly much more to learn about the specific mechanisms of mercury-induced neurotoxicity, the symptoms are fairly clear. The widespread pollution of Minamata Bay in Japan by methylmercury in the 1950s has provided researchers with a clear picture of methylmercury-induced neurotoxicity. Known as Minamata Disease, the neurotoxic signs include ataxia, speech impairment, constriction of visual fields, hypoesthesia, dysarthria, hearing impairment, and sensory disturbances. These neurological problems persisted and were found in other areas of Japan as the mercury contamination spread. Follow-up studies in the Minamata area 40 years after the spill and 30 years since a fishing ban was enacted revealed continued problems. In 1995, male residents of fishing villages in the area reported significantly higher prevalences than "town-resident-controls" for the following complaints: stiffness, dysesthesia, hand tremor, dizziness, loss of pain sensation, cramping, atrophy of the upper arm musculature, arthralgia, insomnia, and lumbago. Female residents of the fishing villages had significantly higher incidences of leg tremor, tinnitus, loss of touch sensation, leg muscular atrophy, and muscular weakness. Amazonian children exposed to methylmercury from gold mining activity have also been studied for methylmercury's neurotoxic effects. In the villages studied, more than 80 percent of the children had hair mercury levels above 10 μg/g (a level above which adverse effects on brain development are likely to occur). Neuropsychological tests of motor function, attention, and visuospatial performance in these children showed decrements associated with hair mercury concentrations. Neurotoxicity is not related only to methylmercury, as a study of 98 dentists and 54 non-dentist controls revealed. The dentists, with an average of 5.5 years of exposure to amalgams, performed significantly worse on all of the following neurobehavioral tests: motor speed (finger tapping), visual scanning (trail making), visuomotor coordination and concentration (digit symbol), verbal memory, visual memory, and visuomotor coordination speed. The dentists' performance on each of these tests diminished as their total exposure increased (amount of daily exposure and years of exposure). Mercury is also implicated in Alzheimer's disease and other chronic neurological complaints. In 1988, Alzheimer's cadaver studies reported mercury was found in much higher levels in the nucleus basalis of Meynert than in controls (40 ppb vs. 10 ppb). Subsequent studies have shown elevated mercury throughout the brain in individuals with Alzheimer's. Furthermore, when rats were exposed to elemental mercury vapor at the same levels as documented in the oral cavity of humans with amalgams, lesions similar to those seen in Alzheimer's disease have occurred. The same lesions have been demonstrated when rat brains were exposed to EDTAmercury complex. While amyotrophic lateral sclerosis (ALS) has been associated in some instances with possible cadmium exposure, a published case history revealed a diagnosed case of ALS recovering after amalgam removal. The individual in question had 34 amalgam fillings. After the first removal her ALS symptoms were exacerbated, but improvement was noted fairly soon after all amalgam fillings were removed. Upon returning to the neurology clinic five months later, she exhibited no evidence of the motor neuron disorder. Mental health symptoms are also quite common with mercury toxicity. Evidence linking mercury exposure to psychological disorders has been accumulating for 60 years. The recognized psychological symptoms of mercury toxicity include irritability, excitability, temper outburst, quarreling, fearfulness, restlessness, depression, and in some cases insomnia. In a study of individuals with amalgam fillings who had them removed, the majority noted psychological improvement. The greatest improvements were found in anger outbursts, depression, irritability, and fatigue. None of these manifestations are surprising when mercury's inhibitory effect on serotonin is considered. The association of mercury to depression has stimulated a number of interesting questions; such as whether mercury toxicity was to blame for Sir Isaac Newton's health problems of 1692-93, and might it have contributed to the depression and apparent suicide of the explorer Meriwether Lewis.