Rethinking treatment of mercury poisoning: the roles of selenium, acetylcysteine, and thiol chelators in the treatment of mercury poisoning: a narrative review

Abstract

We reevaluate the treatment of mercury poisoning, incorporating recent advances in understanding of mercury toxicity and the mercury:selenium interaction. This review focuses on: 1) the role, limitations and benefits of chelation (Unithiol, succimer and N-Acetylcysteine); 2) the role of selenium supplementation; and 3) how the different forms of mercury are impacted by use of chelation and selenium. Unithiol and succimer produce increases in urinary excretion of mercury and to a lesser degree blood and total body mercury. The primary role of N-acetylcysteine is increasing renal mercury excretion, similar to the thiol-chelators. Additional unique features of acetylcysteine include increased efflux of methylmercury from the brain, and reduced oxidative stress via increased glutathione production. The role of selenium includes: 1) restoration of selenoprotein activity, 2) protection against mitochondrial injury and DNA damage, 3) demethylation of methylmercury, 4) sequestering of mercury via Hg:Se complexes, and 5) redistribution of Hg inside organisms. Selenium may increase blood Hg, via a “sink” effect, causing a redistribution of mercury away from the brain. A combined approach for mercury poisoning treatment was developed focusing on restoration of selenoprotein function, reduction of oxidative stress and increased mercury elimination.

Keywords:

• Mercury
• selenium
• acetylcysteine
• poisoning
• DMSA
• DMPS
• unithiol
• succimer
• review

There has been a paradigm shift in our understanding of the pathophysiology of mercury poisoning and the central role of the interaction between mercury and selenium [1]. Despite this change recommendations for the management of mercury poisoning have remained the same [2–4]. Historically mercury poisoning has been managed by removing the patient from mercury exposure and this has been supplemented by increasing excretion of mercury with thiol-based chelators. However, there are no controlled trials evaluating the clinical benefit of the thiol chelators in mercury exposures. Limitations of thiol-based chelation include ineffectiveness in chronic exposures [5–10] and with the organomercurials such methylmercury (MeHg⁺), ethylmercury and dimethylmercury [3, 11–16].

In the case of another metal, lead poisoning, large studies have shown no neurological benefit after chelation in children with blood lead levels between 20 µg/dL and 44 µg/dL, despite lowering blood lead levels and increasing urinary lead excretion [17]. Additionally chelation in the situation of chronic arsenic poisoning has also been found to be ineffective [2]. These studies bring into question the reliance on increasing urine levels and lowering blood levels as a measure of success of chelation therapy [17].

We propose a reevaluation of the treatment of mercury poisoning, using an evidence-based approach and incorporating the recent advances in understanding of the mechanism of mercury toxicity and the mercury selenium interaction. A search was performed using Medline/PubMed, Toxline, Google Scholar, and Google for published work on treatments of mercury toxicity covering the period 1950 through 2020. Multiple searches were performed using combinations of text words: mercury, mercury toxicity, mercury poisoning, inorganic mercury, organic mercury, methylmercury, dimethylmercury, mercuric chloride, chelation, DMSA, 2,3-dimercaptosuccinic acid, succimer, DMPS, 2,3-dimercaptopropane sulfate, unithiol, selenium, selenide, selenite, diphenyl diselenide, selenoprotein, inorganic selenium, organic selenium, selenomethionine, selenocystine and selenocysteine. The citations were screened for appropriateness and relevancy. Publications that did not evaluate treatment of mercury toxicity or selenium status, or evaluated environmental status (e.g. lake or ocean sediment) were excluded, leaving approximately 350 citations. This initial selection was scrutinized carefully and 178 of the most relevant and representative references were selected for use in this review. Numerous clinical reports provided no dosing or timing of treatments (e.g. “chelation was begun”) or insufficient clinical data for evaluation and were excluded. Please see Table 1 for a detailed summary and evaluation of references.

This review will focus on four areas:

1. The mechanisms, limitations and benefits of chelation in mercury poisoning. This is provided because of the past reliance on chelator enhanced elimination as a primary therapy

2. The role of selenium supplementation in mercury poisoning therapy including: restoration of selenoprotein activity, pro-demeythlating action of selenium, sequestering of mercury via Hg:Se complexes, redistribution of Hg inside organisms under the influence of Se, the inhibitory effects of Se on actions of Hg

3. How the different forms of mercury are effected by use of chelation elimination and selenium supplementation

4. Synergy or conflicts between use of selenium, acetylcysteine and the thiol chelators unithiol and succimer

Mechanisms of action and mercury elimination by thiol chelators and acetylcysteine

Thiol-based chelators have been a mainstay of therapy for mercury toxicity for decades [3, 4]. However, there are no randomized clinical trials evaluating clinical outcomes after chelation of mercury in humans. The primary role of chelation for mercury poisoning is a proposed reduction of mercury body burden through increased urinary mercury elimination [3]. While it makes intuitive sense that increasing elimination and therefore reducing the mercury body load should reduce the effect of the injury, the lack of improvement in many cases suggests that this simple approach is insufficient.

Much of the early work on thiol-based chelators focused on the use of dimercaprol. However, dimercaprol is contraindicated in organic mercury exposures and may increase brain mercury [14, 18, 19]. Additional disadvantages of dimercaprol included its intramuscular route, low therapeutic index and toxic effects. Presently the water-soluble oral derivatives of dimercaprol: unithiol (2,3-dimercaptopropane-1-sulfonate; DMPS) and succimer (2,3-dimercaptosuccinic acid; DMSA) [2, 3, 20] are now preferred.

The primary effects of the water-soluble thiol chelators are: 1) to form a complex with mercury in the proximal tubular cells of the kidney which is then excreted to the tubular lumen via the multidrug resistance protein 2 (MRP2) (and possibly other members of this ATP-binding cassette (ABC) transporter superfamily) and 2) to complex with mercury in the blood (unithiol) and increase clearance via glomerular filtration [20, 21] (Figure1). Unithiol and succimer are not able to cross the blood brain barrier or penetrate other target tissues (brain, muscle, thyroid, etc). These other tissues lack a necessary membrane transporter to allow unithiol or succimer cellular penetration, such as the OAT1 in the renal tubules.

A third potential chelator for mercury is acetylcysteine [4, 22–35]. As presently understood, the primary role of acetylcysteine appears to be increased mercury excretion via complexation and renal elimination, similar to the thiol chelators (Figure 1). However additional benefits beyond simple increased urinary Hg excretion have been documented, including: 1) increased demethylation of MeHg, 2) reduced oxidative stress via increased glutathione production, 3) reduced cellular apoptosis, and 4) increased efflux of Methylmercury (MeHg) from the brain may also be important [22, 23, 27, 28, 31, 33, 36–38].

Figure 1. Renal mechanisms for mercury clearance.

Conjugates of acetylcysteine and MeHg⁺ or inorganic mercury (Hg²⁺) form in the blood and act as substrates for the Organic Anion Transporter (OAT1) in the basolateral membrane of the proximal tubular epithelial cells, allowing increased renal uptake of Hg [29, 30, 39]. After renal uptake, the acetylcysteine-Hg complex is excreted to the tubular lumen by the multidrug resistance protein 2 (MRP2) and possibly other members of this ABC transporter superfamily [33] (Figure 1). This accelerates the normal pathway of renal elimination of the Hg-cysteine complex as a substrate for OAT1 and the Hg-glutathione complex as a substrate for MRP2 [20, 40] (Figure 1). Additionally: 1) portions of acetylcysteine-MeHg conjugates formed in the blood may be eliminated by the liver into the bile via the glutathione transporter similar to normal MeHg elimination pathway (Figure 2), and 2) acetylcysteine-Hg conjugates formed in the blood may be eliminated via glomerular filtration similar to acetylcysteine clearance in the urine and the unithiol-Hg complex.

Figure 2. Hepatic mercury elimination.

Acetylcysteine is able to cross the blood brain barrier and is available to all tissues. Increased neuronal glutathione production from acetylcysteine can increase efflux of MeHg⁺ from the brain via the glutathione + MeHg complex using the multidrug resistance protein and reduce brain MeHg⁺ concentrations [41, 42] (Figure 3). A number of studies involving in vitro neurons, astrocytes, neuroblastoma cells and myogenic cells incubated with MeHg⁺ or Hg⁺² and treated with acetylcysteine showed reduced oxidation injury, increased cell viability and blocked Hg-induced reduction of DNA synthesis [36, 37, 43, 44].

Figure 3. Transport of Methylmercury across the blood brain barrier.

Chelation – limitations, blood and urine mercury changes may not equate with clinical improvement

An important limitation of unithiol and succimer is inability to directly remove Hg from target organs such as the brain and liver, due to lack of tissue penetration. While acetylcysteine does assist increased efflux of MeHg from the brain, no chelator appears to effect inorganic Hg brain content directly. A second important limitation of the thiol chelators Unithiol and Succimer is after chronic mercury exposure, decreases in blood Hg concentration or increases in urine Hg concentration do not necessarily equate to improved clinical outcome [12, 13, 16, 45–49]. This is likely because changes in blood and urine mercury levels do not address cellular selenium deficit, selenoprotein inhibition and subsequent cellular mitochondrial injury [1].

Clinical reports using chelation therapies for mercury poisoning have shown significant increases in urine mercury concentrations, but have produced conflicting reports of patient outcomes including: renal, cardiovascular and/or neurological improvement [50–55], prevention of toxicity [56–58], no effect (lack of improvement) [6, 7, 49, 56, 59–65], and continued patient deterioration [12, 13, 16, 46–49, 66, 67]. The inconsistent results seen following chelation draws into question the reliance on changes in blood and urine Hg concentrations when assessing the effectiveness of therapies. Though there have been patients who experience significant clinical improvement following chelation [68–72] (even in patients without elevated blood and urine Hg levels [50, 52]), there are also numerous cases reporting a lack of improvement and even continued deterioration [12, 13, 16, 46–49, 66, 67].

In six reports [13, 51, 61, 73–75] describing unithiol or succimer therapy in patients with either elemental mercury, mercurous chloride or thiomersal [ethymercury] exposure (18 patients in total with daily urinary mercury concentrations), urine mercury concentrations rose dramatically during the first day but returned to near pre-chelation concentrations over the following consecutive days, despite continued therapy [13, 51, 61, 73–75]. Pfab et al. [13] using an alternating oral and IV unithiol (days 1–16 and 23–29) and oral succimer (days 17–22 and 33–70) reported more mercury (as thiomersal) was excreted in the first 3 days than the entire remaining 70 days of chelation [13]. In this case brain levels continued to rise for 18 days with continued patient deterioration, despite ongoing chelation and falling urine mercury levels [13]. This supports the mechanistic understanding that the unithiol and succimer appear to have only limited effect on target organ mercury beyond the kidney.

Likely because of the noted decrease in urine mercury output with continuous dosing, a number of clinicians have employed repeated “pulse” dosing with chelation free periods [51, 74–76]. Four reports describe the use of a repeated “pulse” dosing of unithiol:

1. chronic mercury vapor exposure treated with 30 mg/kg/day (3000 mg/day) for five days repeated three times over 9 weeks [51]

2. chronic mercury vapor treated with 600 mg/day for 14 days with a 38 days break and then 800 mg/day for 20 days [74],

3. chronic occupational mercurous chloride exposure treated with 400 mg/day for 8 days followed by 5 days free of unithiol, then unithiol 400 mg/day orally for 7 days, followed by 5 days free of unithiol, then 6 days of unithiol 400 mg/day orally [75],

4. chronic mercury exposure in a 10 month old treated with unithiol 20mg/kg/day IV for 4 days followed by 4 cycles of 20 mg/kg/day unithiol IV for 4 “cycles” of 2 days each [76].

In all four cases the second, third and fourth unithiol treatments resulted in urine mercury concentrations less than 10% of the first unithiol course [51, 74–76]. Additionally, the majority (>75%) of urine mercury excretion occurred in the first 48 h of the first treatment, supporting the animal data that the primary effect of the thiol chelators is reduction of renal stores of mercury [51, 74, 75, 77]. In chronic mercury poisoning or post distribution phase, unithiol and succimer appear to have only limited effect on target organ mercury beyond the kidney [78].

Several other features may effect clinical outcome greater than simple comparison of urine or blood concentrations. The forms of mercury (elemental mercury and the organic and inorganic salts) have critical differences in target organ, toxicokinetics, clinical presentation, and potency [79, 80]. Chronicity, allowing distribution into target organs, especially the brain, is important [45]. More importantly, a majority of clinical reports and animal studies do not address selenium status or the mercury/selenium interaction. This failure to include assessment of the primary mechanism of toxicity of mercury in the majority of reports may explain some of the conflicting differences in outcome, when using only mercury concentrations as a measure

Mercury kinetics after acute exposure and effect of chelation

The half-lives of organic, inorganic and metallic mercury vary significantly, as do the clearance from target organs such as the brain [81, 82]. The kinetics of the forms of mercury in humans are poorly understood and are quite different depending on the type of Hg. Several human reports in both inorganic and organic Hg suggest a 2-compartment model with an initial distribution phase, supported by significant initial drops in blood Hg, despite in some cases no treatment or total anuria with no urinary mercury elimination [58, 69, 72]. We suggest caution in acute exposures when attributing early drops in blood Hg to effects of chelation, without understanding the distribution phase of that form of Hg.

Chelation: choice of chelator depends on the form of mercury

Choice of a chelator with organic mercury – acetylcysteine

For methylmercury (Hg⁺¹) and dimethylmercury, acetylcysteine appears to be a better choice of chelator [22, 24, 26, 27, 32–34, 68, 83]. Acetylcysteine increases urinary clearance, reduces target organ mercury levels, including increased efflux from the brain, as well as shows improvement in organ function (brain, liver and kidney) [22, 26, 27, 32, 33, 68, 83]. The remediation of neurotoxicity is likely due, in part, to the protective increased glutathione production in the brain, a unique feature of acetylcysteine [22, 31, 36, 44, 83].

Koh et al., compared acetylcysteine, unithiol, succimer, and l-cysteine as substrates for the OAT1 transporter in an in-vitro model of MeHg exposure [30]. Acetylcysteine, and unithiol were equally good substrates for OAT1, and were significantly better substrates than succimer or l-cycteine [30].

With organic mercuries (methylmercury, dimethylmercury, and ethylmercury) the thiol chelators (unithiol and succimer) have shown increases in urinary mercury and in some cases decreases in blood mercury. Unfortunately, even with these mercury concentration changes there has been limited or no clinical improvement in the patients, with numerous cases reporting continued patient deterioration, in some cases to permanent disability or death [12, 13, 16, 45, 59, 66]. This likely reflects in vivo demethylation of the organomercuries in the brain [81, 82]. The inability of the thiol chelators to cross the blood brain barrier and access demethylated inorganic mercury (Hg⁺²) is likely responsible for its poor remediation of neurotoxicity associated with the organomercuries [15].

Ethylmercury has a shorter half-life and greater difficulty crossing the blood brain barrier than methylmercury [84]. Unithiol and succimer have shown limited or no effect on neurotoxicity from ethylmercury when used in humans [13, 50, 69, 85]. Similar to methylmercury this likely reflects dealkylation of ethylmercury to inorganic mercury (Hg⁺²) in the brain and the inability of unithiol of succimer to cross the blood brain barrier [86, 87]. Acetylcysteine has not been evaluated with ethylmercury in humans, but the additional role of increased glutathione production in the brain supports the choice of acetylcysteine [88].

Choice of a chelator with elemental mercury and mercury vapor

Elemental mercury (injection) and mercury vapor are absorbed in the un-ionized state (Hg⁰). This allows for passive diffusion into organs and across the blood brain barrier. Hg⁰ is then oxidized to the toxic form Hg²⁺ after tissue penetration, including in the CNS, RBC, and kidney [9]. The hypertension and tachycardia associated with acrodynia are likely due to intracellular calcium dyshomeostasis (selenoprotein control of endoplasmic reticulum function with increased intracellular release of calcium) in the adrenal glands [1].

In elemental mercury and mercury vapor poisoning the thiol chelators (unithiol and succimer) have shown 1) increases in urinary mercury, 2) decreases in blood mercury, and 3) reductions of kidney and total body Hg [9, 51, 77]. Neither the thiol chelators nor acetylcysteine show any effect on brain mercury concentrations after mercury vapor exposure [8, 9, 15, 77]. This may partially explain the varying responses in the clinical reports after vapor exposure. Acute asymptomatic cases show increased urinary mercury and reduced blood levels and remain asymptomatic [70, 73]. However, chronic exposure after onset of neurotoxicity is generally manifested by prolonged recovery with or without permanent neurologic injury despite increased urine Hg and decreased blood Hg [46, 51, 56, 60, 61, 76, 89]. Additionally, in acute high-concentration mercury vapor cases unithiol or succimer appear to have limited effect on pulmonary injury [60, 88]. Similar to cases of mercury vapor poisoning, chelation appears to be inadequate to manage the large multi-gram doses associated with elemental mercury injection [57, 74, 90].

Acetylcysteine does not appear to decrease tissue mercury after vapor exposure but reduces organ injury in animal studies, likely through a separate mechanism such as increased intracellular glutathione [9, 38, 43].

Choice of a chelator with inorganic mercury salts

In animal studies of mercuric chloride injection unithiol decreased mercury content in all organs, while succimer decreased only kidney and blood concentrations, if therapy was begun within a day of mercury exposure [8, 11, 19]. However, if there was a delay in chelator administration, therapy was less effective and brain mercury was not improved [10, 91, 92]. This again highlights the lack of tissue penetration of unithiol or succimer. Conversely, in mice, prolonged use of unithiol or succimer (4 weeks) increased Hg content of spinal motor neurons 2-fold, likely a consequence of increased blood levels of mercury redistributed from non-neuronal tissues by the chelators [93]. Acetylcysteine after HgCl₂ has also produced conflicting results, with 1) no effect on mercury organ content [27], or 2) reduced kidney and liver mercury content along with restoration of organ function [23, 28]. In clinical reports of ingestion and dermal exposure to inorganic mercury unithiol and succimer increased urine mercury and decreased blood hg significantly (See limitations, Blood and Urine mercury changes above) [51, 75, 94, 95].

For both inorganic mercury and elemental mercury/vapor the initial use of a thiol chelator for 3 to 4 days (see Blood and Urine mercury changes above), to clear renal Hg may be appropriate. However, after 3–4 day the switch to acetylcysteine for continued chelation, reduced organ injury, and synergy with Se is suggested.

Dose and timing of chelators

The effect of timing, route of administration (bioavailability) and dose of unithiol on the elimination of mercury is complex and requires explanation. The water-soluble thiol chelators lack the ability to penetrate tissues and therefore are most effective when they are able to access mercury in the blood and kidney prior to tissue distribution [15, 20, 21, 77, 92]. In animal studies, if given within 5 days (prior to mercury distribution) unithiol was effective at reducing total body mercury and all organ mercury content. This is likely due to access to mercury still in the blood prior to distribution [77, 92]. However if administration is delayed beyond 5 days unithiol is only effective in reducing blood and kidney mercury with no significant effect on mercury content of other important target organs such as the brain and liver [15, 77, 92].

Data obtained from animal studies suggest that the primary effect of the thiol chelators is reduction of renal stores of mercury [77, 78]. In two human cases of chronic elemental mercury exposure, use of unithiol 600 mg/day orally resulted in peak urine mercury excretion of 2000 µg/L [90], while quadrupling the dose resulted in peak urine mercury concentrations of only 1500 µg/L [57]. In unithiol chelation studies involving both animals and humans, urine mercury decreases rapidly after 2–4 days, with urine mercury levels returning to near pre-chelation levels despite continued therapy even when high doses are used (up to 200 mg/kg IV) [10, 13, 15, 51, 57, 73–75, 77].

Oral bioavailability of unithiol in humans is only approximately 40% [96]. Therefore, some authors suggest that current oral dosing regimens for unithiol are inadequate and should be increased [51, 96]. Though the relationship between urine mercury concentration and increasing oral unithiol doses is linear in the case of early presenting, acute mercury toxicity, this is not the true in the setting of chronic poisoning and cases of delayed presentation, when tissue distribution of mercury is complete [15, 77, 92]. In these cases, there is no apparent benefit to increased unithiol doses.

Increasing the dose of acetylcysteine increases MeHg⁺ excretion but not Hg⁺² in a proportional manner [34]. In rats, given a MeHg dose of 0.1 µmol/kg (21.4 µg/kg), increasing the dose of acetylcysteine from 0.25 mmol/kg (40.5 mg/kg) to 1.5 mmol/kg (244.8 mg/kg) showed a near linear increase in mercury elimination, from 2% of total dose eliminated in 2 h to 10% of total dose eliminated in 2 h, respectively, compared with 0.1% elimination in controls (MeHg⁺ but no acetylcysteine) [34].

Selenium

Selenium supplementation

Early studies in cats and quail suggested selenium supplementation might provide a protective effect from mercury toxicity [97, 98]. Similar “protective” effects have been reported in additional animal models and humans [99–104]. However, more recent studies on the pathophysiology of mercury, suggest selenium supplementation may not only be protective, but also corrective of a mercury-induced selenium deficiency state [1, 105]. There is convincing evidence that the primary target of mercury is inhibition of the selenoproteins in the thioredoxin system (thioredoxin reductase) and glutathione-glutaredoxin system (glutathione peroxidase), along with secondary involvement of selenoproteins P, K, T, and W [1, 105–112]. Mercury binds to the selenium moiety of the selenoprotiens with high affinity, which unless removed permanently inhibits their activity. The loss of selenoprotein activity causes disruption of the cellular redox environment, lipid and protein peroxidation, disruption of intracellular calcium homeostasis, mitochondrial injury/loss and an intracellular selenium deficiency [1].

The role of selenium supplementation in mercury poisoning is complex and includes 1) restoration of selenoprotein activity, 2) protection against mitochondrial injury and DNA damage, 3) pro-demethylating action of selenium, 4) sequestering of mercury via Hg:Se complexes, 5) redistribution of Hg inside organisms under the influence of Se, and 6) the inhibitory effects of Se on actions of Hg [99, 113–123]. However, similar to the limitations of increased urinary elimination of Hg by the thiol chelators, the amelioration of mercury toxicity from simple resupply of selenium has important limitations [105, 119, 124].

Numerous studies of simultaneous administration of selenium and mercury over extended periods showed beneficial effects as evidenced by reduced mercury tissue concentrations, reduced mercury whole body retention, improved thioredoxin reductase activity, improved glutathione peroxidase activity, reduced oxidative stress, reduced DNA damage, mitochondrial rescue, improved muscle strength and body weight gain [100, 102, 114, 117, 124–129]. Study methods have used Mercury vapor (Hg⁰) with oral selenium for 4 weeks in rats [126] oral MeHg⁺ with diphenyl diselenide injection in mice [117], oral mercury (MeHg⁺ and Hg⁺²) with oral selenite for 14 days in mice [128], oral MeHg⁺ with oral selenate for 100 days in rats [126], oral MeHg⁺ with oral selenite for 16 months in rats [130], oral MeHg⁺ with injection of diphenyl diselenide in mice for 21 days [129], and oral MeHg⁺ with oral selenite for 19 weeks in rats [100]. While these studies are important in understanding the mechanism and interaction of selenium and mercury, they show primarily evidence of adequate or supratheraputic selenium status during ongoing mercury poisoning. The studies do not address what benefit selenium supplementation might provide if begun after mercury toxicity has already occurred, which is the question often faced in human events. However, a number of studies looking at effects of selenium supplementation initiated after mercury exposure have reported positive effects in both organic and inorganic mercury [22–24, 48, 81, 83, 131–135].

Selenium acetylcysteine synergy

Several studies have reported improved outcomes from the combined use of selenium supplementation and acetylcysteine [22–24, 81].

Use of selenium and acetylcysteine with inorganic mercury poisoning – mercuric chloride (Hg + 2)

Joshi et al. [23] looked at selenium administration as selenite with and without acetylcysteine given after mercury exposure had ceased. Using HgCl₂ (2.83 mg/kg i.p. × 1) in rats and waiting 24 h to begin selenium (500 µg/kg/day times 3 days) and/or acetylcysteine (0.6 mg/kg/day times 3 days), Joshi et al. [23] showed reduced lipid peroxidation, improved oxidation status, restored kidney function, improved liver function and reduced measures of liver injury (bilirubin, cholesterol, triglycerides, AST, ALT, and LDH) when compared with HgCl₂ poisoned rats receiving no treatment. Selenium alone was more effective than acetylcysteine alone, but selenium plus acetylcysteine together restored the rat (hepatic function, renal function and hisptopathoogical exam of liver and kidney post mortem) to within 80% of control (no HgCl₂) in four days, at the time of sacrifice [23]. Additionally, selenium and acetylcysteine administered together reduced kidney and liver mercury concentrations by 70% and 80%, respectively, in four days, at the time of sacrifice compared with HgCl₂ poisoned rats receiving no treatment [23].

Use of selenium and acetylcysteine with organic mercury poisoning – methylmercury (MeHg+) and dimethylmercury

Similar results (improved oxidation status, improved organ function and reduced injury) were found in a methylmercury rat model (MeHg⁺ 1.5 mg/kg/day orally for 21 days), with a 24 h delay followed by selenium (500 µg/kg/day orally for 5 days) and/or acetylcysteine (0.6 mg/kg/day i.p. for 5 days) [22]. Selenium alone was more effective than acetylcysteine alone, but selenium plus acetylcysteine together restored the rat (reduced brain lipid peroxidation, increased brain acetyl cholinesterase and increased brain, liver and kidney glutathione) to within 80% of control (no MeHg⁺) in 7 days, at the time of sacrifice [22]. Additionally, selenium and acetylcysteine administered together reduced brain, kidney and liver mercury concentrations by 87%, 88% and 86%, respectively, in 7 days, at the time of sacrifice compared with MeHg⁺ poisoned rats receiving no treatment [22].

In a model using dimethylmercury, perhaps the most neurotoxic form of mercury, selenium with acetylcysteine and zinc showed promising results. Joshi et al. [24] used three groups 1) controls (no mercury and olive oil as vehicle for 5 days), 2) dimethylmercury 1.5 mg/kg/day orally for 21 days, with a 24 h delay, and olive oil as vehicle for 5 days, and 3) dimethylmercury 1.5 mg/kg/day orally for 21 days with a 24 h delay followed by 5 days of selenium 0.5 mg/kg p.o. plus acetylcysteine 624 mg/kg i.p. plus zinc 2 mM/kg p.o. The treatment group showed significant reduction of brain, kidney and liver mercury concentrations by 46%, 64%, and 43%, respectively, compared to Hg poisoned rats with no treatment group [24]. Additionally, treated rats show significant restoration of organ function including brain (acetylcholinesterase activity and adenosine tryphosphate), kidney (adenosine triphosphate, creatinine, BUN and urea) and liver (bilirubin, serum triglicerides, gamma glutamyl tranpeptidase, and adenosine triphosphate), compared with no treatment group [24]. Histopathological examination of the three groups showed restoration of the treatment group near to controls (no Hg and no treatment) and compared with significant injury in the Hg only group [24]. In the treatment group brain there were well formed nerve filaments, recovered glial cells and the number of neurons and nerve fibers were restored, compared with reduction of nerve fibers, neuronal degeneration and fusion of nerve bundles in the Hg no treatment group [24]. Similar restoration of histopathological structure in the kidney and liver to near controls was seen in the treatment group [24].

Use of selenium and acetylcysteine with mercury vapor

A 15-year-old boy with mercury vapor exposure presented with a 2-month progression of neurologic and cardiovascular symptoms, including hypertension, tachycardia, tremor, insomnia, muscle pain, diaphoresis, altered gait, weight loss and a 1-month removal from mercury exposure, with a blood mercury concentration of 30 μg/L [48]. He was treated with oral Se 500 mcg/day (as sodium selenite) and oral acetylcysteine 50 mg/kg/day associated with significant clinical improvement including weight gain (50 pounds, 22.7 kg over 3 months), increased muscle strength, correction of hypertension, tachycardia, and tremor. Within 90 days there was full return to age appropriate norms for weight, physical and academic performance and resolution of neurological (tremor, gait) and cardiovascular (heart rate, blood pressure) symptoms [48].

Selenium alone – methylmercury

In a rat model of chronic methylmercury exposure until evidence of toxicity (4 mg/kg MeHg⁺ every other day via oral gavage for 4 weeks), the effects of selenium supplementation was evaluated [134, 135]. In comparing Se (2.74 mg/kg as sodium selenite via oral gavage every other day after MeHg⁺ exposure had ceased, equivalent to a 1:1 Hg:Se molar ratio) to no Se controls (saline via gavage), the Se treated rats showed increased weight gain, reduced oxidative damage and reduced Hg in the brain, liver and blood, compared with controls (no Se) [134, 135]. In these animals Se supplementation increased selenoprotein P, with 73% of Hg bound to selenoprotein P, suggesting this may be the mechanism for sequestration of Hg from target organs and transport for elimination [135]. In a rat model of MeHg, three groups were compared 1) control no Hg, no Se, 2) MeHg (4 mg/kg/day for 4 weeks) and 3) MeHg (4 mg/kg/day for 4 weeks) with Se as selenite (1.5 mg/kg/day), Se treatment ameliorated evidence of apoptosis and autophagic dysfunction in the pituitary and protected histopathological structures [136]. Additional in vitro evidence showed selenocysteine increased hepatic uptake of MeHg⁺ as a Se-MeHg complex, and reduced cytotoxicity of the MeHg [137].

In a chronic methylmercury rat model (MeHg⁺ 4 mg/Kg p.o. every other day for 28 days) the addition of selenium (Se 2.74 mg/kg p.o., equimolar dose 1:1 to MeHg) on day 29 for 90 days, showed restoration of gut flora, increased total mercury in feces and decreased the portion of MeHg⁺ in feces, supporting increased demethylation [138]. This was a small study of only 5 rats per group but this study suggests that Se promoted the decomposition and excretion of methylmercury, which can be partially ascribed to the modulation of gut flora [138].

Clinical studies of selenium in mercury poisoning

Residents (n = 103) of a mercury mining and smelting district in Wanshan China with elevated urine mercury concentrations were either administered selenium 100 µg/day (n = 53) or placebo (n = 50). Selenium supplementation significantly reduced markers of oxidative stress, as measured by urinary malondiadehyde and 8-hydroxy-2-deoxyguanosine levels [132]. Additionally selenium significantly increased urine mercury concentrations compared with controls: from a mean of 18 µg/L to 50 µg/L vs no change, respectively [132]. In a similar group of 5 residents with elevated urine Hg, Se supplementation increased Urine Hg from mean 173 µg/L (day 0) to 1018 µg/L (day 90). Ninety-five percent of Hg excreted was inorganic Hg. Urine Se did not change with supplementation [131]. The increase in urine mercury excretion did not begin for 15 to 30 days, suggesting redistribution of tissue mercury, rather than a direct renal effect [131, 132].

Draz et al. [133] compared 36 lamp factory workers in Egypt with ongoing occupational exposure to mercury, lead and cadmium to 20 non-exposed age matched controls [133]. Daily supplementation with selenium 100 µg/day for 2 months and vitamin E 100 mg daily for 2 months significantly (p < 0.05) reduced blood mercury concentrations in exposed workers (22%) and returned markers of oxidative stress (serum malondiadehyde) to those of non-exposed controls [133].

There is evidence that adequate or supratherapeutic selenium status provides benefits in the presence of elevated blood mercury or total body mercury concentrations [139–142]. Li et al. [143] reported on 4 groups from 4 geographic areas (3 groups from a mercury mining region and 1 from a non-mining region) in Wanshan China. In the 3 mining areas blood total Hg and blood MeHg⁺ were significantly elevated (means 12.5 to 14.7 µg/L and 6.64 to 7.93 µg/L, respectively) compared with the non-mining region (means 5.5 µg/L and 3.83 µg/L). However serum selenium concentrations were also significantly elevated in the 3 mining region groups vs the non-mining region group (219 to 274 µg/L vs 157 µg/L), with all groups showing an Se:Hg molar ratio of >10, suggesting a protective effect [143].

Lemire et al. [139] reported on a group from the Amazon basin with high mercury contamination (Median blood mercury concentration 42.5 µg/L), presumably from dietary sources. While elevated blood mercury concentrations showed a negative association with motor function tests, residents with elevated plasma selenium concentrations (median 135 µg/L, also from dietary sources) showed amelioration of these effects and positive association with improved motor functions.

Nakamura et al. [140] looked at a group in Taiji Japan with a history of whale meat consumption and measured blood mercury, hair mercury and blood selenium. Despite having chronic mercury exposure (hair mercury >50 µg/g) they did not detect neurologic impairment expected from chronic mercury exposure. They attributed the lack of neurologic impairment to the near equimolar mercury/selenium balance found in these residents [140].

Dose of selenium

In humans with mercury poisoning, 100 µg/day for 90–120 days (as selenomethoinine) and 500 µg/day for 6 months (as selenite) have been used successfully [48, 131–133]. While the upper level of safety with selenium supplementation is not defined, selenium supplementation in humans of up to 800 µg/day for 16 weeks (as selenite and selenomethionine) showed no evidence of toxicity [141]. In humans chronic ingestion of sodium selenite 40, 800 µg/day for a median of 29 days produced significant selenosis and mean serum selenium levels of 761 µg/L [142].

In mercury toxicity studies using rats, larger doses of selenium for shorter periods of time have been used with positive effects (500 µg/kg/day for 4 to 7 days and 865 µg/kg/day for 21 days) [22, 23, 83, 119]. However, larger doses (32 mg/kg as diphenyl diselenide) appeared to increase lethality [144]. Conversely, in an animal model of selenium toxicity (40 ppm Se in daily feed, total quantity of Se/day not measured), the addition of Hg⁺² (500 ppm, 1000 ppm as HgCl), significantly reduced the toxicity of the Se, as measured by weight gain and percent mortality at 2 and 3 weeks [145].

In the presence of Hg²⁺ 5 µmol, selenium 2 µmol was more effective than the thiol chelators dimercaptol, unithiol and succimer in restoring thioredoxin reductase activity [125]. However, in the presence of Hg²⁺ 10 µmol, it required selenium 8 µmol for significant rescue. For comparison 1 µmol of Hg²⁺ in cortical cell cultures (containing both neurons and glial cells) caused 40% cell death and 5 µmol Hg⁺² caused 100% cell death [146]. For comparison, in one human case peak clinical effects occurred with a CSF of thiomersal (ethylmercury) of 0.11 µmol (25 µg/L) [13]. Normal human reference plasma selenium concentrations range from 50 to 160 µg/L [147]. This equates to solutions containing selenite 0.5–2.0 µmol/L [143]. However, healthy populations have been recorded with higher serum selenium in the range of 219 to 274 µg/L [148, 149].

Effects on mercury kinetics after selenium supplementation

Selenium demethylation of organic mercuries and sequestration of mercury

Selenium supplementation may increase demethylation of organic mercuries, change mercury distribution and increase sequestration via binding to colloidal insoluble Hg:Se complexes. Inorganic mercury (Hg²⁺) does not readily cross the blood brain barrier, while both mercury vapor (Hg⁰) and MeHg⁺ more readily cross the blood brain barrier. The mechanism of transfer across the blood brain barrier might be passive infusion (Hg⁰) or as a substrate for the L-type large neutral amino acid transporter (MeHg⁺ and likely ethylmercury) [8, 80, 128, 150–152] (Figure 3). Once in the brain, portions of both Hg⁰ (oxidation) and MeHg⁺ (dealkylation) are converted to Hg²⁺ and are therefore trapped in the brain [8, 81, 82, 153, 154].

In monkeys, a chronic diet-source MeHg⁺ model demonstrated that the estimated half-life of MeHg⁺ in the brain was 37–45 days, but increased to 230–300 days for the demethylated inorganic Hg²⁺ [81]. Brain inorganic Hg was formed by demethylation in the brain, not by brain uptake of inorganic Hg demethylated elsewhere in the body [81].

Selenium supplementation and selenoprotein activity is likely responsible for in vivo demethylation of MeHg⁺ and conversion to inorganic Hg²⁺ in tissues, including the brain [101, 103, 138, 153, 155]. In comparing chronic exposure in mice (30 days), rats (18 weeks) and post-natal rat pups (10 days), both mercury exposure groups (mercury vs mercury plus selenium) showed increases in brain mercury, but the selenium supplementation groups did not display the clinical and pathological evidence of mercury toxicity [100, 102, 156]. In a rat model of oral MeHg⁺, (MeHg⁺ 40 mg/L in freely available water for 21 days), daily injection of Se (as sodium selenite 865 µg/kg/day i.p. for 21 days) effectively eliminated deposition of mercury in the brain [119].

The supplemental selenium may produce this protective effect by binding with the available mercury, producing an inert colloidal mercury:selenium complex [101, 119, 120, 127, 135, 137, 155, 157–159]. Support for this theory comes from autopsy studies in occupationally exposed mercury mine workers in Indrija Slovenia (compared with non-exposed population), who had elevated brain mercury content found 5 to 16 years after retirement [157]. Autopsy results compared three groups: 1) occupationally exposed mercury mining workers, 2) non-occupationally exposed residents from the mining district (Indrija Solvenia), and 3) non-exposed population from a non-mining region of Slovenia [157]. Despite a 20 fold increase in brain Hg (occupationally exposed vs non-occupational exposed local residents) and a 100 fold increase in brain Hg (occupationally exposed vs non-exposed from a non-mining region) all autopsies showed a near 1:1 molar Hg:Se ratio in the brain, thyroid and kidney, suggesting an active biological sequestration via an inert Hg:Se colloidal complex [157].

While it seems intuitive that redistribution away from target organs and increasing mercury elimination are important treatment goals, it may be that complexing with and sequestering already distributed mercury is an additional role of selenium supplementation [119–121].

Effect of selenium supplementation on selenoprotein activity

Selenoproteins are critical endogenous proteins that regulate: 1) the cellular redox environment protecting against protein and lipid peroxidation within the cells (e.g. thioredoxoin reductase, glutathione peroxidase); 2) calcium release from the endoplasmic reticulum (e.g. selenoprotien T, K, W); and 3) selenium delivery to organs and mercury distribution (e.g. selenoprotein P) [1, 160].

In in vitro models of Hg⁺² poisoning, activity of the selenoproteins thioredoxin reductase and glutathione peroxidase was restored by selenium supplementation (as selenite) [105, 107, 125]. Selenium supplementation may produce restoration of selenoprotein activity via several pathways: 1) supply of selenium needed during de novo regeneration of the selenoproteins; 2) direct scavenging of the mercury to a colloidal mercury:selenium complex; or 3) stimulation of increased genomic signaling that ultimately leads to enhanced selenoprotein expression [105, 107, 122, 125, 161]. Additionally, in a mouse model of MeHg⁺ exposure, selenium as diphenyl diselenide was able to restore mitochondrial function and increase mitochondrial biogenesis, likely by activating transposition of the nuclear factor E-2-related factor 2 to the nucleus [114, 129]. Selenium supplementation may ultimately perform better than the thiol chelators at restoring selenoprotein function, as the thiol chelators lack the ability to penetrate into the CNS. In an in vitro model of rat hepatocytes treated with HgCl₂ and MeHg, selenium at 0.5–1 µmol was as effective at restoring thioredoxin reductase activity as unithiol (10 µmol), succimer (10 µmol) or BAL (10 µmol) [125]. However, unlike selenium, unithiol and succimer lack the ability to penetrate the CNS, so restoration of selenoprotein activity in the brain following administration of the thiol chelators would not be expected [8]. In an in vivo model, unithiol showed no effects on the activity of the CNS selenoprotein, neuronal gluthathione peroxidase [162]. In an in vitro model, Se at 50 nmol was able to restore Selenoprotein W production (responsible for cellular calcium homeostasis) after incubation with 1.4 µmol MeHg [163].

Selenium alone was less effective in restoring function of the CNS selenoproteins thioredoxin reductase 1 and 2 inhibited by MeHg⁺, compared with inhibition by HgCl₂ [105, 115, 123]. MeHg⁺ may need to be demethylated prior to direct benefits from selenium, however selenite in the presence of glutathione increased demethylation of MeHg⁺ [22, 103, 117, 164].

Effect of selenium on mercury blood concentrations – redistribution away from target organs

Selenium supplementation may initially result in an increase in blood mercury concentrations [48, 99, 123, 131, 132, 135]. This is a result of increased selenoprotein P production in the liver [135, 165]. Selenoprotein P is a selenium-rich (10 selenocysteines) serum selenoprotein that acts partially as a “sink” for tissue mercury and a transport of Hg:Se complexes away from target critical organs [99, 123, 134, 135, 160, 165] (see Figure 4). In rats poisoned until neurological symptoms appeared (4 weeks of 2 mg/kg/day MeHg⁺ orally) selenium supplementation begun after Hg exposure ceased (150 µg/kg/day orally as selenite for 90 days) showed a 30% increase in serum mercury, suggesting a sink effect of mercury from tissues [99]. In a similar MeHg⁺ model of rats poisoned until evidence of neurotoxicity, Se supplementation begun after Hg exposure ceased, significantly increased selenoprotein P levels in the blood, allowing for increased distribution of mercury away from target organs like the brain [135]. In a third methylmercury rat study poisoned until neurological symptoms occurred, Hg in serum increased 240% (50 µg/l to 120 µg/l) at 30 days after selenium supplementation and 300% (50 µg/l to 150 µg/l) at 90 days, again suggesting a significant tissue sink effect [123]. The mercury in serum was bound to high molecular weight proteins in the 170 KDa range, likely selenoprotein P [123, 135]. A similar increase in blood mercury, with associated clinical improvement, was seen in one human case after selenium and acetylcysteine were initiated (500 µg/day and 50 mg/kg/day orally, respectively) [48]. Selenium status and the mercury:selenium molar ratio is a more important indicator of patient status than blood mercury concentrations [48, 100, 124, 132, 166].

Figure 4. Actions of Selenoprotein-P in mercury poisoning.

Effect of thiol chelators vs acetylcysteine on selenoprotein activity and interaction with selenium

There is a potential problem when considering use of unithiol or succimer together with selenium supplementation. One of the initial effects of selenium supplementation is a redistribution of mercury secondary to increased serum selenoprotein P. In the early phases (days to weeks), selenium supplementation produces increased liver mercury and decreased kidney mercury concentrations [99, 156, 167–169]. Over time this effect tends to revert to normal distribution patterns [1]. This early redistribution may pose a problem when selenium supplementation is used simultaneously with the thiol chelators, as the primary source of excreted mercury for the thiol chelators is kidney stores of mercury [168, 169]. In rats and mice with a single acute mercury injection, simultaneous administration of selenium supplementation (either as diphenyl diselenide or sodium selenite) and unithiol or succimer, showed lower urine mercury concentrations, compared with succimer or unithiol alone [168, 169]. Additionally, the thiol chelators may have an effect on tissue disposition and elimination of selenium: reducing serum selenium concentrations, reducing selenium availability for cells and increasing urine selenium excretion [170–172]. Conversely, simultaneous use of selenium with acetylcysteine appears to be synergistic, with increase mercury elimination, improved organ function and reduced mitochondrial injury [22, 23, 83, 119]. Additionally acetylcysteine promotes efflux of Hg from the brain via increased glutathione-MRP1 transport [41].

Failure of selenium supplementation

Comparison of outcomes from selenium supplementation studies can be difficult because of differences in doses used (mercury and selenium), model used (e.g. mouse vs rat), duration of the study and moieties used (e.g. MeHg⁺ vs Hg⁺², selenite vs diphenyl diselenide).

In an in vitro study of seal leukocytes, co-incubation of selenite (7.5 µmol) or selenomethionine (7.5 µmol) with MeHg⁺ (0.75 µmol) provided no protection against mercury-induced inhibition of cell proliferation [173]. In rats given high dose MeHg⁺ for 21 days (MeHg⁺ 5 mg/kg/day with co-administration of 1 mg/kg/day of diphenyl diselenide), MeHg-induced motor deficits and body weight loss worsened [174]. In addition, liver and brain mercury concentrations increased [174]. In a mouse study using Hg⁺² and a very high dose of diphenyl diselenide, (HgCl₂ 4.6 mg/kg/day for 3 days, followed by a single dose of diphenyl diselenide 100 µmol/kg [31.2 mg/kg]), there was 100% lethality [146]. Mice were euthanized at 4 h because the Se dose of 32 mg/kg was previously established to cause 100% death in mice in 5 h [144].

In a rat study using concurrent MeHg⁺ (at varying doses) and selenium as selenite for 50 weeks (24 µg/kg/day Se, a molar ratio of 18:1), selenium supplementation delayed long-term behavioral and motor effects of MeHg⁺ exposure compared with MeHg⁺ poisoned rats receiving no selenium [124]. In this study the dose of MeHg⁺ and the Hg:Se molar ratio played a significant role in outcome, as measured by onset of aging, run tests, forelimb grip strength, flexion, hind limb crossing, and motor neuron degeneration [124]. In rats receiving MeHg⁺ 0.4 mg/kg/day and selenium 24 µg/kg/day (6.3:1 Hg:Se molar ratio) there was significant protection from toxicity, however in groups receiving MeHg⁺ 1.2 mg/kg/day and selenium 24 µg/kg/day (18:1 Hg:Se molar ratio) increasing evidence of neurological and motor injury occurred [124]. In this same study lower dose selenium supplementation with larger Hg:Se molar ratios preformed worse: Hg:Se ratio of 187:1 (MeHg⁺ 1.2 mg/kg/day with selenium 2.4 µg/kg/day) and Hg:Se ratio of 63:1 (MeHg⁺ 0.4 mg/kg/day with selenium 2.4 µg/kg/day) [124]. While the dose of MeHg⁺ was important, the molar ratio was the most predictive of toxicity and outcome with Hg:Se ratios of 187 > 63 > 18.7 > 6.3 [124].

These results following acute co-administration of Hg and Se are not consistent across all studies. In a mouse study of 35 days of MeHg⁺ (2 mg/kg/day MeHg⁺ with co-administration of 1 mg/kg/day of diphenyl diselenide), there was evidence of decreased oxidative stress in the brain and liver, with decreased Hg deposition in the cerebrum, cerebellum, kidney and liver when compared with MeHg⁺ poisoned mice receiving no treatment [119].

Alternate markers of mercury toxicity

Selenium supplementation may initially result in an increase in the blood mercury concentration, which is not an indication for discontinuation of selenium supplementation. We would caution against focusing too heavily on mercury concentrations either in the blood or urine as selenium status appears to be more important in determining patient outcome.

Several alternate markers of mercury toxicity have been suggested to monitor ongoing injury and perhaps response to therapy: 1) neurologic injury – serum neuron-specific enolase (NSE), S100B, and glutamate receptor levels, and 2) evidence of oxidative stress – serum malondiadehyde and urinary malondiadehyde and 8-hydroxy-2-deoxyguanosine [131, 133, 175–177]. However, further validation of these markers are needed and may not be widely available.

Summary of selenium supplementation

The primary role of selenium supplementation appears to be correction of mercury-induced selenium deficiency state, restoration of critical selenoprotein activity and subsequent reduction of oxidative stress and cellular calcium dyshomeostasis (restoration of selenoprotein control over endoplasmic reticulum release of intracellular calcium). Additive roles of selenium may be redistribution of Hg away from target organs, demethylation of organic mercury and possible sequestration of Hg as Hg:Se complexes. A limitation of selenium supplementation is dose. As the intracellular molar ratio of mercury to selenium increases the efficacy of selenium decreases. In very high doses of mercury poisoning, safe doses of selenium supplementation may not be sufficient to approach a protective equimolar ratio. Attempting to manage with selenium alone using a very high dose of selenium may produce significant adverse events and worsen the patient's condition. A second limitation is that selenium has only a modest effect on increased mercury elimination. However, this increased elimination is from a reduction of total body mercury from target organ tissue redistribution, and not an increase from kidney mercury stores.

Limitations

There are no randomized clinical trials in humans evaluating any therapy for mercury poisoning. The existing widespread recommendations for the use of thiol chelators are based on evaluation of animal studies and human case reports and fail to take into account the mechanism of toxicity of mercury. These recommendations have not been tested in randomized clinical trials. The dosing and duration of therapy for unithiol and succimer are based on different metals (i.e. lead) with different kinetics and target organs. The recommendations for management of mercury poisoning in this review are based on evaluation of advances in understanding of mechanism of mercury toxicity, in vitro studies, animal studies and human case reports, but also lack a randomized clinical trial. Randomized clinical trials are recommended, but are likely to prove difficult due to limited patient populations and ethical reasons.

Conclusions

The primary consequence of mercury poisoning is the creation of a selenium deficient state. Previous management of mercury poisoning focused solely on increased renal elimination of mercury via the thiol chelators, did not address selenium status and consequently has produced limited benefit. A combined approach which focuses on restoration of selenoprotein function, reduction of oxidative stress along with increased mercury elimination is suggested.

Selenium supplementation will help restore selenoprotein concentrations and may allow for reactivation of some of the existing selenoproteins, which will help restore intracellular calcium homeostasis and the cellular redox environment via correction of the mercury-induced selenium deficiency state. Additionally selenium supplementation may increase distribution of mercury away from target organs, increase mercury elimination, and help sequester mercury as the inert Se:Hg colloidal complex. Dosing and duration of therapy for selenium supplementation have not been established. Duration of therapy may be based on patient specific determinants (e.g. clinical severity, chronicity). An initial selenium supplementation of 100 µg/day in asymptomatic patients and 500 µg/day in symptomatic patients for 90 days is recommended and has been used by the authors (see Figures 5 and 6). Selenium as sodium selenite and selenomethionine have been used. Continued supplementation should be based on reevaluation of a number of patient factors, including response to treatment, adherence, and the presence and severity of any drug effects that may warrant discontinuance of selenium. The recommendation for 90 days is based on available human reports and appears to be a reasonable time for patient reevaluation [48, 131–133]. Further research on dose and duration of therapy of selenium is warranted.

Figure 5. Suggested management guideline for Organic Mercury (Methylmercury, dimethylmercury, etc).

Figure 6. Suggested management guidelines for Inorganic Mercury or Mercury Vapor.

For organic mercury, the ability of acetylcysteine to penetrate the CNS, increase glutathione production, ability to complex with mercury and act as a potent chelator argue that it may be a better choice as a complexing agent. The drawbacks of the thiol chelators are their limited effectiveness with organic mercuries, such as methylmercury and thiomersal, inability to cross the blood-brain barrier, increased excretion of selenium and their short-term effect on increased mercury elimination. Simultaneous use of selenium with unithiol or succimer may initially reduce the efficacy of the thiol chelators and possibly reduce availability of the supplemental selenium. Conversely, simultaneous use of selenium with acetylcysteine appears to be synergistic. For organic mercuries, we recommend selenium supplementation and acetylcysteine for mercury elimination (see Figure 5). Dosing and duration of therapy for acetylcyteine supplementation have not been established. Continued supplementation should be based on patient reevaluation.

For inorganic mercury we recommend a combined chelator approach. In the initial few days following inorganic mercury exposure (HgCl₂ or mercury vapor), unithiol may be more effective than acetylcysteine in increasing Hg⁺² elimination from renal stores and reducing kidney inorganic mercury. For inorganic mercuric salts and elemental mercury, we recommend limiting the use of the thiol chelators and switching to acetylcysteine for continued mercury elimination once the initial phase of renal Hg clearance is achieved. Based on animal and human data this appears to be 2 to 4 days. After switching to acetylcysteine, we recommend continuing acetylcysteine for 90 days. Simultaneous use of selenium with acetylcysteine appears to be synergistic. Unithiol, if available, is more effective than succimer (see Figure 6).

Further research is warranted on establishing a more definitive recommendation for selenium dosing and duration of therapy, the form of selenium that may provide best results; investigation of a Hg:Se molar ratio needed to optimize outcomes; and continued examination of the role that thiol-based chelators and acetylcysteine should play in the treatment of mercury poisoning.

Table 1. Evaluation and review of refenced studies.

Type of study	Form of mercury	Intervention	Findings	Comments	Reference (# from refence list)
Human study – succimer challenge test in occupationally exposure workers	3 groups − 1) control – not exposed, 2) removed from exposure due to high urine Hg (urine > 100 mcg/g Hg) and 3) presently occupational exposed	Succimer 2 gm p.o. once. 1) Routine 24 h urine Hg measurements and 2) 24 Urine measured before and after succimer	2 compartment model – distribution 2–5 days and elimination 70 to 109 days. Mercury removed by succimer is primarily kidney mercury. Majority of mercury removed occurred in 1^st 8 h post succimer	Challenge test. No assessment of long term therapy or outcome measures	Ref # 5 Roels et al. Brit J Indust Med. 1991;48:247–253.
Human study – case series –occupationally exposed workers to mercury vapor	26 workers exposed to heated liquid mercury vapor while welding. 10 patients with long term (570 days) neuropsych follow up	Therapy begun 19–36 days post exposure. Succimer 30 mg/kg Q 8 hr for 2 weeks or penicillamine 250 mg Q 6 hr for 2 weeks 11 patients were given a second course of succimer 300 mg/kg q 8 hrs for 4 days	Urine mercury increased 46% during succimer. No effect on blood concentrations. Mercury mean half-life of 56 days. 10 patients with long-term follow up continued to show neurologic sequelae 570 days post exposure.	It remains to be shown that a difference in chelation mobilization of mercury and increased urinary mercury excretion confers benefit to the patient.	Ref # 6 Bluhm RE, et al. Human Exp Toxicol. 1992;11:201–210.
Case report – human	2 month occupational exposure to mercury vapor	Therapy begun 2 months after onset of symptoms – penicillamine 250 mg Q 6 hr for 5 months. Unithiol 500 mg/day Iv for 4 days	Quadraplegia, pneumomediastinum, subcutaneous emphysema of the neck together with atelectasis and consolidation in the lower segments of the left lung, resolved after 5 months in ICU. Discharged with persistent severe polyneuropathy in lower extremities at 196 days.	It remains to be shown that a difference in chelation mobilization of mercury and increased urinary mercury excretion confers benefit to the patient.	Ref # 7 Smiechowicz J, et al. Sage Open Med Case Report 2017
Animal study – rat –Acute methylmercury – delay before Intervention	MeHg 1 mg/kg i.p. once	Unithiol or succimer 0.1 mmol/kg i.p. 4 times/week for 4 weeks (16 doses) begun 1,7, and 14 days after Hg injection	Unithiol was more effective in reducing kidney Hg (80% removed after 4 weeks). Succimer was more effective in reducing liver and blood Hg. If treatment initiation delayed 7 or 14 days, effectiveness decreased, with no effect on brain Hg, and significantly increased body burden	Delay in treatment, allowing of distribution reduced effectiveness in all organs, except kidney	Ref # 8 – Planas-Bohne F. J Pharmacol Exper Therap 1981;217:500–504
Animal study – rats – Acute inorganic HgCl – delay before intervention	HgCl2 − 0.5 mg/kg HG^2+ i.v., once	Unithiol − 300 µmol/kg p.o. by gavage [68.4 mg/kg] administered daily for 4 days and given 24 h post Hg^2+ injection	Decreased the mean kidney mercury content by 78% and doubled the urine mercury concentration. No impact on the mercury content of other tissues, including brain, blood and liver	Acute exposure	Planas-Bohne F. Toxicol 1981;19:275–278
	HgCl2 − 0.5 mg/kg HG^2+ i.v., once	Unithiol or succimer − 100 µmol/kg i.p. administered daily for 4 times/week for 4 weeks (16 doses). Begun 24 h post Hg^2+ injection	Prolonged i.p. Unithiol decreased mercury content in kidney, blood, liver, blood and muscle but not the brain, which showed no changes from control. Succimer decreased mercury the kidney but not brain, blood, muscle or blood, which showed no changes from control	Acute exposure	Planas-Bohne F. Toxicol 1981;19:275–278
Animal study – rats – chronic elemental mercury vapor – delay before intervention	Mercury vapor 2 hrs/day for 7 days then 7 days wait until tx arm.	Unithiol 1.5 mmol/KG/day i.p. for 7 days, or 1.5 mmol/kg/day i.p. for 7 days or acetylcysteine 1.5 mmol/kg/day i.p. for 6 days	NO change in brain Hg. Unithiol and succimer decreased kidney mercury	Unable to remove Hg from the brain after chronic exposure	Ref # 9 Aposhian HV, et al. Clin Toxicol 2003;41:339–347
Animal study – rats – chronic Inorganic HgCl – delay before intervention	HgCl2 (0.5 mg/kg HgCl2 i.p.) for 32 to 41 days	unithiol − 0.27 mmol/kg i.p./day [62 mg/kg/day) – four groups given either 1,2,3 or 4 days of unithiol. Begun 16 days after Hg injection	Reduced Kidney Hg content, but no change in brain Hg. No difference between tx with days 1–4 of unithiol.	Inorganic mercury has poor penetration across the blood brain barrier, but thiol chelators do not effect brain Hg^+2 content. However, this study of chronic inorganic mercury appears to reflect chronic human mercury poisoning better than the acute animal models as it produced brain and kidney content similar to chronic occupational human exposures.	Ref # 10 Aposhian, et al. Toxicol 1996;109:49–55
Case report – Human – dermal dimethylmercury	Single dermal Dimethylmercury exposure	Therapy begun 168 days post exposure succimer 30 mg/kg/day for 21 days with continued multiple 21-day cycles of 20 mg/kg/day	Significant increase in 24/hour urinary mercury excretion (234 µg/L to 39,800 µg/l), but urine mercury declined rapidly and returned to near prechelation concentrations despite continued succimer therapy. distribution phase − 17 days, Half-life (hair) 74 days, No impact of continued chelation therapy or blood exchange transfusion on clinical status with continued patient deterioration: coma unresponsive to verbal or visual stimuli (20 days post-chelation initiation) and death (130 days post-chelation initiation).	Long delay before therapy begun. No evidence of clinical improvement with prolonged chelation therapy	Ref # 12 Nierenberg, et al. New Engl J Med. 1998;338:1672–1676
Case report – Human – ingestion ethylmercury	Acute ingestion of Thiomersal (ethylmercury)	unithiol and succimer begun within hours of ingestion, using a complicated regimen of alternating oral and IV unithiol (days 1–16 and 23–29) and oral succimer (days 17–22 and 33–70) No chelating therapy was given on days 6, 30 − 32, and 47 − 50.	Neither antidote had an impact on blood or urine mercury concentrations. Despite continued unithiol and succimer therapy, the cerebrospinal fluid mercury concentrations (brain mercury) continued to rise and peaked on day 17 post-ingestion (25 µg/L). During ongoing therapy with unithiol and succimer, neurologic and renal effects continued to worsen, including ascending peripheral axonal polyneuropathy (day 6), delirium (day 11), coma (day 13), mechanical ventilation (day 16), with improvement beginning day 19 to day 40.	The authors concluded chelation therapy with unithiol or succimer has not been proven to be effective and that survival may have been due to the relatively low dose ingested (83 mg/kg).	Ref # 13 Pfab R, et al. J Toxicol Clin Toxicol. 1996;34:453–460
Animal study – mice – chronic methylmercury – Simultaneous intervention	Methylmercury 14 mg/kg/day i.p. for 17 days	Either BAL 20 mg/kg/day i.m. for 17 days or unithiol 500 mg/kg/day i.p. for 17 days	BAL increased brain Hg. Unithiol decreased brain Hg, restored weight gain and animal deaths (0) to controls (No Hg, no Tx) measured at 20 days.	Simultaneous daily administration of Hg and chelator are unrealistic to human experience.	Ref # 14 Kostyniak PJ, et al. J App Toxicol. 1984;4:206–210.
Animal study – rats – chronic MeHg – Delay before intervention	MeHg 10 ppm in freely available water for 9 weeks.	Unithiol − 1) 100 mg/kg i.p. once or 2) 200 mg/kg i.p. once or 3) 100 mg/kg every 72 h x 3 – all tx begun after MeHg stopped.	Single injection of unithiol decreased kidney Hg (both organic and inorganic) and increased brain Hg. No difference between 100 and 200 mg/kg dose. Repeated unithiol dose decreased MeHg in all organs but no effect on brain Hg^+2. No difference between dose 2 and 3 in repeat doses.	The inability of the thiol chelators to cross the blood brain barrier and access dealkylated inorganic mercury (Hg^+2) is likely responsible for its poor remediation of neurotoxicity associated with the organomercuries	Ref # 15 Pingree SD, et al. Toxicol Sci. 2001;61:224–233.
Case report – chronic dermal methylmercury iodide	MeHg iodide in skin cream – dermal	Succimer 30 mg/kg/day	Initial symptoms included dysarthria, which progressed to blurry vision, gait unsteadiness and agitated delirium. 2 weeks after onset of neurological effects, blood and urine mercury were 2620 µg/L and 110 µg/L, respectively. Mercury blood levels decreased to 1114 µg/L (11 days of chelation) and 528 µg/L (21 days of chelation), without clinical or neurological improvement. Blood methylmercury was determined as 87% (460 µg/L of 528 µg/L). Despite prolonged chelation therapy, after 5 months the patient remained unable to verbalize or care for herself, requiring ongoing tube feeding for nutritional support.	The inability of the thiol chelators to cross the blood brain barrier and access dealkylated inorganic mercury (Hg^+2) is likely responsible for its poor remediation of neurotoxicity.	Ref # 16 Mudan A, et al. MMWR 2019;68:1166–1167
Animal study – mice – acute inorganic HgCl – Simultaneous intervention	HgCl2 2 mmol/kg i.v once	Tx given 24 h after Hg. Experiment 1 -Unithiol 0.5 mmol/kg i.v. once or succimer 0.5 mmol/kg i.v. once Experiment 2 – Unithiol 1 mmol/kg/day po for 4 days or succimer 1 mmol/kg/day for 4 days	Experiment 1 – unithiol and succimer reduced kidney Hg but no effect on brain Hg. Bal increased brain Hg Experiment 2 – unithiol reduced blood, brain and kidney HG. Succimer reduced only kidney Hg	Unithiol reduced total body Hg better than succimer with continued administration. Simultaneous daily administration of Hg and chelator are unrealistic to human experience.	Ref # 19 Aaseth, et al. J Toxicol Clin Toxicol. 1982;19:173–186.
Animal study – rats – Acute inorganic HgCl -	HgCl2 0.5 µmol/kg i.p, (0.118 mg/kg), once	unithiol 100 mg/kg (0.39 μmol/kg) i.p., Twice, 24 and 28 h post Hg^2+ injection	Kidney and blood mercury content reduced by 87% and 30% respectively, compared with control (no unithiol). No effect on liver Hg. Brain mercury content was not assessed.		Ref # 21 Bridges CC, et al. J Pharmacol Exp Ther. 2008;324:383–390.
Animal study – rats – Acute inorganic HgCl -	HgCl2 0.5 µmol/kg i.p, (0.118 mg/kg), once	Succimer 100 mg/kg i.p. (0.55 μmol/Kg) , twice. 24 and 28 h post Hg^2+ injection	Kidney and blood mercury content reduced by 80% and 30% respectively, compared with control (no succimer). No effect on liver Hg. Brain mercury content was not assessed.		Ref # 21 Bridges CC, et al. J Pharmacol Exp Ther. 2008;324:383–390.
Animal study – Rats – Chronic methylmercury – delay before intervention	MeHg 1.5 mg/kg/day orally for 21 days	After 24 h – selenium 500 µg/kg/day i.p. times 5 days and/or acetylcysteine (0.6 mg/kg/day i.p. times 5 days	reduced brain lipid peroxidation, increased brain acetyl cholinesterase and increased brain, liver and kidney glutathione to within 80% of control (no MeHg^+) in 7 days. Additionally, selenium and acetylcysteine administered together reduced brain, kidney and liver mercury concentrations by 87%, 88% and 86%, respectively compared with MeHg^+ poisoned rats receiving no treatment	Selenium alone was more effective than acetylcysteine alone, but selenium plus acetylcysteine together were most effective	Ref #22 Joshi D, et al. Cell Biochem Funct. 2014;32:351–360.
Animal study – Rats – acute dimethylmercury – delay before intervention	10mg/kg dimethylmercury p.o. once	After 72 h dithiothreitol 15.4 mg/kg p.o. and Se 0.5 mg/kg and Zn 2 mmol/kg p.o. for 3 days	Reversed lipid peroxidation level and mercury ion concentration in liver, kidney and brain. and histopathological changes of liver, kidney and brain,		Joshi D, et al. J Trace Elem Med Biol. 2013;27:249–256.
Animal study – Rats – Acute inorganic HgCl – delay before intervention	HgCl 12 µmol/kg (2.83 mg/kg) i.p. once	After 24 h –selenium 500 µg/kg/day i.p. times 3 days and/or acetylcysteine (0.6 mg/kg/day i.p. times 3 days	Reduced lipid peroxidation, improved oxidation status, restored kidney function, improved liver function and reduced measures of liver injury (bilirubin, cholesterol, triglycerides, AST, ALT, and LDH) when compared with HgCl2 poisoned rats receiving no treatment. Selenium and n-acetylcysteine administered together reduced kidney and liver mercury concentrations by 70% and 80%, respectively, in four days, at the time of sacrifice compared with HgCl2 poisoned rats receiving no treatment.	Selenium alone was more effective than acetylcysteine alone, but selenium plus acetylcysteine together restored the rat (hepatic function, renal function and hisptopathoogical exam of liver and kidney post mortem) to within 80% of control (no HgCl2) in four days, at the time of sacrifice.	Ref # 23 Joshi D, et al. J Trace Elem Med Biol. 2014;28:218–226.
Animal study – rats – chronic dimethylmercury – delay before intervention	dimethylmercury 1.5 mg/kg/day p.o. for 21 days	After 24 h – Se 0.5 mg/kg p.o. plus acetylcysteine 624 mg/kg i.p. plus zinc 2 mmol/kg p.o.	The treatment group showed significant reduction of brain, kidney and liver mercury concentrations by 46%, 64% and 43%, respectively, compared to Hg poisoned rats with no treatment group. Additionally, treated rats show significant restoration of organ function including brain (acetylcholinesterase activity and adenosine triphosphate), kidney (adenosine triphosphate, creatinine, BUN and urea) and liver (bilirubin, serum triglycerides, gamma glutamyl transpeptidase and adenosine triphosphate), compared with no treatment group. Histopathological examination of the 3 groups showed restoration of the treatment group near to controls (no Hg and no treatment) and compared with significant injury in the Hg only group. In the treatment group brain there were well formed nerve filaments, recovered glial cells and the number of neurons and nerve fibers were restored, compared with reduction of nerve fibers, neuronal degeneration and fusion of nerve bundles in the Hg no treatment group. Similar restoration of histopathological structure in the kidney and liver to near controls occurred in the treatment group.		Ref # 24 Joshi D, et al. Environ Toxicol Pharmacol. 2010;29:97–103.
Animal study – Mice – Acute Methylmercury and inorganic HgCl – Delay before intervention	Male mice HgCl 0.2 µmol/kg i.p. once and Female mice MeHg 0.5 or 25 µmol/kg i.p. once	n-acetylcysteine 10 mg/ml in freely available water begun 48 h after Hg	N-acetylcysteine accelerated MeHg elimination via urine		Ref # 26 Ballatori N, et al. Amer J Pathol. 1998-152:1049–1055.
Animal study – Mice – Acute Methylmercury and inorganic HgCl – Delay before intervention	HgCl 0.2 µmol/kg i.p. once or MeHg MeHg 0.5 or 25 µmol/kg i.p. once	n-acetylcysteine 10 mg/ml in freely available water begun 48 h after Hg	NAC in drinking water vs no NAC for 5 days there was significant reduction of mercury in the brain (40% in males, 58% in females), blood (87% in males, 91% in females), kidney (91% in males, 85% in females) and liver (75% in males, 85% in females) after MeHg exposure. NAC vs no NAC Rats excreted 94% (female) 99% (male) of total dose vs 29% (female ) 59% (male) of total dose, respectively	In contrast to methylmercury excretion, clearance of inorganic mercury was not accelerated by NAC	Ref # 27 Ballatori N, et al. Environ Health Prospect. 1998;106-267–271.
Animal study – Rat – acute inorganic HgCl – simultaneous intervention	HgCl 5 mg/kg s.c. once	N-acetylcysteine 2 mmol/kg (326 mg/kg) i.p. once	NAC reduced kidney Hg, increased Urine Hg and improved renal function (BUN) compared with controls (no NAC)	Simultaneous administration	Ref # 28 Girardi G, et al. Toxicol. 1993;81:57–67.
In vitro Hepatic MDCK cells – inorganic HgCl and Methylmercury – co-incubation	Conjugates of (Acetylcysteine) NAC-Hg and NAC-MeHg	Inhibition of OAT transporters	MeHg-NAC and NAC-Hg-NAC are transportable substrates of OAT1 and thus potentially transportable mercuric species taken up in vivo at the basolateral membrane of proximal tubular epithelial cells.		Ref # 29 Zalups RK, et al. J Pharmacol Exp Therap. 2005;314:1158–1168.
In vitro –Xenopus laevis oocytes expressing rat Oat1 – methymercury – co-incubation	Conjugates of NAC-MeHg and unithiol-MeHg	Inhibition of OAT transporters	MeHg antidotes Acetylcysteine (NAC) and unithiol and their mercaptide complexes are transported by Oat1	Suggests the complexes are transported more efficiently than the parent chelating agents, which in turn would promote more MeHg complexation and excretion.	Ref # 30 Koh AS, et al. Mol Pharmacol. 2002;62:921–926.
In vitro – Mouse cerebellar neuron and astrocytes – Methylmercury – co-incubation	1 mmol MeHg	12 h before MeHg – Neurons 250 µmol NAC or 3 mmol di-ethyl maleate (DEM) or Astrocytes 200 µmol NAC or 1.8 mmol di-ethyl maleate (DEM)	Acetylcysteine (NAC) enhanced glutathione (vs depletion via DEM) protects against MeHg-induced oxidative stress in primary cell cultures of neurons and astrocytes.	The limited GSH availability might be one of the mechanisms responsible for making neurons more susceptible to MeHg toxicity versus astrocytes	Ref # 31 Kaur P, et al. Neurotoxicol. 2006;27:492–500.
Animal study – Rats – acute methylmercury – simultaneous intervention And In vitro methylmercury	Animal – MeHg 5 mg/kg s.c. once In vitro MeHg 0.1 to 6 µmol	NAC 10 mg/kg i.p. every 2 h times 4 In vitro – NAC 3 to 1000 µmol	In vivo – Treatment of MeHg-exposed rats with repeated injections of NAC abolished MeHg toxicity. NAC prevented the reduction in DNA synthesis. The intermediate-term decrease in hippocampal cell number provoked by MeHg was fully blocked by NAC In vitro – MeHg (3 µmol) induced a > 50% decrease in DNA synthesis at 24 h, an effect that was completely blocked by NAC incubation.		Ref # 32 Falluel-Morel A, et al. J Neurosci Res. 2012;90:743–750
Animal study – Rats – acute methylmercury – simultaneous and delayed intervention	0.5 µmol/Kg i.v. once	NAC 0.42 or 0.84 mmol/kg, given 2 h after MeHg NAC given once or twice 4 h apart Or 10 mg/ml NAC in free water for 10 days	Intracellular MeHg is transported across the apical membrane of the cells into the tubular fluid as a MeHg-NAC complex using the multidrug resistance-associated protein. NAC markedly stimulated urinary MeHg excretion and a second dose of NAC was as effective as the first dose in stimulating MeHg excretion. increasing the dose of acetylcysteine from 0.25 mmol/kg (40.5 mg/kg) to 1.5 mmol/kg (244.8 mg/kg) showed a near linear increase in mercury elimination, from 2% of total dose eliminated in 2 h to 10% of total dose eliminated in 2 h, respectively, compared with 0.1% elimination in controls (MeHg but no acetylcysteine)		Ref # 33 Madejczyk MS, , et al. J Pharmacol Exp Therap. 2007;322:378–384
Animal study – Rats – acute methylmercury – simultaneous intervention	MeHg 0.1 µmol/Kg i.v. once	NAC 1 mmol/kg i.v., given 1 h after MeHg And 1 mmol/kg i.v., given 2 h after MeHg	NAC produced a transient, dose-dependent acceleration of urinary MeHg excretion in rats of both sexes. Approximately 5% of MeHg was excreted in urine 2 hr after injection of 1 mmol/kg NAC. NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain		Ref # 34 Aremu DA, et al. Environ Health Perspect. 2008;116:26–31.
Animal study – rat – Acute inorganic HgCl	HgCl i.p. dose not provided	NAC 100 mg/kg i.p,	No data provided on Hg – states no change in Hg urine excretion		Ref #35 Ottenwalder H, et al. Arch Toxicol. 1987;60:401–402
In vitro – C2C12 myogenic cell line – methylmercury – co-incubation	MeHg 1 µmol	Acetylcysteine 200 µmol, 500 µmol and 1000 µmol	Acetylcysteine prevented cell apoptosis 80% in control vs 10 % with NAC (500 µmol)		Ref # 36 Usuki F, Ishiura S. Clin Neurosci. 1998;9:2291–2296.
In vitro – neuroblastoma cell cultures –inorganic HgCl – co-incubation	HgCl − 1 µmol to 1 mmol	Glutathione and acetylcysteine	Measured increased intracellular glutathione production Suggested a direct protective effect of acetylcysteine – Cell viability 74–90% vs 10% (control, no NAC). from increased cellular glutathione production with subsequent scavenging of reactive oxygen species		Ref # 37 Becker A, et al. Neurochem Res. 2009;34:1677–1684
Animal study – Rat – acute inorganic HgCl – simultaneous intervention	HgCl 5 mg/kg s.c. once	N-acetylcysteine 2 mmol/kg (326 mg/kg) i.p. once At 1 h and 2 h post Hg	significant decrease in kidney and liver Hg content protection against renal injury and elimination of Hg-induced lipid peroxidation		Ref # 38 Girardi G, et al. Toxicol. 1991;67:155–164
In vitro –cultured rat astrocytes – methylmercury	MeHg 10 µmol For 30 min	2-oxothiazolidine-4-carboxylic acid (increased cellular glutathione)	Conjugation with GSH is the major pathway for MeHg efflux in rat astroglia. elevation in the cellular GSH level promotes the accelerated elimination of MeHg from the critical tissue		Ref # 41 Fujiyama J, et al. Biochem Pharmacol. 1994;47:1525–1530
In vitro – Methylmercury -cortical cell cultures (containing mixed neurons and glial cells – co-incubation	Cell bath MeHg 5 µmol	Co-treatment glutathione monoethyl ester (GSHME)	blockade of oxidative stress alone is insufficient to prevent MeHg-induced neuronal death, Elimination of MeHg from the cell by conjugation to GSH (and transport via MDRP1) is necessary.	conjugation with MeHg and subsequent export of glutathione from the cytosol is crucial to alleviate or prevent MeHg-induced neurotoxicity and that solely blocking oxidative stress is not likely to offer significant neuroprotection.	Ref # 42 Rush T, et al. Neurotoxicol. 2012;33:476–481.
Animal study – Rats – acute elemental Mercury Vapor	Mercury vapor 27 hg/M^3 for 1 h or Mercury vapor 27 hg/M^3 for 2 h	NAC 300 mg/kg/day i.p. for 6 days prior to Hg vapor	N-acetylcysteine treatment increased survival time and the percentage of living animals. The lung superoxide dismutase was lower than in the non-treated animals indicating an antioxidant effect. Hg levels were decreased in blood and lung, suggesting some chelating effect of N-acetylcysteine.	NAC tx prior to Hg exposure does not reflect human experience	Ref # 43 Livardjani F, et al. Toxicol. 1991;66:289–295
In vitro – rat astrocyte cultures – methylmercury – co-incubation	MeHg 5 µmol	Acetylcysteine 5 µmol	Autophagy is an evolutionarily conserved catabolic pathway. MeHg activates prosurvival autophagy via ROS production and that induction of autophagy protects against MeHg neurotoxicity. N-acetylcysteine attenuates autophagy in astrocytes.		Ref # 44 Yuntao F, et al. Arch Toxicol. 2016;90:333–345.
Case report – Methylmercury	MeHg Source never determined	Hemodialysis, Unithiol- both i.v. and p.o. (dose not provided) for 90 days.	Over several weeks the patient deteriorated from progressive fatigue and weakness to undirected movements in response to painful stimuli, absent reflexes in arms and legs and requiring mechanical ventilation and renal failure. Blood from the time of patient presentation showed a whole blood mercury level was 4255 µg/L. . Whole blood mercury several days after unithiol was begun showed total mercury 2929 µg/L of which 1538 µg/L was determined to be methylmercury. The patient died 7 months after presentation from refractory status epilepticus. An autopsy revealed severe atrophy of cerebellum, pons, and medulla oblongata, findings that are common after severe mercury intoxication.	The authors concluded that treatment with unithiol effectively lowered blood levels of mercury, however its benefit on brain levels and neurologic damage was rather limited. The inability of the thiol chelators to cross the blood brain barrier and access dealkylated inorganic mercury (Hg + 2) is likely responsible for its poor remediation of neurotoxicity.	Ref # 45 Napp LC, et al. Case Reports Crit Care 2019: 4275918
Case report – chronic dermal use	3 month use of skin cream containing 27% Hg (mercuric and mercurous chloride)	Unithiol 12 mg/kg/day p.o. for 14 days	Presented with weight loss, tachycardia, hypertension, muscle weakness, desquamation on palms, insomnia and new onset seizure. Blood and 24-hour urine mercury concentrations were 32.5 µg/L and 41.1 µg/L, respectively. During oral unithiol therapy neurologic symptoms worsened, including a recurrence of seizures. On day 7 of unithiol therapy new hyperintense lesions were documented on MRI (compared with pre-chelation MRI) in the subcortical white matter and the parietal lobe. The patient did not improve over the remaining 7 days of unithiol therapy.	The authors speculated that unithiol may be the cause or trigger for the patient deterioration and MRI findings in their patient. Revaluation at 4 months showed resolution of the lesions and within 6 months neuropsychological status normalized.	Ref # 47 Benz MR, et al. Eur J Pediatr 2011;170:747–750
Case report – Chronic Elemental mercury vapor inhalation	Hg Vapor – one month exposure	Succimer 30 mg/kg/day for 5 days and 20 mg/kg/day for 14 days	2-month progression of hypertension, tremor, insomnia, muscle pain, weight loss and tremor and a 1-month removal from mercury exposure, with a blood mercury concentration of 32 μg /L. post succimer the patient deteriorated, including worsening tachycardia, increased weight loss, hypertension, diaphoresis, muscle weakness, altered gait, persistent tremor, insomnia and hallucinations. Pre- and post-chelation blood and urine concentrations fell (blood 32 μg/L to 19 μg/L and urine 330 μg/l to 44 μg/L, respectively), with continued patient deterioration	Reflects difficulty of removing brain Hg by succimer after chronic exposure.	Ref # 48 Spiller HA, et al. Toxicol Comm. 2017;1:24–28
Case report – Chronic elemental mercury vapor inhalation	Hg Vapor – one month exposure	Se 500 µg/day p.o and acetylcysteine 50 mg/kg/day p.o for 90 days	weight gain (50 pounds, 22.7 kg over 3 months), increased muscle strength, correction of hypertension, tachycardia, and tremor. Within 90 days there was full return to age appropriate norms for weight, physical and academic performance and resolution of neurological (tremor, gait) and cardiovascular (heart rate, blood pressure) symptoms	Reflects Se and acetylcysteine ability to restore selenoproteins	Ref # 48 Spiller HA, et al. Toxicol Comm. 2017;1:24–28
Case series – Chronic elemental mercury Vapor	Chronic Hg vapor (3 months) − 4 family members	Unithiol i.v. and succimer i.v., multiple doses, multiple sessions over 172 days	Malaise, fever, erythematous rash, pulmonary problems, hypertension, encephalopathy, nephrotic syndrome and polyneuropathy. Symptoms resolved slowly over 5 months to 1 year despite multiple chelation sessions. Nephrotic syndrome and polyneuropathy persisted in one patient.	The relative impact of time and removal from the mercury source versus the impact of chelation on recovery in these cases is unclear	Ref # 49 Oz SG, et al. Inhal Toxicol. 2012;24:652–658.
Case series – chronic ethylmercury ingestion	EthylHg contaminated rice − 27 patients	5 months after ingestion of rice, 27 patients received unithiol 250 mg/day i.m. for 3 days and repeated after 4 days, for 3 to 8 sessions and/or succimer 1000 mg/day p.o. for 3 days and repeated after 4 days, for 3 to 8 sessions	Chelation continued for two months and the author states that unithiol was more effective than succimer in "chelating effect" but present no urine or blood mercury concentration data to justify this claim. After chelation "all had some relief; 19 became asymptomatic, but two cases showed only slight improvement." The improvement occurred in patients with gingival hypertrophy/gingivitis/gingival pigmentation and in those with tremor, peripheral neuritis and hepatomegaly. Patients with moderate or severe presentation that received chelation therapy had limited improvement of neurologic and cardiovascular effects.	Urine Hg did not appear to reflect level of intoxication (4 mild, 1 moderate and 1 severe outcomes had normal Urine Hg on presentation). Limited clinical details provided. The relative impact of time and removal from the mercury source versus the impact of chelation on recovery in these cases is unclear	Ref # 50 Zhang J. Amer J Indust Med 1984;5:251–258
Case report – chronic inhalation mercury vapor	Hg vapor – Jeweler with a 1-year history of worsening neurologic symptoms	Unithiol – three 5-day courses of oral unithiol 30 mg/kg/day over a 9 week period	Objective improvement in speech, severity of tremor, handwriting and coordination, with significant excretion of mercury (41 mg). 79% of total Hg excreted in 1st two days of unithiol course − 32,424 μg of total 41,012 μg excreted in the first 48 h.	The second and third unithiol treatments resulted in urine mercury concentrations less than 10% of the first unithiol course. The report did not address selenium status or dietary access to selenium.	Ref # 51 Bradberry SM, et al. Clin Toxicol. 2009;47:894–898
Case report – Hg vapor	Presumed Hg Vapor − 8 YO male	Succimer 30 mg/kg/day for 5 days and 20 mg/kg/day for 14 days p.o.	Significant clinical improvement of acrondynia and only modest increase in urine mercury:12 μg/L to 48 μg/L	Lack of association with Urine Hg and clinical effects.	Ref # 52 Gattineni J, et al. Clin Pediatr. 2007;46:844–846.
Case report – Chronic mercury vapor inhalation	Hg vapor − 6 YO female and 4 YO male	Succimer (dose not given) p.o. for 4 months	New onset seizure (male), hypertension, irritable, diaphoretic, tremulous, rash desquamation of palms. Blood and urine Hg were 24 µg/l and 324 µg/l, respectively. After 4 months of succimer Urine hg decreased to 30 µg/l.	Limited clinical details provided. The relative impact of time and removal from the mercury source versus the impact of chelation on recovery in these cases is unclear	Ref # 53 Torres AD, et al. Pediatr. 2000;105:e34.
Case report (letter) – elemental mercury vapor	Hg vapor family of 5	Succimer 30 mg/kg/day for 5 days to 2 months (until resolution of sx)	Four children, ages 3 to 6 y presented with a combination of neurobehavioural disorders (4/4), dermatological manifestations (4/4) and cardiovascular disturbances (3/4) reminiscent of acrodynia. The mother had symptoms (irritable, anorexia) without hypertension. Urine Hg levels were more elevated (300–600 mg/l) than blood levels (10–20 mg/l).	no correlation between the level of mercury and the clinical severity or the evolution of the disease	Ref # 54 Laurens M, et al. Acta Pediatr. 2001;90:593–594.
Case report – Elemental mercury vapor	3 YO with Hg vapor in home (40,000 µg⁄m^3)	Succimer (dose not given) p.o. for 5 weeks	Hypertension, diaphoresis, pain, irritable, rash, desquamation of palms. Initial Urine Hg 174 µg/l. poor Hx of exposure, no follow levels or clinical follow up. Symptoms resolved in 5 weeks.	The relative impact of time and removal from the mercury source versus the impact of chelation on recovery in this case is unclear	Ref # 55 Mercer JJ, et al. Pediatr Dermatol. 2012;29:199–201.
Case report – Elemental mercury vapor inhalation	Hg Vapor − 3 month exposure 13 YO male and 15 YO female	Succimer 30 mg/kg/day for 5 days and 20 mg/kg for 16 days p.o., 22 day no tx and then repeat Succimer 30 mg/kg/day for 5 days and 20 mg/kg for 16 days p.o.,	improvement of acrondynia but continued to have elevated 24 h urine mercury concentrations (101 µg/L and 352 µg/L) after two successive 21 day courses of succimer and 3 month cessation of exposure. Neurophychological evaluation of these children immediately after the 2nd chelation treatment and again one year later showed continued deficits in visuoperceptual and construction skills, nonverbal memory and abstract reasoning, likely associated with damage to white matter pathways	Reflects difficulty of removing brain Hg by succimer after chronic exposure.	Ref # 56 Yeats KO, et al. J Clin Exp Neuropysch. 1994;16:209–222. Mortensen ME, et al. MMWR. 1990;39:424–425.
Case report – element Hg injection	Elemental mercury injection	Unithiol 2400 mg/day p.o for 2 months	Increase in the urine mercury concentration from 320 µg/L to 1580 µg/L initially but decreased to prechelation concentration within 3 days of continued therapy. The blood mercury concentration fell from 140 µg/L to 104 µg/L during initial unithiol and fell to 64 µg/L after surgical removal of mercury deposits from the patients forearms and elbows	Pt lost to follow up. No clinical condition reported. Estimate 1 mg/day Hg excreted, would take 30 years to remove injected Hg of 10 gm.	Ref # 57 Vallant B, et al. Clin Toxicol. 2008;46:566–569
Case report – acute ingestion of HgCl	Acute ingestion of HgCl2	BAL 5 mg/kg i.m. once. Unithiol was begun 10 h post ingestion (1500 mg/day IV for 2 days, 1000 mg/day IV for 2 days and 750 mg/day PO thereafter) and continued for 7 weeks.	The patient experienced anuric renal failure, hypovolemic shock and erosions of the esophageal, gastric and duodenal mucosa. After 3 weeks, the blood mercury concentration had declined from greater than 10,000 µg/L to 1000 µg/L, despite total anuria. In a 4-month follow-up period, recovery was uneventful and complete.	However > 80% of the decrease in blood mercury could not be accounted for (total anuria), suggesting a 2-compartment model with distribution to tissues or unmeasured loss via bile into feces. Changing from the parenteral to the oral route of administration did not affect urinary mercuric cation excretion	Ref # 58 Toet AE, et al. Human Eper Toxicol 1994;13:11–16
Case series – chronic methylmercury ingestion	MeHg contaminated grain − 10 patients	unithiol − 11 mg/kg/day i.m. for 4 to 15 days	Mean mercury elimination half-life was reduced from 55.5 days (no treatment) to 10.1 days with unithiol. Urine excretion data were only available on two patients, but was substantially increased. No clinical improvement was seen.	Based on reduced blood concentrations the authors suggested unithiol was probably clinically useful if given before neurological injury had occurred. The inability of the thiol chelators to cross the blood brain barrier and access dealkylated inorganic mercury (Hg + 2) is likely responsible for its poor remediation of neurotoxicity.	Ref # 59 Clarkson TW, et al. J Pharmacol Exp Therap. 1981;218:74–83.
Case report − 3 YO female -elemental mercury inhalation	Elemental mercury – inhalation	Succimer 16 mg/kg/day continued for 2 ½ months	Urine mercury initially rose (60 mcg/24 h to 170 mcg/24 h, measured 7 days after initiation of succimer) but fell despite continued 2.5 months succimer therapy. The child experienced acrondynia with hypertension requiring labetalol and amlodipine for 2.5 months, after removal from home exposure.	The child appeared asymptomatic 3 months later.	Ref # 61 Brannon EH, et al. Pediatr Emerg Care 2012;28:812–814
Case report – inorganic Hg	Hg based “teething” powder containing 435 mg/g Hg (type of mercury not specified)	Succimer 300 mg/day p.o. for 5 days followed by 200 mg/day p.o for 14 days	The children presented with developmental regression, loss of speech, weight loss, diffuse pain, tachycardia, rash, palmoplantar desquamation and hyporeflexia. After succimer there was no clinical improvement and continued elevated blood Hg concentrations. They received a second course of succimer therapy and gradually improved over a one-year period. Elimination half-life during succimer therapy was 42–43 days	This supports the very limited or lack of effect of succimer on total body mercury and brain mercury after chronic mercury exposure.	Ref # 62 Fayez I, et al. Pediatr Drugs. 2005;7:397–400.
Case series – Chronic methylmercury in food	Chronic MeHg (from contaminated pigs that had been fed contaminated grain)	BAL 15 mg/kg i.m. one day, 10 mg/kg i.m. day 2, 2.5 mg/kg for 8 days One month later penicillamine 50 mg/kg p.o. for 5 days , then 100 mg/kg po. For 5 days	Continued neurologic deterioration to coma or non-responsive state. Treatment with BAL and n-acetyl-d, I-penicillamine was not associated with clinical improvement (2 year follow up). Both drugs appeared to increase urinary excretion of mercury.	The inability of the chelators to cross the blood brain barrier and access dealkylated inorganic mercury (Hg^+2) is likely responsible for its poor remediation of neurotoxicity.	Ref # 63 Pierce PE, et al. J Amer Med Ass 1972;220:1439–1442
Case report – Acute methylmercury ingestion	MeHg (0.69%) fungicide ingestion	Penicillamine 2 g/day begun 4–5 h after ingestion for 3 days. Hemodialysis (for 5.3 h) begun 36 h after ingestion with acetylcysteine infused into blood as it entered the dialyzer at a rate to produce a concentration of 10 mmol. On day 4 unithiol 800 mg/day 14 days.	Urine mercury excretion increased 40-fold from 0.9 µg/h to 44.0 µg/h during dialysis with n-acetylcysteine added to the dialysate. Urine mercury excretion was 84-fold greater in the 16.5 h after hemodialysis (0.9 µg/h to 84.3 µg/h). In contrast, unithiol administration resulted in urine mercury elimination of only 3.4–6.5 µg/h. Acetylcysteine added to dialysate did not increase the mercury removed by dialysate, but increased the mercury excretion via kidneys. The patient received a daily oral dietary supplement that included selenium (100 mcg as sodium selenate), zinc and copper; and Neurologic effects from mercury did not occur despite very high mercury blood concentrations (1930 μg/L on arrival, 355 μg/L on discharge on day 14, and 200 μg/L day 50 post-ingestion)	Acetylcysteine appeared superior to unithiol after acute MeHg ingestion	Ref # 68 Lund ME, et al. Clin Toxicol. 1984;22:31–49
Case report – Acute ethylmercury infusion	EthylHg infusion (thiomersal preservative)	Succimer 1800 mg/day p.o. for 30 days, begun 10 days after Hg infusion	Initially blood Hg was 2250 µg/L, which fell to 421 and 299 µg/L on days 2 and 5 post-exposure, without elevations of urine Hg or chelation therapy. On the third day of succimer therapy (day 13 post exposure) urine Hg rose to 1976 µg/L, but rapidly returned to pre-chelation concentrations during continued succimer therapy. Blood Hg concentrations continued to fall at a rate similar to the 10 days prior to succimer therapy with a blood concentration of 179 µg/L of day 5 of succimer therapy (day 15 post-exposure). No neurological effects or renal effects occurred during one year follow up despite the elevated blood and urine Hg concentrations.	Initial rapid drop in blood Hg likely reflects initial distribution phase, rather than elimination.	Ref # 69 Koch M, et al. Am J Kidney Dis 2005;47:E31-E34
Case series – acute mercury vapor inhalation	Hg Vapor − 9 children	succimer 30 mg/kg/day for 5 days and 20 mg/kg/day for 14 days p.o.	All children arrived asymptomatic. Succimer therapy showed a 268% increase in urine mercury during the 30 mg/kg period of chelation (mean 214 µg/g creatinine prechelation to mean 573 µg/g creatinine of days 1–5 of treatment). Blood concentrations were not measured and 35 days after chelation urine mercury remained elevated (mean 102 µg/g creatinine). Children remained asymptomatic	Early chelation prior to distribution into the brain may help prevent neurotoxicity.	Ref # 70 Forman J, et al. Environ Health Perpect 2000;108:575–577
Case report – acute ingestion of mercuric sulphate	Ingestion of 1 g of mercuric sulphate	unithiol (1500mg/day IV for 4 days, 750 mg/day IV 6 days and 200 mg/day p.o. for 9 days) initiated 4 h post-ingestion. High-flux CVVHD also performed 12 h post-ingestion due to acute anuric renal failure.	Measurement of the filtrate from CVVHD showed removal of 127 mg (12.7%) of mercury over 14 days, with 112 mg in the first 3 days. There was a rapid decline in blood Hg (15,580 µg/L to 3370 µg/L) in the first 24 h, which likely represented tissue distribution (total anuria)	Despite the presence of mercury-induced gastric ulcers and gastrointestinal bleeding, which required the transfusion of 15 units of blood over 11 days and anuric renal failure, there were no neurological effects. This confirms that Hg^2+ does not readily cross the blood brain barrier well	Ref # 71 Dargan PL, et al. Crit Care 2003;7:R1-R6
Case report – mercuric oxide ingestion	40 g mercuric oxide	BAL 12 mg/kg/day i.m. for 4 days followed by succimer 30 mg/kg/day p.o for 10 days)	Urine Hg was 2200 µg/L on arrival and 2170 µg/L after one day of BAL. Urine Hg rapidly declined to 540 µg/L on day 3 and a urine Hg of 330 µg/L on day 18 (day 14 of succimer therapy). Blood Hg rose during the first day of BAL therapy from 1300 µg/L on arrival to 1850 µg/L on day 1 and remained elevated 4 days after cessation of succimer therapy at 150 µg/L. No cardiovascular, renal or neurological effects were noted beyond the tachycardia that occurred during initial presentation with abdominal pain and vomiting.	This again supports that Hg^2+ does not readily cross the blood brain barrier in acute exposures.	Ref # 72 Ly BT, et al. Ann Emerg Med 2002;39:312–315
Case report – Occupational Hg Vapor inhalation	Hg vapor − 2 Jewelers – acute inhalation	BAL 18 mg/kg/day i.m. for 2 days, 12 mg/kg/day i.m. for 2 days succimer 30 mg/kg/day p.o. for 10 days	Decreased plasma Hg concentrations (293 µ/L to 50 µ/L and 93 µ/L to 29 µ/L, respectively) in the first 24 h of therapy. In the subsequent 9 days of therapy with daily measured blood and urine mercury concentrations, no further changes were seen in urine or blood mercury concentrations. No symptoms were observed in either patient during the 10 days of therapy and observation.		Ref # 73 Houeto P, et al. Human Exp Toxicol. 1994;13:848–852
Case report – Elemental Hg injection	Elemental mercury injection	unithiol − 600 mg/day p.o. for 14 days 2 months post injection, Patient represented 15 months post injection – unithiol 800 mg/day for 20 days	Urine Hg increase peaked at 18 mg/day (day 2 of unithiol). After 20 days of unithiol Blood Hg decreased from 200 µg/L to 150 µg/L, Neuropsychological examinations before and after unithiol treatment showed a selective cognitive deficit in the area of visual attention, executive functions (set shifting) and impaired motor speed of the dominant upper extremity.	The authors concluded that unithiol therapy does not effectively remove intravenous deposits of metallic mercury	Ref # 74 Pelclova D, et al. Basic Clin Pharmacol Toxicol. 2017;120:628–633
Case series – human – Chronic occupational Mercurous chloride	8 workers (5 female, 3 male) occupational exposure (2–15 years) mercurous chloride skin cream	Unithiol 400 mg/kg/day p.o. for 8 days with 5 days rest (no tx), then 400 mg/kg for 7 days p.o. with 5 day rest (no tx) then 400 mg/kg p.o. for 6 days	24 h urine mercury excretion increased 4.5 % (pre-chelation vs 1st chelation session showed urine Hg means of 327 µg/g creatinine 1501 µg/g creatinine, respectively) The 2^nd and 3^rd unithiol tx session had mean 24 h urine Hg concentrations 20% and 10%, respectively, of the 1^st session (296 µg/g creatinine and 135 µg/g creatinine, respectively)	There is no evaluation of clinical effects after therapy. 78% of Hg urine excretion was found in 1^st 3 days (of 8 days) of unithiol therapy. The primary effect of the thiol chelators appears to be reduction of renal stores of mercury	Ref # 75 Gonzalez-Ramirez D, et al. J Pharmacol Exp Therap. 1998;287;8–12
Case report – chronic Hg vapor inhalation	Unknown source, believed old battery recycling	Unithiol 20 mg/kg/day i.v. for 4 days. Repeated 4 more sessions over 137 days	A 10 month old presented with hypertension, tachycardia, palmer desquamation, weakness, hypotonia and failure to thrive. Urine mercury rose with unithiol (500 to 4500 µg/g creatinine). However, urine mercury rapidly fell below and remained below pre-chelation levels. Blood mercury remained between 15 and 20 µg/L. despite 4 additional IV unithiol treatments over 137 days	There is limited follow up information. The authors conclude there was marked clinical improvement after chelation (time line and clinical details not provided) and there is no explanation why multiple chelation sessions were continued for 137 days. The child remained asymptomatic two years later.	Ref # 76 Bjelosevic M, et al. Balkan Med J 2018;35:451–452
Animal study – rats – chronic HgCl, PhenylHg or Mercury vapor – delay before intervention	HgCl 0,5 mg/kg/day i.p. or phenylHg 0,5 mg/kg/day i.p or mercury vapor 5 days/week for 3 weeks Or Hg vapor inhalation for 5–14 days.	Unithiol − 1) 60 mg/kg/day i.p or 220 mg/kg/day i.p (1 mmol/kg/day) for 5 days/week for 4 weeks or succimer 1) 60 mg/kg/day i.p or 180 mg/kg/day i.p (1 mmol/kg/day) for 5 days/week for 4 weeks	Kidney Hg was reduced and urine Hg was increased by unithiol and succimer. Unithiol was more effective than succimer. The larger dose was more effective. Neither treatment nor dose had an effect on brain or liver Hg. 65% (succimer) to 90% (unithiol) urine Hg occurred in the first 2 days of therapy.	Inorganic mercury has poor penetration across the blood brain barrier, but with chronic exposure higher doses accumulate in the brain. Mercury vapor has much higher Hg brain levels. The thiol chelators did not affect brain Hg content in this chronic exposure model.	Ref # 77 Buchet, et al Toxicol 1989;54:323–333
Animal study – monkeys – Chronic methylmercury	MeHg 50 µg/kg p.o. for 6,12 and 18 months	none	Half-life of MeHg in the brain was 37 days, but increased for inorganic Hg (230–540 days). Brain inorganic Hg formed by demethylation in the brain, not by brain uptake of inorganic Hg demethylated elsewhere in the body. The concentration of brain inorganic Hg (but not the MeHg) increased in all sites of the brain but especially the thalamus (9% at 6 months to 12 % at 18 months) and the pituitary (20% at 6 month to 46%).	Dealkylation of methylmercury traps Hg in the brain, due to inability of Hg^+2 to cross the blood brain barrier.	Ref # 81 Vahter ME, et al. Toxicol App Pharmacol 1995;134:273–284
Animal study – infant Monkeys – acute Methylmercury, Ethylmercury,	MeHg 20 µg/kg p.o. at birth and days 7, 14 and 21 Or Ethylmercury in vaccines 20 µg/kg i.m. at birth and days 7, 14 and 21	None	Half-life in blood of ethylmercury vs MeHg was 8.6 days vs 21.5 days, respectively. Brain clearance for Hg was 24 days and 60 days for EthylHg vs MeHg. Blood Hg levels may not be a good indicator of Brain Hg after MeHg or EthylHg. A higher percentage of the total Hg in the brain was in the form of de-alklylated inorganic Hg for the thimerosal-exposed monkeys vs MeHg monkeys (34% vs. 7%). The results indicate that MeHg is not a suitable reference for risk assessment from exposure to thimerosal-derived Hg.	Dealkylation of organic mercuries can trap Hg in the brain, due to inability of Hg^+2 to cross the blood brain barrier.	Ref # 82 Burbacher TM, et al. Environ Health Perspect 2005;113:1015–1021
Animal study – Rats – Acute – dimethylmercury – delay before intervention	Dimethyl Hg 10 mg/kg p.o. once	72 h delay after Hg NAC 2 mMol/Kg/day, i.p. for 3 days or dithiothreitol 15.4 mg/kg/day i.p. for 3 days	NAC reduced brain, liver and kidney Hg by 31%, 48% and 37%, respectively compared with the thiol Chelator (Dithiothreitol) by 7%, 14% and 25%, respectively. N-acetylcysteine improved lipid peroxidation and liver and kidney function.	NAC performed better with organic Hg than thiol chelator.	Ref # 83 Joshi D, et al. Bull Environ Contam Toxicol 2010;84:613–617
In vitro study – cultures of cerebellar granule cells from rats – thimerosal (ethylmercury)	Thimerosal (ethylHg) – cell bath 500 nmol concentration	Media containing L-cystein, N-acetylcystiene (NAC), reduced glutathione, and methionine	Incubation with NAC or glutathione prevented disturbances in calcium homeostasis, prevented mercury induced calcium release and mitochondrial depolarization.		Ref # 88 Zieminska E, et al. Toxicol 2010;276:154–163
Case series – Acute mercury vapor inhalation	Hg vapor – A family of 8 were exposed to heated mercury vapor in an apartment. 4 members in the room with the heated mercury (2 adults and 2 infants) and 4 children in another room of the apartment.	succimer 30 mg/kg/day for 5 days and 20 mg/kg/day for 14 days p.o.	Initial blood and urine levels ranged from 117 to 275 µg/L and 35 to 485 µg/L, respectively. Seven patients were treated with succimer. Of the 4 patients in the room, the mother and infant treated with succimer died from pulmonary failure and one infant recovered after significant pulmonary support without residual pulmonary disease or obvious developmental delay 25 days post exposure. The second adult did not receive succimer therapy. A telephone interview with family reported he suffers from periods of confusion, persistent cough and insomnia. The remaining 4 children (age 3–11) received succimer therapy There were no during- or post-chelation blood or urine levels provided. Clinical effects are described as dry cough and headache. One-month post discharge they are described as no evidence of chronic mercury toxicity without greater clinical detail.	The authors report a lack of correlation between clinical toxicity and mercury levels in both blood and urine.	Ref # 89 Solis MT, et al. Am J Emerg Med 2000;18:599–602
Case report – Elemental Hg injection	Elemental mercury injection	Unithiol 600 mg/day for 5 days − 37 h after IV Hg injection	Total elimination of approximately 8 mg of mercury in the urine over 5 days but did not affect blood Hg	The authors concluded that evidence of benefit was doubtful as clinically relevant elimination did not occur	Ref # 90 Eyer F, et al. Clin Toxicol. 2006;44:395–397
Animal study – Rat – Chronic methylmercury – delay before intervention	MeHg 1 mg/kg/day p.o, for 6 days	Succimer – begun 3 days after MeHg ceased. 2.5 mg/ml in freely available water for 3 days	Reduced total body, brain, blood, kidney and liver Hg. Early succimer administration allowing access prior to distribution may be responsible for total body and Brain reduction	No evaluation of behavioral effect. Succimer administered prior to full Hg distribution may be responsible for increased access to Hg and effectiveness. Succimer appears more effective with MeHg than inorganic Hg.	Ref # 91 Magos L. Br J Pharmacol 1976;56:479–484
Animal study – Rat – Acute inorganic HgCl – delay before intervention	HgCl 0.5 mg/kg i.p once	Succimer − 60 mg/kg i.p. over 24 h, begun 8 days after Hg injection	Reduced only kidney Hg, No effect on blood, liver or spleen. 8 Day delay in succimer administration reduced access to Hg and the only Hg reduction seen in Kidney	No evaluation of behavioral effect. Succimer appears more effective with MeHg than inorganic.	Ref # 91 Magos L. Br J Pharmacol 1976;56:479–484
Animal study – rats – Acute methylmercury – Immediate intervention	MeHg 0.23 mg/kg i.v. once	Experiment 1 Tx begun 6 h after MeHg -Unithiol −0.1, 0.5, 1 and 2.5 mmol/kg/day p.o. and 0.1, 0.3, 0.8 mmol/kg/day i.p. for 5 days	Unithiol increased total Hg excretion from 20% (control, no tx) to 76% of total dose after 7 days. Increasing unithiol dose increased urine Hg concentrations and total excretion. Unithiol decreased feces Hg excretion. i.p. more effective that p.o., supporting data that approximately 30% of unithiol is absorbed orally in rat.	Immediate treatment prior to distribution into target organs may not reflect human conditions. No evaluation of behavior or outcomes.	Ref # 92 Gabard B. Toxicol Appl Pharmacol 1976;38:415–424
Animal study – rats – Acute methylmercury – delay before intervention	MeHg 0.23 mg/kg i.v. once	Experiment 2 Unithiol − 1) tx begun 5 days after MeHg −1 mmol/kg/day i.p. for 5 days	Delayed unithiol therapy decreased kidney, blood and plasma Hg, with limited effect on brain Hg	The reduction of brain Hg after immediate tx is due to decreased brain Hg uptake rather than genuine reduction of brain Hg content. No evaluation of behavior or outcomes.	Ref # 92 Gabard B. Toxicol Appl Pharmacol 1976;38:415–424
Animal study – mice – Acute HgCl – delay before Intervention	HgCl2 − 1 mg/kg HG^2+ i.p., once	Experiment 1 unithiol (220 mg/kg/day i.p.) 5 days/week for 4 weeks (one week delay after Hg injection)	Mercury deposits in spinal motor neurons significantly increased compared with controls (no unithiol) 7.4% vs 4.3%, respectively. Likely through increased entrance across the neuromuscular junction.	The authors concluded the increase in inorganic mercury in motor neurons following chelation is probably a consequence of increased blood levels of mercury redistributed from non-neuronal tissues by the chelators. The uptake of mercury into motor neurons differs from the uptake of inorganic mercury into neurons of the cerebrum and cerebellum, primarily because of the difficulty of Hg^2+ crossing the blood brain barrier.	Ref # 93 Ewan KBR, et al . Neurotoxicol 1996;17: 343–350
Animal study – mice – Acute HgCl – delay before Intervention	HgCl2 − 1 mg/kg Hg^2+ i.p., once	Experiment 2 Succimer (180 mg/kg/day i.p.) 5 days/week for 4 weeks (one week delay after Hg injection)	Mercury deposits in spinal motor neurons significantly increased compared with controls (no unithiol) 8.0% vs 4.3%, respectively. Likely through increased entrance across the neuromuscular junction.	The authors concluded the increase in inorganic mercury in motor neurons following chelation is probably a consequence of increased blood levels of mercury redistributed from non-neuronal tissues by the chelators. The uptake of mercury into motor neurons differs from the uptake of inorganic mercury into neurons of the cerebrum and cerebellum, primarily because of the difficulty of Hg2+ crossing the blood brain barrier.	Ref # 93 Ewan KBR, et al . Neurotoxicol 1996;17: 343–350
Case series – human – Chronic dermal use of Hg Skin cream	8 females chronic (2–10 years) dermal use of mercurous chloride (5.9%) cream	unithiol 200 mg/day orally for 5 days	Peak urine mercury excretion increased 9-fold 24 h after initiation of unithiol (pre-chelation and 1^st day of chelation showed urine Hg means of 851 µg/g creatinine 4323 µg/g creatinine, respectively). Post treatment mean was 218 µg/g creatinine. Of the 8 patients, 6 were asymptomatic prior to chelation and two had documented tremor, which resolved in one patient and persisted in the second patient.	No relationship found between duration of exposure or initial urine level and levels of Hg excretion during therapy.	Ref # 94 Garza-Ocanas L, et al. Clin toxicol. 1997;35:653–655
Case series – chronic occupational mercury	Occupational Hg group − 10 males (initial urine Hg > 50 µg/L)	Unithiol 300 mg/day p.o. for 5 days	Unithiol significantly increased urinary Hg. Initial Urine Hg did not predict peak response to unithiol.	No clinical evaluation provided. It is unclear if the occupational Hg exposure was ongoing or remote.	Ref # 95 Torres-Alanis O, et al. Clin Toxicol. 1995;33:717–720.
Animal study – rat – Chronic methylmercury – delay before intervention	MeHg 4 mg/kg p.o every other day for 4 weeks until Neurotoxicity	After MeHg ceased – Se selenite 300 µg/Kg/day p.o. every other day for 90 days, begun after Hg ceased	Se treated rats showed increased serum Hg and Se vs control (no se), suggesting increased Hg source was removal of Hg from target organs.		Ref # 99 Li Y, et al. Biometals. 2016;29:892–903.
Animal study – Rats – Chronic Methylmercury – simultaneous intervention	Rats fed fish-cake diet with MeHg (pike) vs no MeHg (trout) for 4 weeks. Diets with Pike (207–236 µg/day MeHg) and trout (no MeHg 26–30 µg/day MeHg)	Se deficient diet (NaCL added) vs selenomethionine 3.4 mg/kg vs inorganic Se 3.4 mg/kg every 4 days for 4 weeks	Inorganic Se decreased blood and liver MeHg and total Hg by 25%, likely by binding Hg in gut Selenomethionine decreased total mercury in blood.	Simultaneous Se and Hg in food may bind Hg in the GI tract, decreasing absorption	Ref # 101 Seppanen K, et al. Biol Trace Elem Res. 1998;65:197–210.
Animal study – Mice – chronic Methylmercury – simultaneous intervention	MeHg in freely available water for 30 days	3 groups – for 30 days − 1) no MeHg, no Se, 2) MeHg no Se, 3) Se 6 mg/kg and MeHg	Se supplementation decreased Hg induced immunosuppresion, oxidative stress and impaired weight gain. Se increased glutathione peroxidase activity, Se supplementation decreased kidney, thymus, spleen and muscle Hg, but increased brain liver and blood Hg	Se improved outcomes, but showed increased organ Hg content. Supports using behavioral or clinical outcomes vs Hg concentrations to measure effects of therapy	Ref # 102 Li X, et al. Food Chem Toxicol. 2014;72:169–177
Animal study – Rats – Chronic Methylmercury – simultaneous intervention	Diets containing 25 ppm MeHg for 6 weeks	4 groups − 1) no supplement (control), 2) 6 ppm Se, 3 ) 0.4 % cysteine and 4) 6 ppm Se plus 0.4% cysteine	All animals without supplement died by 6 weeks. Se and cysteine protective of MeHg toxicity. Se reduced brain and kidney Hg, but increased Blood Hg. Cysteine decreased Kidney Hg and increased Blood Hg.	Se may help by demethylation of MeHg.	Ref # 103 Stillings BR, et al. Toxicol Pharmacol. 1974;30:243–254.
Animal study – Mice – Chronic Methylmercury – simultaneous intervention	MeHg in drinking water − 40 mg/L in freely available water for 21 days	Se 5 µmol/kg/day i.p. for 21 day. Se given as diphenyl diselenide (PhSe)2	(PhSe)2 reduced Brain Hg deposition, reduced MeHg-induced mitochondrial dysfunction. (PhSe)2 treatment completely prevented the MeHg-induced lipid peroxidation, and also inhibited the spontaneous lipid oxidation seen in brain control animals		Ref # 114 Glaser V, et al. Chem Biol Interact. 2013;206:18–26.
Animal study –Mice – chronic Methylmercury – simultaneous intervention	MeHg 2 mg/kg/day p.o. for 35 days	diphenyl diselenide 0.4 mg/kg/day s.c. or 1 mg/kg/day s.c. for 35 days	(PhSe)2 conferred protection against MeHg-induced hepatic and renal lipid peroxidation and conferred a partial protection against MeHg-induced oxidative stress in liver and cerebellum. (PhSe)2 decreased deposition of Hg in cerebrum, cerebellum, kidney and liver.	Co administration of Se and MeHg is difficult to translate to human condition. 20 % of MeHg-only group died (2 mg/kg/day MeHg, no Se Tx)	Ref # 117 De Freitas AS, et al. Brain Res Bull. 2009;79:77–84.
Animal study – Mice – Chronic Methylmercury – simultaneous intervention	MeHg in drinking water − 40 mg/L in freely available water for 21 days	Se 5 µmol/kg/day i.p. for 21 day SE given as selenite (Na2SeO3)	The use of the seleno-compound elicited a marked reduction of cortical Hg deposition and a partial protection against MeHg-induced mitochondrial dysfunction.	More effective and protective effects could be obtained if Se and cysteine or glutathione are co-administered	Ref # 119 Glaser V, et al. Int J Devel Neurosci. 2010;28:631–637.
Animal study – Whales – Methylmercury	MeHg in nature		Shows formation of Se:Hg particles in muscle of whales. Demethylation of sequestering of Hg in muscle, in nature. And binding to Se proteins,		Ref # 120 Gajdosechova Z, L et al. Sci Reports. 2016;6:34361 DOI: 10.1038/srep34361
Human cohort – chronic mercury – postmortem study	Postmortem Hg and Se − 5 individuals − 2 poisoned during life, and 2 fish eaters		In the two poisoned individuals higher brain Hg bound to Se, Evidence of demethylation in brain as form of detoxification to make Hg chemically inert.		Ref # 121 Korbas M, et al. ACS Chem Neurosci. 2010;1:810–818
In vitro – inorganic HgCl – co-incubation	HgCl in human prostate cancer cell line	selenite, selenomethionineor methyl-Se-cysteine	Hg prevents the increase of Selenoprotein glutathione peroxidase activity only when selenite provided but not selenomethionine or methyl-Se-cysteine. Hg^+2 does not directly inhibit selenoperoxidase activity. Hg^+2 prevents selenium delivery to cells by forming ionic complexes when the source of selenium is selenite or seelnoprotein-P.	Shows mercury inhibits production of de novo protein, by interrupting supply of ionic Se form	Ref # 122 Bulato C, et al. Free Biol Med. 2007;42:118–123
Animal study – Rats – Chronic methylmercury – delay before intervention	MeHg 4 mg/kg p.o. every other day for 28 days Until behavioral Sx	Se (as nanoparticles) begun after MeHg ceased. Se 0.3 mg/kg p.o. every other day for 90 days. Particle size range was 39.2 ± 19.2 nm.	increased both Hg and Se levels in serum samples from MeHg-poisoned rats. Se nanoparticles promoted the formation of Hg-Se proteins with high molecular weights 62 and 170 KDa, likely selenoprotein P	Increased Hg and Se contents can be attributed to the release of Hg from internal tissues.	Ref # 123 Li Y, et al. Ecotoxicol Environment Safety 2019;169:128–133
Animal study – Rats – Chronic Methylmercury – Simultaneous intervention	MeHg in drinking water − 0.5 ppm, 5 ppm and 15 ppm for 16 months	Diet containing 0.06 ppm Se or 0.6 ppm Se	Se significantly delayed or blunted MeHg’s effects. Nerve pathology studies revealed axonal atrophy or mild degeneration in peripheral nerve fibers, which is consistent with abnormal sensorimotor function in chronic MeHg neurotoxicity.	Supports the safety and efficacy of Se in ameliorating MeHg’s neurotoxicity. The concentration of MeHg in the diet was the most important determinant of neurotoxicity, but dietary selenium influenced the toxicity.	Ref # 124 Heath JC, et al. Neurotoxicol. 2010;31:169–179.
In vitro – human Thioredoxin reductase in HEK cells– Methylmercury and inorganic HgCl – simultaneous intervention	Incubation in MeHg 0, 25, 37.5, 50, 62.5, 75, 100, 200, 400, and 800 nmol and HgCl 0, 25, 37.5, 50, 62.5, 75, 100, 200, 400, and 800 nmol	Co-incubation with unithiol, succimmer, BAL, alpha-lipoic acid, and selenite 1–50 µMol	Selenite in a concentration of 0.5–1 µMol is as effective as any chelating agent tested for reactivation of HgCl2-inactivated thioredoxin reductase activity. Unithiol and succimer both attenuated HgCl toxicity, but the protection was lacking against MeHg.	In vivo unithiol and succimer do not cross the blood brain barrier. MeHg may have to be demethylated for Se benefit.	Ref # 125 Carvalho CML, et al. FASEB J. 2011;25:370–381
Animal study – Rats – chronic elemental mercury vapor – simultaneous intervention	30 mg/m^3 12 hrs/day for 4 weeks, equals approximately to the occupational TLV of 50 mg/m^3 for 8 h, 5 days a week.	No Se or Se 0.5 ppm in freely available water for 6 weeks	Se supplementation decreased Hg in brain, spinal medulla, lung and muscle, but increased Hg in blood and liver. Hg^0 and Hg^2+ seems to be distributed by different routes in the rat brain. blood Hg values are not a valid indicator of Hg exposure due to the fact that dietary Se influences Hg concentration in the blood.	Co administration of Se and Hg Vapor is difficult to translate to human condition. Hg^0 and Hg^2+ seems to be distributed by different routes in the rat brain.	Ref # 126 Nygaard SP, Hansen JC. Bull Environ Contam Toxicol. 1978;20:20–23
Animal study – Rats – Chronic Methylmercury – simultaneous intervention	MeHg 100 µg/day p.o. for 100 days	Se 2 mg/L or 6 mg/L in freely available water for 100 days	Se supplementation reduced MeHg-induced DNA damage and restored glutathione peroxidase activity	Co administration of Se and MeHg is difficult to translate to human condition.	Ref # 127 Grotta D, et al. Arch Toxicol. 2009;83:249–254.
Animal study – Rats – acute and chronic inorganic HgCl and Methylmercury – simultaneous intervention	MeHg 1 µg/kg p.o. once or 6 ng/l in drinking water for 14 days or HgCl 1 µg/kg p.o. once or 6 ng/l in drinking water for 14 days	Se in diet for 5 weeks (3 prior to Hg and 2 weeks during Hg) 12.5 µg/kg/day, 62.5 µg/kg/day and 112.5 µg/kg/day in food.	Se effects differed depending on single acute vs chronic Hg dose and by MeHg vs HgCl. In chronic Hg dosing Se reduced whole body retention (WBR). In acute Hg dose Se increases WBR by increasing systemic deposition/retention. In chronic Hg dose Se reduces WBR, high dose Se increased kidney deposition	Drinking-water (chronic) exposure is more relevant for human dietary Hg exposure than single-dose exposures.	Ref # 128 Anderson O, et al. Environ Health Perpect. 1994;102:321–324.
Animal study – Mice – Chronic Methylmercury intervention – simultaneous intervention	MeHg in drinking water − 40 mg/L in freely available water for 21 days	Se 5 µmol/kg/day i.p. for 21 day SE given diphenyl diselenide (PhSe)2	(PhSe)2 co-treatment rescued from MeHg-induced mitochondrial alterations. (PhSe)2 also behaved as an enhancer of mitochondrial biogenesis, by increasing cortical mitochondria content.	(PhSe)2 may trigger the cytoprotective Nrf-2 pathway for activating target genes.	Ref # 129 Glaser V, et al. Mol Cell Biochem. 2014;390:1–9.
Animal study – Rats – Chronic Methylmercury – simultaneous intervention	MeHg 0, 0.5 and 5 ppm MeHg in drinking water for 6 and 18 months	Diets with 0.06 and 6 ppm Se for 6 and 18 months	All animals exposed to 5 ppm of Hg experienced a molar excess of Hg over Se. Animals exposed to 0.5 ppm Hg showed a balance between Hg and Se or a Se excess,		Ref # 130 Newland MG, et al. Neurotoxicol 2006;27:710–720
Human study – case series –environmental mercury	5 volunteers in Hg mining district with elevated urine Hg.	selenium 100 µg/day for 90 days	Urine Hg increased from mean 173 µg/L (day 0) to 1018 µg/L (day 90). 95% of Hg excreted was inorganic Hg. Urine Se did not change with supplementation.	The increase in urine Hg excretion did not begin for 15 to 30 days, suggesting redistribution of tissue mercury, rather than a direct renal effect.	Ref # 131 Li YF, et al. J Anal Atom Spectrom. 2007;8:925.
Case Series – chronic environmental mercury	103 volunteers in Hg mining district with urine Hg (>10 µg/L and < 50 µg/L)	selenium 100 µg/day (n = 53) or placebo (n = 50) for 90 days	Se significantly reduced markers of oxidative stress, as measured by urinary malondiadehyde and 8-hydroxy-2-deoxyguanosine levels. Se significantly increased urine mercury concentrations compared with controls: from a mean of 18 µg/L to 50 µg/L vs no change, respectively.	The increase in urine Hg excretion did not begin for 15 to 30 days, suggesting redistribution of tissue mercury, rather than a direct renal effect.	Ref # 132 Li YF, et al. Environ Sci Technol. 2012;46:11313–11318.
Human study – case series –occupationally exposed workers to mercury vapor	36 workers (20 males and 16 females) occupational exposed (lamp factory, Hg Vapor) compared with non-exposed controls	Se 100 µg/day for 2 month and vitamin E 100 mg/day for 2 months	Decrease in Hg blood levels and serum malondialdehyde (evidence of oxidative stress.	Difficult to interpret due to limited data presented	Ref # 133 Draz E, et al. Mansoura J Forensic Med Clin Toxicol. 2009;17:87–107
Animal study – Rats – Chronic Methylmercury – delay before intervention	MeHg 4 mg/kg p.o every other day for 4 weeks until Neurotoxicity	After MeHg ceased – Se selenite 2.7 mg/Kg/day p.o. every other day for 30 days	Majority of Se (93.6%) and Hg (73%) in the serum were bound to selenoprotein P. After 30 days serum Hg was reduced by 49% compared with controls (no Se) 90% of serum Hg was MeHg, indicating selenoprotein P binds MeHg as well as Hg. Such complexes may facilitate the sequestration and excretion of Hg in rats	NO follow up on behavioral effects	Ref # 135 Liu Y, et al. J Trace Elem Med Bio 2018;50:589–595
Animal study – Rats – Chronic Methylmercury – simultaneous intervention	MeHg 4 mg/kg/day p.o. for 4 weeks	No Tx or Se 1.5 mg/kg/day p.o. for 4 weeks	Selenium treatment ameliorated the mercury-induced apoptosis. Selenium also improved mercury-induced autophagic dysfunction in the pituitary and protected histopathological structures		Ref # 136 El Asar HM, et al. Life Sci 2019;231:116578
In vitro – HepG2 cells – Methylmercury – coincubation	MeHg and co-incubation of MeHg with selenocysteine	MeHg and co-incubation of MeHg with selenocysteine	MeHg and SeCys2 aggregation promotes the uptake of MeHg. MeHg transforms into small molecular complexes (MeHg-glutathione (GSH) and MeHg-cysteine (Cys)) in HepG2 cells. MeHg-GSH is the elimination species, which results in reducing the cytotoxicity of MeHg.		Ref # 137 Wang H, et al. Sci Rep 2017;7:147 doi: 10.1038/s41598-017-00231-7
Animal Study – Rats – chronic Methylmercury –delay before intervention	MeHg 4 mg/kg p.o. every other day for 28 days until behavioral sx,	3 groups − 1) no MeHg no Se, 2) MeHg for 28 days until behavioral sx, then no tx and 3) MeHg 28 days until behavioral sx then Se 2.74 mg/kg/day p.o. for 90 days	MeHg poisoning damaged the abundance of gut flora and decreased their capacity for the decomposition of MeHg. After Se treatment, the abundance of gut flora was partially restored and the decomposition and excretion of MeHg was enhanced.		Ref # 138 Liu Y, et al. Ecotoxicol Environ Safety 2019;185:109720
Human cohort – chronic mercury from diet	Hg from diet, contaminated mining region (Large cohort n = 448), high Se in diet, Amazonian population		Plasma Se ranged from 53.6 to 913 mg/L (median 135 mg/L), and median blood Hg and blood lead levels were 42.5 mg/L and 113 mg/L, respectively. Plasma Se biomarkers were positively related to better performance on all motor tests. For this population with elevated Hg exposure, high dietary Se intake may be critical for brain and muscle functions.	High Se in diet, may not be applicable to other populations	Ref # 140 Lemire M, et al. Neurotoxicol. 2011:32:944–953.
Human cohort – chronic Methylmercury from diet	MeHg from whale meat in diet, Inuit population		Positive correlation between whole blood Hg and Se levels was observed and the whole blood Hg/Se molar ratios of all subjects were 1/1. These findings suggested that sufficient Se intake might be one of causes of the absence of adverse effects of MeHg exposure in this study.	Small subject cohort (n = 23)	Ref # 141 Nakamura M, et al. Environ Inter. 2014;68:25–32
Human cohort − 81 volunteers	None	Se − 0, 200 µg, 400 µg, 600 µg, and 800 µg, per day for 18 weeks as Selenite or selenomethionine	Se 800 µg/day for 16 weeks. No signs of selenium toxicity were detected		Ref # 142 Burk RF, et al. Cancer Epidemiol Bio-markers Prev. 2006;15:804–810
Animal study – Mice – acute inorganic HgCl – simultaneous intervention	4.6 mg/kg/day s.c. for 3 days	30 min after later Hg injection – diphenyl diselenide 32 mg/kg s.c.	A known fatal dose of Se did not alter Hg toxicity.	Mice euthanized at 4 h because The Se dose of 32 mg/kg was previously established to cause 100% death in mice in 5 h	Ref # 144 Brandao R, et al. J Appl Toxicol. 2010;31:773–782.
Animal study – Chickens – Selenium toxicity – simultaneous phenyl Hg	No Hg or 25 ppm HgCl and HgCl 50 ppm in available diet	No Se, 10, ppm in diet, 20 ppm in diet and 40 ppm Se in available diet	Se alone at 10 and 20 ppm decreased weight gain. Adding HgCl reversed Se toxicity at 10, 20 and 40 ppm in diet.	Evaluated effect of Hg on Se toxicity.	Ref # 145 Hill CH. J Nutri 1974;104:593–598
In vitro – cortical cell cultures – inorganic HgCl, methylmercury and thimerosal (ethylmercury), Iron and lead – co-incubation	Cell bath of HgCl, MeHg and thiomerosal	Unithiol and succimer cell baths	HgCl − 1 µmol and 5 µmol caused 40% and 100% cell death, respectively. MeHg and thiomersol 1 µmol and 5 µmol caused 20% and 40% cell death, respectively. Unithiol and succimer reduced cell death in HgCl, had no effect on MeHg and worsened toxicity of thiomersol.	In vitro The fact that all of the chelators cause potentiation of some form of metal toxicity is of concern regarding their widespread, use for chelation therapy	Ref # 146 Rush T, et al. Neurotoxicol 2009;30:47–51
Human cohort – chronic Methylmercury from diet	MeHg from diet, Inuit population (cohort n = 223)		Blood Hg range from 15.9 to 40.4 µg/L, blood Se range from 181.4 to 669.9 µg/L. Oxidative stress associated with Hg exposure was highly modulated by tissue Se. The Inuit may be protected from Hg-induced oxidative stress because of their high Se status.	High Se in diet, may not be applicable to other populations	Ref # 148 Alkazemi D, , et al. J Lipid Res. 2013;54:1972–1979
Human cohort – chronic mercury and selenium from diet	Hg from diet, contaminated mining region		4 groups from 4 geographic areas (3 in a mining region, 1 not) in China. In the 3 mining areas blood total Hg and blood MeHg^+ were significantly elevated (means 12.5 to 14.7 µg/L and 6.64 to 7.93 µg/L, respectively) compared with the non-mining region (means 5.5 µg/L and 3.83 µg/L). serum Se were also significantly elevated in the 3 mining region groups vs the non-mining region group (219 to 274 µg/L vs 157 µg/L), with all groups showing an Se:Hg molar ratio of > 10, suggesting a protective effect		Ref # 149 Li P, et al. Sci Total Environ 2016;572:376–381
Human cohort – chronic Selenium from diet	Not evaluated	Se from diet, (Large cohort n = 448), high Se in diet, Amazonian population	The median levels of B-Se and P-Se were 228.4 μg/L (range 103.3–1500.2 μg/L) and 134.8 μg/L (range 53.6–913.2 μg/L) respectively. Although B-Se and P-Se surpassed concentrations considered toxic no dermal or breath signs or symptoms of Se toxicity were associated with the biomarkers of Se status.		Ref # 150 Lemire M, et al. Eviron Intern 2012;40:128–136
Animal Study – Rat – Chronic inorganic HgCl and Methylmercury – simultaneous intervention	No Hg or HgCl 20 mg/L or MeHg 20 mg/L in drinking water every other day for 95 days	No Se or Se 2 mg/L in drinking water every other day for 95 days	Se treatment delayed the functional toxic effects of MeHg. However, Se and MeHg co-administration increased staining for Hg in cerebral cortex, thalamus, hypothalamus, and brain stem nuclei. Se did not affect brain cell (neurons or glia) levels of HgCl. HgCl has poor penetration across blood brain barrier		Ref # 151 Moller-Madsen B, et al. Toxicol. Appl. Pharmacol. 1991;108:457–473.
Animal study – post-weanling Rats – Chronic methylmercury – Simultaneous intervention	MeHg 8/mg/kg/day p.o. for 10 days	Selenomethionine 2 mg/kg/day p.o. for 10 days	Se tx increased weight gain and Prevented Neuronal degeneration, reactive astrocytosis and evidence of liver and kidney injury. Kidney and liver Hg was reduced	Simultaneous administration of Se appeared protective of MeHg toxicity.	Ref # 157 Sakamoto M, et al. Environ Sci Technol. 2013;47:2861–2868
Human cohort – chronic Hg – postmortem study	Postmortem Hg and Se in 3 groups (occupationally exposed mercury miners, non-exposed living in mining district, and non-exposed living non-mining district)	Post-mortem organ values of Hg and Se	The Se:Hg molar ratio in thyroid, pituitary, liver and brain was 1:1 in both exposed and non-exposed. Despite 1000 fold differences in Hg organ concentrations in the exposed and non-exposed individuals. Suggesting direct Se:Hg linkage	The highest Hg accumulation (in ranked order) occurred in thyroid, pituitary, kidney and brain. A Hg:Se molar ratio of 1:1 occurred naturally in both exposed and non-exposed.	Ref # 158 Kosta L, et al. Nature. 1975;254:238–239
In vitro – Rat hepatic cells – Methylmercury – Co-incubation	Incubation in MeHg 25 µmol	Co-incubation with diphenyl diselenide 0.5 and 5 µmol for 30 min, then washed out	Co-incubation of Se compounds and MeHg did not decrease Hg levels in tissues, but protected against MeHg toxicity. (PhSe)2 could exert its previously demonstrated protective effects not by reducing MeHg levels, but forming a complex with MeHg. Eliminating the active MeHg, to bind to critical molecules in cell.	In vitro Co-incubation is difficult to translate to human condition	Ref # 159 Della Corte CL, et al. Biometals 2016;29:543–550.
Human cohort – chronic mercury from occupational exposure	Chloralkali workers (n = 131) vs non-exposed control, mercury vapor		higher Hg levels among the exposed workers in comparison to control group (12-times higher median for Hg-B and almost 74-times higher median for Hg-U concentration in chloralkali workers). Selenoprotein-P was also significantly higher (Me (median): 82.85 μg/L for chloralkali workers vs. Me: 72.74 μg/L for control group.	Se-P correlated inversely with Hg-U in chloralkali workers suggesting depletion of the Se protection among the workers with the highest Urine Hg concentration	Ref # 160 Kuras R, et al. J Trace Elem Med Biol 2018:49:43–50
Animal study -Zebra fish – Methylmercury – simultaneous intervention	MeHg in zebra fish larva Diets containing 0.05 and 12 mg/kg	Diets containing Se 0.7 and 10 mg/kg 78 to 97 days of exposure	Seleno genes involved in antioxidant pathways were down regulated by MeHg and Se deficiency and were rescued by elevated Se supply. – suggesting that Se deficiency Is a contributing factor to MeHg toxicity.	Elevated Se could only partially prevent the MeHg-induced depression of GPX and locomotor activity, indicating that the interaction between MeHg and Se is one part of a much larger set of underlying cellular mechanisms disrupted by MeHg.	Ref # 162 Penglase S, et al. Free Rad Biol Med 2014;75:95–104
Animal study – mice – Chronic methymercury – simultaneous intervention	MeHg 40 mg/L in freely available water for 17 days	Unithiol 150 mg/kg/day i.p. for 3 days on day 15,16 and 17.	Behavioral tests were performed 24 h after the last unithiol dose and then the mice were sacrificed. Unithiol reduced locomotor deficits (decreased locomotor activity in the open field and decreased falling latency) from MeHg and cerebellar mercury content.	The authors suggested unithiol showed a redistribution of MeHg out of the brain However, a limitation of this study is that the unithiol was given during methylmercury exposure, allowing for greater access in the blood prior to distribution into the tissues. The reduction of mercury content in the cerebellum may in fact reflect interruption of methylmercury distribution into the brain.	Ref # 163 Carvalho MC, et al. Toxicol. 2007;239:195–203.
In vitro – human neuronal cell line – methylmercury – co-incubation	MeHg 0.1 to 10 µmol for 48 h	Se and reduced glutathione	Neurotoxicity of MeHg is primarily mediated through the depletion of GSH and down-regulation of the abundance of Selenoprotein W (SeW). Suggests that SeW is the molecular target of MeHg in human neuronal cells. Down-regulation of this selenoenzyme by MeHg is dependent not on generation of Reactive oxygen species but on depletion of GSH.		Ref # 164 Kim YJ, et al. Biochem BioPhys Res Com. 2005;330:1095–1102
In vitro – Methylmercury	MeHg	Se, reduced and oxidized glutathione	H2Se is involved in demethylation of MeHg to inorganic Hg		Ref # 165 Iwata H, et al. Life Sci. 1982;31:859–866
Animal study – Rats – acute inorganic HgCl – simultaneous intervention	HgCl 0.5 µmol/kg i.v. once	Se 0.5 µmol/kg i.v. once	A complex containing equimolar amounts of Se and Hg is formed between the reduced form of Se and Hg in the blood. This complex binds to a specific plasma protein to form the highly stable complex. The formation of the stable complex seems to be related to the detoxification mechanism of Se against Hg.	The corresponding plasma protein is likely seleoprotein P	Ref # 166 |Yoneda S, et al. Toxicol App Pharmacol 1997;143:274–280
Animal study – female Mice – acute Methylmercury	MeHg 2 µMol/kg p.o. once	Se 0.6 mg/L or 3 mg/L in available water for 8 weeks	Se supplementation shortened half-life of Hg and reduced total body Hg, Did not affect brain, kidney or liver Hg content at 56 days	In female brain Hg half-life is significantly slower than blood Hg	Ref # 167 Glynn AW, et al. Pharmacol Toxicol. 1995;77:41–47.
Animal study – Mice – inorganic HgCl – simultaneous intervention	HgCL 0.2 mg/kg/day s.c. For 10 days	Se 05 mg/kg/day in feed for 10 days	Hg concentration increased in serum and liver but decreased in kidney. Selenoprotein P in serum increased 100%, in association with increased serum Hg		Ref # 168 Garcia-Sevillano MA, et al. Chemico Biol Interact. 2015;229:82–90
Animal study – Rat – Acute inorganic HgCl – Simultaneous intervention	HgCl 1.5 µMol/kg i.p. once	Se 1.5 µMol/kg i.p. once or unithiol 300 µMol/kg i.p. once or succimer 500 µMol/kg i.p. once, or Se and unithiol or Se and succimer together once	Animal euthanized 24 h after dose. Se increased serum and liver Hg but decreased kidney and urinary Hg. Simultaneous Se and unithiol or simultaneous Se and succimer together decreased urinary Hg compared with unithiol or succimer alone.	Transient effect, during initial SelP production in liver. Did not evaluate Se effect on renal injury or function	Ref # 169 Juresa D, et al. Toxicol Let. 2005:155:97–102.
Animal study – mice – chronic inorganic HgCl – delay before intervention	HgCl2 1 mg/kg/day s.c. for 2 weeks	After Hg injections stopped 1) diphenyl diselenide 15.6 mg/kg p.o for 1 week or 2) unithiol 12.6 mg/kg/day p.o, for 1 week or 3) both Se and unithiol	Both Se and unithiol reduced kidney Hg and reduced oxidative stress. Unithiol was more effective in reducing kidney Hg. Together (Se and unithiol) were less effective than unithiol alone.		Ref # 170 Brandao R, et al. Food Chem Toxicol. 2009;47:1771–1778.
Study – human Unithiol challenge	Unithiol challenge of trace element excretion	Unithiol 3 /g/kg i.v. once	Increase excretion of Hg (3–107 fold) Se (3–44 fold) Zn (4–44 fold)	Unithiol increased Se excretion, which may complicate Hg induced Se deficiency	Ref # 171 Torres-Alanis O, et al. Clin Toxicol. 2000;38:697–700.
In vitro – seal leucocytes – methymercury – co-incubation	Co incubation MeHg 0.75 µmol	co-incubation with selenite (7.5 µmol) or selenomethionine (7.5 µmol)	provided no protection against mercury-induced inhibition of cell proliferation	In vitro – does not approximate whole organ effects and demethylation of MeHg in organisms	Ref # 174 Das K, et al. Marine Poll Bul. 2016;108:70–76.
Animal study – Rats – Chronic Methylmercury – Simultaneous intervention	MeHg 5 mg/kg/day p.o. for 21 days	diphenyl diselenide 1 mg/kg/day i.p. for 21 days	Cotreatment protected hepatic and cerebral mitochondrial thiols from depletion by MeHg but failed to completely reverse MeHg’s effect on hepatic and cerebral mitochondrial dysfunction. Additionally, the cotreatment with (PhSe)2 increased Hg accumulation in the liver and brain and increased the MeHg-induced motor deficits and body-weight loss	Chronic co-administration did not ameliorate MeHg toxicity	Ref # 175 Della Corte CL, et al. BioMed Res Intern 2013; Article ID 983821,
Case Series – elemental mercury Vapor	Hg vapor −169 children Hg exposed and 45 matched non-exposed control	Measurement of blood Hg, Urine Hg, neuron-specific enolase (NSE), S100B, and glutamate receptor (GRIA 1)	Serum NSE, GRIA 1, and S100B were increased with mercury exposure. GRIA 1 and S100B levels were observed to have the power to discriminate neurological symptom positive and negative groups. The increase in S100B levels thought to be protecting the neurons and preventing further NSE elevations.		Ref # 176 Yilmaz FM, et al. Clin Toxicol 2014;52:32–38
Animal study – male Mice – acute Methylmercury -	MeHg 2 µMol/kg p.o. once	Se 0.6 mg/L or 3 mg/L in available water for 7 weeks	Se supplementation shortened half-life of Hg and reduced total body Hg, Did not affect brain, kidney or liver Hg content at 49 days		Glynn AW, et al. Bio Trace Elem Res. 1993;39:91–107
Case report – Elemental mercury injection	Elemental mercury injection	Unithiol 600 mg/day p.o. for 6 days. Then Unithiol 600 mg/day p.o. for 6 days repeated at 1 year, 2 years and 5 years post injection	The serial X rays and CT scans over five years confirmed the persistence of metallic densities in the chest and abdomen. The first 3 Unithiol session produced increases in Urine Hg (7500 to 11,000 µg/l) but post chelation urine Hg returned to 1100 µg/l. Tremor and lower extremity persisted.	The mg doses of Hg removed by unithiol were unable to effect the gm dose injected.	Torres-Alanis O, et al. Clin Toxicol 1997;35:8387
Case report – mercuric chloride ingestion	37 g HgCl2	BAL 18 mg/kg/day i.m. for 5 days, followed by succimer 30 mg/kg/day p.o. for 5 days and 20 mg/kg day for 14 days.	Initial serum and urine mercury reported as 152 µg/L and 1290 µg/g creatinine. On day 10 post-ingestion serum and urine Hg were 26 µg/L and 160 µg/g creatinine, respectively and on day 24 the results were 6 µg/L and 63 µg/g creatinine, respectively.	There are no results between day 0 and day 10, and it is unclear if the blood hg changes are related to renal/hepatic clearance or tissue distribution or a mixture or both. Supports that Hg^2+ does not readily cross the blood brain barrier in acute exposures.	Wang EE, et al. J Emerg Med 2007;32:289–294
Case report – chronic elemental mercury vapor	Chronic mercury vapor − 6 months	Succimer 30 mg/kg/day for 5 days and 20 mg/kg/day for 15 days	Severe fatigue, generalized muscle pain, and weakness, present for a month. Whole blood and 24-hour urinary mercury concentrations were 23.2 mg/L and 175 m/L, respectively. 3 days after chelation begun, pt showed new onset intracranial hypertension. Acetazolamide was started. The patient stayed in the hospital for 35 days and was then discharged with acetazolamide, vitamin B6, and gabapentin and followed as an outpatient. His clinical findings were relieving day by day.	Pt neurological condition worsened under chelation	Gebcpinar et al. J Child Neurol 2015;30:760–763
Animal study – Mice – Chronic inorganic HgCl – simultaneous intervention	HgCl 1 mg/kg/day s.c. for 2 weeks	Diphenyl diselenide 15.6 mg/kg p.o. for 2 weeks	Se protected against immunological and histopathological effects of Hg	the antioxidant action of this compound or the formation of an inactive complex between Hg and Se, or Hg, Se, and seleneprotein P, reducing the availability of Hg	Brandao R, et al. J Biochem Mol Toxicol. 2008;22:311–319.
Animal study and in vitro study – perfused Rabbit liver and kidney – acute inorganic HgCl – simultaneous intervention	HgCl 1.5 µmol/Kg i.v. once	Se 1.5 µmol/Kg i.v. once	Simultaneous injection reduced Kidney Hg and increased blood, plasma and liver Hg, at 1 and 24 h, compared with controls (Hg but no Se) A high molecular weight complex, quickly formed by the interaction of mercury and selenium in blood stream, decreasing the acute renal toxicity of inorganic mercury	Se likely formed a Hg-Se complex, found bound to high molecular weight plasma protein, likely Selenoprotein P.	Naganuma A, et al. Biochem Behav. 1980:13:537–544
Animal study – weanling rats – inorganic HgCl – simultaneous intervention	HgCl 6.45 µmol/kg p.o. for 4 days (day 10–14 post natal)	Se 6.45 µmol/kg p.o or 12.9 µmol/kg p.o or 19.4 µmol/kg p.o for 4 days (day 10–14 post natal) Se: Hg Molar ratio of 1:1, 1:2 or 1:3	Compared with controls (Hg but no Se) Se decreased brain and kidney Hg and decreased urinary Hg with increased blood Hg. Increasing Se: Hg molar ratio decreased Brain and kidney Hg and increased Blood Hg. Increasing Se increased urinary Se	Se likely formed a Hg-Se complex, found bound in blood but not plasma, likely selenoprotein P	Orct T, et al. J Appl Toxicol. 2009;29;585–589.
In vitro – mouse neurons – Methylmercury – co-incubation	Incubation in MeHg 0, 10, 30 100 µmol	Co-incubation with diphenyl diselenide 100 µmol	Co-incubation completely eliminated Me-hg induced MeHg-induced lipid peroxidation and mitochondrial damage	In vitro Co-incubation is difficult to translate to human condition	Meinerz DF, et al. Braz J Med Bio Res. 2011;44:1156–1163.
Animal study – Mice – Acute inorganic HgCl – simultaneous intervention	HgCl 4.6 mg/kg/day s.c. for 3 days	Unithiol 400 µmol/kg (91 mg/kg) i.p once or acetylcysteine 400 mg/kg i.p. once or diphenyl diselenide 100 µmol/kg (32 mg/kg) i.p once	Unithiol and acetylcysteine showed increased evidence or renal injury. (PhSe)2 produce 100 % lethality.	(PhSe)2 at 32 mg/kg alone known to be toxic. Very high doses of unithiol may be toxic.	Brandao R, Santos FW, Zeni G, et al. Biometals. 2006;19:389–398
Case report – elemental mercury vapor	Hg vapor from heated elemental Hg	Acetylcysteine p.o., for 14 days, dose not provided	36 YO female with tachycardia, fever, abdominal pain. On hospital day 7, blood Hg was 30 µg/dl.	Limited information provided. No clinical details or follow up.	Sarikaya S, et al. BMC Emerg Med 2010;10:7 10:7 http://www.biomedcentral.com/1471-227X/10/7
Case series – elemental mercury vapor − 21 children	Hg vapor from thermometer	Acetylcysteine 15 mg/kg/day p.o., for 1 week (13 patients), 2 weeks (7 patients) and 1 month (1 Patient) and D-penicillamine 25–50 mh/Kg/day	In the first month, slight neurological symptoms (anxiety, decreased concentration, short term memory loss and headache) were present in 3 of their patients. At the end of the third month, all patients were asymptomatic.	Rapid decrease in Blood Hg, may be distribution phase.	Akyildiz BN, et al. Pediatr Emerg Care. 2012;28:254–258

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