The toxicology of elemental mercuryHg

3.1 Absorption, disposition in the body, and elimination

Hg° is the only metal that takes the form of liquid at room temperature, and releases monoatomic vapours (Hg° vapours) that are very stable and may remain in the atmosphere for months or even years on end. Their pressure is in equilibrium with the metal, and their concentrations attain a value of 18.3 mg/ m3 at a room temperature of 24°C, which is 360 times above the "permissible level" for occupational exposure (0.05 mg Hg°/m3) prescribed in the Environmental Health Criteria 1, Mercury (WHO, 1976). We know today that Hg° vapours enter the body mainly through inhalation. As much as 80% of the inhaled amount of Hg° is absorbed in the lungs and then passes across the alveolar membrane very quickly into the plasma and erythrocytes, and through blood circulation into CNS, kidneys and other organs. In the tissue, Hg° oxidizes into the ionic divalent form (Hg++), which takes place by way of the hydrogen peroxide-catalase compound I enzyme system. The oxidation of Hg° in blood, although rapid, is sufficiently prolonged so that the Hg° dissolved in blood can be conveyed to the brain, where it passes the blood-brain barrier and cell membranes. Only a small amount of Hg° is oxidized during the transit time from the lungs to the brain, so that over ninety percent of dissolved Hg° arrives in the brain unoxidized. It is then oxidized in brain cells and complexed to the SH-group of the cell (Hursh et al., 1988; Magos et al., 1978). The divalent ionic Hg++ accumulates primarily in astrocytes, where it mostly binds to reduced glutathione (GSH), cystein, and metallothioneins (MTs) (Aschner, 1997; Tusek-Znidaric et al., 2007). After Hg° vapour exposure of animals, a marked accumulation of Hg was observed in the cerebellum, nucleus olivarius inferior in the brainstem, and in the nucleus subtalamicus (Berlin et al., 1969). In autopsy samples of retired and ex-miners previously intermittently exposed to Hg°, substantially higher accumulations and retention of Hg were observed in the pituitary gland, pineal gland, hippocampus, nucleus dentatus, and in the cereballar cortex in comparison with the control group (Falnoga et al., 2000; Kosta et al., 1975) (Tab.1). Hg is eliminated in the urine, feces, expired air, sweat, saliva, and milk. In long-term occupational exposure, the kidneys are the major pathway of Hg excretion, and are not only an indicator of kidney burden, but may also be a rough indicator of total body burden. The retention of Hg in the brain observed several years after remote exposure in retired mercury miners suggests that the brain does not follow the some kinetics of elimination as the kidneys (Falnoga et al., 2000; Kosta et al., 1975; WHO, 1991). In the case of intermittent exposure to Hg°, blood Hg was very positively correlated with the spot urine

Hg mercury concentration (r=0.68, p < 0.001), which, in such types of exposure, allows use of urine Hg as a biological indicator of recent exposure (Kobal, 1991).

Ex-miners

Controls

Pituitary gland (ng/g)

39100 (N-l)

36.9 ±62 (N-13)

Piniel gland (ng/g)

1109 (N-l)

9.5 ± 9.2 (N-15)

Hyppocampus (ng/g)

251, 309, 337 (N-3)

3.9 ±1.6 (N-6)

Nucleus dentatus (ng/g)

2090, 2363, 4428 (N-3)

137 ±77 (N-7)

Cerebellar cortex (ng/g)

43, 108, 110, 301 (N-4)

2.1, 2.5, 2.9 (N-3)

Table 1. Total Hg concentration in autopsy samples (homogenised tissue) of pituitary gland, pineal gland, hippocampus, nucleus dentatus and cereballar cortex (ng/ g fresh weight) in ex-miners of the Idrija Mercury Mine and controls (data adapted by Falnoga et al., 2000).

Table 1. Total Hg concentration in autopsy samples (homogenised tissue) of pituitary gland, pineal gland, hippocampus, nucleus dentatus and cereballar cortex (ng/ g fresh weight) in ex-miners of the Idrija Mercury Mine and controls (data adapted by Falnoga et al., 2000).

3.2 Toxic effects of Hg°

Various Hg species, as Hg°, methyl-Hg ore ethyl-Hg, accumulates in the central nervous system (CNS) and has extremely neurotoxic effects, including the appearance of well-known clinical symptoms and signs. In case of occupational exposure to Hg°, the most frequent symptoms and signs include "erethism", increased irritability, depression and other neurobehavioral changes, sleep disturbances, oral disturbances, gingivitis and stomatitis with excessive salivation, intentional tremor, peripheral neuropathy (lower sensor and motor conduction velocities), and renal impairment. In vitro and in vivo studies showed that Hg can stimulate free radical generation as a catalyst in Fenton-type reactions and through some other mechanisms, and can promote oxidative stress, peroxidation of lipids and DNA bases, disturbances in cell membrane permeation and calcium homeostasis in cells, impairment and even apoptosis of monocytes, T cells, glial cells and neurons, disturb the functioning of neurotransmitters, and cause immune disorders (Aschner, 2000; ATSDR, 1999; Castoldi et al., 2001; Clarkson & Magos, 2006; Kobal et al., 2004; Kobal-Grum et al., 2006; Lund et al., 1993; Magos, 1997; Pollard & Hultman, 1997; Schara et al., 2001; WHO, 1991).

3.2.1 Interaction with neurotransmitters

Various Hg species presynaptically blocks sodium and calcium channels and thus inhibits the uptake of some neurotransmitters, especially glutamate into astrocytes, which increases their extracellular concentration, thus increasing the sensitivity of neighbouring neurons for stimulating excitotoxic effects (Aschner et al., 2007; Brookes, 1996; Castoldi et al., 2001; Sirois & Atchison, 1991; Trotti et al., 1997). Many studies reviewed by Mottet et al. in 1997 showed that astrocytes, which accumulate a high level of Hg++, play a fundamental role in regulating glutamate level. In cases of methyl-Hg exposure, it seems that the Hg++ ions formed after the demethylation of methyl-Hg may also be responsible for the disruption of normal Ca++ ion channels.

Hg may affect sleep because it can: (i) increase extra-cellular glutamate concentrations associated with the activation of some cytokines, which can reduce the serotonin level by lowering the availability of its precursor, tryptophan, through the activation of its metabolizing enzyme, indoleamine 2,3-dioxigenase (McNally et al., 2008); (ii) increase the production of nitrogen oxide (NO) (Ikeda et al., 1999), which can directly, or in interaction with melatonin, decrease the active form of serotonin (Fossier et al., 1999; Kopczak et al., 2007); and (iii) Hg can also increase the consumption of serotonin and melatonin because of its potential oxidation in interaction with the increased production of free radicals observed in microglial cell cultures (Huether et al., 1997; Tan et al., 2000).

It is suggested that inorganic Hg potentiate and inhibite the neuronal nicotinic acetylcholine receptors, depending on its concentration (Mirzoian & Luetje, 2002). Another animal study shows that up-regulation of cerebral acetylcholine receptor can occur in chronic methyl-Hg exposure to compensate the early stage reduction of brain acetylcholine, as a consequence of acetylcholinesterase inhibition (Basu et al., 2006). It is evident from some studies on occupationally and environmentally Hg°-exposed subjects that Hg enhances the dopaminergic effect in CNS, which otherwise leads to cortical hyperexcitability and changes in the control of locomotor function, emotions, and behaviour (Burbure et al., 2006; EntezariTaher et al., 1999; Lucchini et al., 2003; Missale et al., 1998).

3.2.2 Subcellular protective mechanism

Particularly significant in reducing the effects of Hg binding with SH groups of GSH and its biochemical precursors, cystine and cysteine, as well as its binding with MTs a cysteine rich low molecular weight proteins and with selenium (Se) an essential element and an integral part of a type of Se-proteins. The two major thiols, GSH and MTs, appear to be most important in regulating the accumulation and detoxification of Hg in CNS. The induction of GSH and MTs in astrocytes leads to greater detoxification of Hg and protection of CNS. Astrocytes represent the first line of CNS's defence against Hg (Aschner et al., 2007; Dringen et al., 2000). GSH (L-y-glutamyl-L-cysteinyl-glycine) is synthesized from its precursors, glutamate, cysteine and glycine, in the cytosol of cells by the ATP-requiring enzymes y-glutamilcysteine ligase and GSH synthetase (Meister & Andersen, 1983). Most of the free intracellular GSH (98%) is in thiol-reduced form (GSH) rather than in disulfide form (GSSG). From the cytosol, GSH is delivered into the mitochondria, endoplasmatic reticulum and nucleus, but much of it is delivered to extracellular spaces, where its degradation begins to occur on the surface of cells that express the enzyme y-glutamil transpeptidase. GSH, as a nonenzymatic antioxidant, participates in a variety of detoxification, transport, and metabolic processes (Ballatri et al., 2009; Rossi et al., 2002). It is speculated that GSH may also function as a neuromodulator and neurotransmitter, since the degradation of extracellular GSH by y-glutamil transpeptidase liberates glutamate and, subsequently, the hydrolysis of cysteinylglicine liberates cysteine and glycine, which function as a source of neuroactive amino acid (Oja et al., 2000).

Some other protective mechanisms, such as Se, antioxidative enzymes and melatonin, are also important in the detoxification of Hg and its peroxidative effect on the body, and particularly CNS. Se that binds with Hg in CNS in a molecular ratio of 1:1 into a nontoxic complex, which in lysosomes represents the last stage of detoxification of Hg (Falnoga et al., 2002; Kosta et al., 1975;).

It is evident from the study of ex-mercury miners that the Hg accumulated in the pineal gland and bound to Se did not impair its function, while the blood melatonin level was still high, probably due to the slow release of Hg from the gland and the adaptive response to free radical production induced by Hg (Kobal et al., 2004). Melatonin and free radicals form stable secondary and tertiary products, biogene amines, which also enter into reactions with free radicals. So melatonin inhibits the excessive formation of NO and its free radicals, peroxinitrites, and in this way also reduces the excitotoxic effects of glutamate (Sener et al., 2003; Tan et a!., 2000).

The main enzymes that provide cellular protection against damage by reactive oxygen species mediated by Hg++ are Cu/Zn superoxide dismutase, catalase and the selenoenzyme glutathion peroxides, which transform the superoxide anion radical into hydrogen peroxide and then into oxygen and water (Lund et al., 1993). It is evident from some studies that repeated-intermittent occupational Hg° exposure induced an adaptive response and increase of GSH and catalase activity in erythrocytes, as well as the melatonin level in blood. The actual levels of GSH and catalase in erythrocytes depend on the actual level of blood Hg, both of these decreasing at higher blood Hg concentrations during actual exposure (Kobal, 1991; Kobal et al., 2004, 2008).

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