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Clinical pearls: Mercury toxicity

August 30, 2021

 

Written by Mariam Imran


This article is part of a series written and researched by CSHP students for Interactions, our biweekly newsletter. We've created this series as a learning activity for pharmacy students undertaking rotations at CSHP. Crafting these pieces not only helps students gain in-depth knowledge of specific conditions, treatments, and resources, it also helps them hone their skills in research, critical appraisal, evaluation, synthesis, and writing – all of which will serve them well in clinical practice. The Professional Practice Team works with the students to select hot topics that are of interest and utility to both the students and to you, the reader. We hope you enjoy this piece by our future colleagues! Let us know what you think: If you would like to provide any comments or constructive feedback for our students, please email us at [email protected]. 


Background 

Heavy metal toxicity resulting from cadmium, arsenic, mercury, lead, and chromium has become a global public health concern. Human exposure to these toxins is increasing due to industrial, medical, and agricultural sources.1 Individuals affected by mercury toxicity exhibit serious neurobehavioural symptoms such as memory loss, depression, paranoia, ataxia, and hallucinations.2 This article will highlight the populations at risk, diagnosis, and treatment of ingested methylmercury toxicity.

Mercury occurs in three forms: elemental, organic and methylmercury. In aquatic systems, microbial activity converts elemental and organic mercury to methylmercury.2 Methylmercury is the most concerning toxin for humans, particularly for individuals who rely on rivers and lakes for food, medicine, and livelihood. This neurotoxin is ubiquitous in nature and accumulates in the muscle tissues of aquatic animals we consume as food.8 Once the mercury-containing animal is eaten, the gastrointestinal tract absorbs 95% of the methylmercury.2

In adults, children, and neonates, the brain and nervous system are the primary target sites of methylmercury, as it is actively transported through the blood-brain and blood-placental barrier.2 One study found that in pregnant women, mercury concentrations were 1.5 times higher in umbilical cord blood samples compared to maternal blood samples during delivery.3 Evidence from the Nunavik Child Development Study indicates that pre-natal and post-natal exposure to mercury has a negative impact on child neurodevelopment: it causes an increased prevalence of attention-deficit/hyperactivity disorder (ADHD), and poorer immediate memory and long-term recollection memory.3 Studies have shown that methylmercury conjugates with L-cysteine residues on red blood cells to enter the endothelial cells of the blood-brain barrier via the L-type amino acid transporter 1 system.4 Within the neuronal and glial cells of the brain, methylmercury induces oxidative stress and increases in excitotoxicity and neuroinflammation. It also alters neurotransmission. This leads to neurotoxicity in the nervous system, as seen in Figure 1.


Figure 1: The neurotoxic impact of methylmercury on neuronal and glial cells within the brain.4

 

Diagnosis

Health Canada has advised the following tolerable daily intake levels of mercury: 0.47 μg/kg body weight per day for adults, and 0.2 μg/ kg body weight per day for women of child-bearing age.5 Healthcare professionals can calculate a patient’s probable daily intake of mercury using the following formula: [fish portion (g) × frequency of consumption (times/day) × mercury in fish (μg/g)] ÷ body weight (kg).3 In individuals who have been chronically exposed to mercury, blood mercury concentrations remain high even when the exposure has been discontinued.6

To determine the concentrations of methylmercury in a patient, samples of blood, urine, and hair are used as biomarkers of mercury intoxication.6

  • Blood tests
    • Red blood cells have a high rate of uptake of methylmercury.7
    • Blood mercury levels can increase to 35 μg/L after chronic mercury exposure.
    • Concentrations above 20 μg/L are considered abnormal and can lead to toxicity.6
  • Hair tests
    • Mercury irreversibly binds to the sulfhydryl groups within the hair keratin, so when chronic mercury exposure has occurred, high levels of mercury can be detected in hair samples.
    • The World Health Organization (WHO) recommends that hair mercury concentrations should not exceed 1 mg/kg.6 However, studies have shown that individuals with moderate to severe mercury intoxication had hair mercury concentrations ranging from 200 mg/kg to 2400 mg/kg.6
  • Urine tests
    • Similarly to blood mercury concentrations, individuals who suffered from long-term exposure to mercury will exhibit high concentrations of mercury in the urine.6
    • Urine tests are a reliable biomarker of inorganic mercury, since 90% of organic mercury is excreted through the feces.6
    • Neurological symptoms such as ataxia, depression, and hallucinations can develop when mercury concentrations in urine are higher than 100 μg/L.6

Treatment

Individuals exhibiting symptoms of ingested methylmercury intoxication should be treated with chelating agents. Chelating agents bind to the heavy metal ion within the body and the chemical complex is then excreted in the urine.8

The following treatments should be selected based on patient-specific factors (such as neurobehavioural symptoms or pregnancy): 

Meso 2,3-dimercaptosuccinic acid (Succimer/DMSA)
This is a water-soluble chelating agent that prevents methylmercury intoxication symptoms by inhibiting the activity of sulfhydryl- containing enzymes.9 DMSA is a commonly used chelating agent that excretes elemental and organic forms of mercury through the urine. Evidence from animal studies show that DMSA is also effective in excreting methylmercury from the brain tissues.6 Treatment with DMSA should be initiated in symptomatic individuals.6 This chelating agent is administered orally. For individuals who have trouble swallowing whole capsules, the capsules can be opened to mix the granules with soft food or a room temperature fruit drink immediately prior to administration12. The recommended oral dose of DMSA is 10 mg/kg every 8 hours for 5 days, then 10 mg/kg every 12 hours for 14 days.6 Some studies have suggested that the dosing for obese individuals should be based on lean body weight.12 Avoid administering DMSA to pregnant woman, as adverse fetal effects have been observed in animal studies.12 Adverse effects of DMSA include gastrointestinal issues and an increase in serum transaminase, however these effects resolve once the medication has been halted.6

2,3-dimercapto-1-propane sulfonic acid (Unithiol/DMPS)
This is also a water-soluble chelating agent which binds to mercury in renal tissues and is excreted through the urine.9 Evidence suggests that DMPS eliminates both elemental and organic mercury deposits from all tissues within the body except the brain. This chelating agent can be given orally or through an intravenous injection.9 Treatment with DMPS should be initiated in symptomatic individuals.6 The recommended adult dose is 250 mg IV every 4 hours for the first 48 hours, then 250 mg IV every 6 hours for 48 hours and then 250 mg IV every 8 hours. The patient can be stepped down to oral therapy of 300 mg three times daily for 7 weeks after IV administration.9 The duration of therapy of DMPS is dependent upon the blood and urine mercury concentrations. DMPS may be administered during pregnancy, however trace elements such as zinc and copper should be closely monitored.12 Adverse effects of DMPS include skin rashes, fatigue, and gastrointestinal disturbances.9

Neither Succimer nor Unithiol treatment options are available in Canada. However, these treatments are approved by Health Canada for specific patients through the Special Access Program.10

Dimercaprol (BAL)
This chelating agent was initially used during World War II as an antidote to lewisite, an arsenical chemical weapon.11 Since then, it has been used as a treatment for certain heavy metal poisoning, including mercury. BAL promotes elimination of mercury in the urine by forming a ring structure between its sulfhydryl groups and mercury.11 Do not administer BAL to individuals exhibiting neurotoxicity caused by methylmercury, as BAL may enhance methylmercury distribution to brain.12 This chelating agent is administered through an intramuscular injection and its peak blood concentrations occur within 30-60 minutes.12 In moderate to severe cases of mercury intoxication, 5 mg/kg of BAL should be administered IM every 4 hours for 1 to 2 days, then the dose should be reduced to 2.5 mg/kg IM 1 to 2 times/day for 10 days.11 The adverse effects of BAL are dose dependent and are often eliminated 1 to 2 hours after administration. BAL is contraindicated in individuals who have a peanut allergy as BAL is formulated in peanut oil. The adverse effects include contact dermatitis, vomiting, and transient elevations of liver enzymes.12

Impacted populations

Mercury exposure in northern communities, specifically those where fish and marine mammals are a significant food source, continues to be a major public health concern in Canada.3 Compared to more southern communities, the north of Canada is more likely to be impacted by mercury poisoning. This is the direct result of industrial activity: Mercury from coal combustion and gold mining released into the oceans and atmosphere travels long distances and accumulates at higher latitudes.3 The Grassy Narrows First Nations community in Northwestern Ontario is one example of a population impacted by methylmercury intoxication.13 This community relied on the English-Wabigoon River system for their basic daily needs. Between 1962 and 1970, Dryden Chemicals pulp and paper mill dumped approximately 9000 kilograms of mercury into their river system, concentrating the area’s fish, animals, and soil with high levels of mercury.13 A few years later, the Weyerhauser logging company deposited cancer-causing toxins into the English-Wabigoon River system. As a result, the Grassy Narrows First Nations community continues to be exposed to mercury to this day. In 2007, numerous children in the community were born with seizures, and two children were born with brain cancer. In 2012, an eight-year-old girl was reported to have mercury poisoning.13 Considering the detrimental effects of mercury intoxication in the Grassy Narrows First Nations community, the federal government of Canada has agreed to build a 24-bed treatment centre for mercury poisoning within the community, slated to open in 2023.14

References

  1. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Exp Suppl. 2012;101:133-164. doi:10.1007/978-3-7643-8340-4_6
  1. Andreoli, V., & Sprovieri, F. (2017). Genetic Aspects of Susceptibility to Mercury Toxicity: An Overview. International journal of environmental research and public health, 14(1), 93. https://doi.org/10.3390/ijerph14010093
  2. Pirkle, C. M., Muckle, G., & Lemire, M. (2016). Managing mercury exposure in northern Canadian communities. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 188(14), 1015–1023. https://doi.org/10.1503/cmaj.151138
  1. Novo,J.P.;Martins,B.; Raposo, R.S.; Pereira, F.C.; Oriá, R.B.; Malva, J.O.; Fontes-Ribeiro, C. Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation. Int. J. Mol. Sci. 2021, 22, 3101. https://doi.org/ 10.3390/ijms22063101
  1. Human Health Risk Assessment of Mercury in Fish and Health Benefits of Fish Consumption. (2008, November 03). Retrieved from https://www.canada.ca/en/health-canada/services/food-nutrition/reports-publications/human-health-risk-assessment-mercury-fish-health-benefits-fish-consumption.html#table4.5
  1. Ye, B., Kim, B., Jeon, M., Kim, S., Kim, H., Jang, T., . . . Hong, Y. (2016). Evaluation of mercury exposure level, clinical diagnosis and treatment for mercury intoxication. Annals of Occupational and Environmental Medicine, 28(1). doi:10.1186/s40557-015-0086-8
  1. Lambrinos, A. (2014, October). Testing for Blood Mercury Levels in the General Population. Retrieved from https://www.hqontario.ca/Portals/0/Documents/evidence/cwc/report-mercury-testing-1410-en.pdf
  2. George, G. N., Prince, R. C., Gailer, J., Buttigieg, G. A., Denton, M. B., Harris, H. H., & Pickering, I. J. (2004). Mercury Binding to the Chelation Therapy Agents DMSA and DMPS and the Rational Design of Custom Chelators for Mercury. Chemical Research in Toxicology, 17(8), 999-1006. doi:10.1021/tx049904e
  1. Rafati-Rahimzadeh M, Rafati-Rahimzadeh M, Kazemi S, Moghadamnia AA. Current approaches of the management of mercury poisoning: need of the hour. Daru. 2014;22(1):46. Published 2014 Jun 2. doi:10.1186/2008-2231-22-46
  1. Thompson, M. (2020, June 19). Further Update on BAL Shortage 2020. Retrieved from https://www.ontariopoisoncentre.ca/siteassets/news/expert-alerts/2020-june19-alert-further-update-bal-shortage.pdf
  1. Dawn L, Whited L. Dimercaprol. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549804/
  1. Kent DA, editor. Poison management manual. 5th ed. Vancouver: British Columbia Drug and Poison Information Centre; 2015.
  1. Ilyniak, N. (2014, February). Mercury Poisoning in Grassy Narrows: Environmental Injustice, Colonialism, and Capitalist Expansion in Canada. Retrieved from https://www.mcgill.ca/msr/msr-volume-4/mercury-poisoning-grassy-narrows
  1. Wright, T. (2020, April 03). Grassy Narrows signs deal with Ottawa on mercury poisoning treatment centre. Retrieved from https://www.ctvnews.ca/canada/grassy-narrows-signs-deal-with-ottawa-on-mercury-poisoning-treatment-centre-1.4881372

 

 

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