Author

Chiara Scicluna 3rd Year Medical Student at the Faculty of Medicine & Surgery, Heavy Metal University of Malta. Reviewer

Chev. Dr. Renald Blundell Senior Lecturer at the Department of Intoxication Physiology & Biochemistry, University of Malta.

Although some debate exists with regards to the subject, elements which are classified under ‘heavy metals’ have come to be those which pose a threat to humans in terms of toxicity. Intoxication with heavy metals is not a typical diagnosis as it is fairly uncommon. This can impose a risk on people who fail to be diagnosed and removed from the source of exposure, increasing morbidity and mortality.

For the purposes of this review, Cadmium and Mercury will be discussed. A brief introduction of each element’s chemical and physical properties will be given, as well as its sources in the environment and any uses. Each metal’s toxicity will be illustrated using actual cases of poisoning. Any treatments for intoxication will be explained at the end of each section.

Overview on Cadmium substances. The more soluble forms tract than males. The highest amounts of have the ability to migrate in water, Cd were found in leafy vegetables such as whereas insoluble forms tend to adsorb spinach and lettuce, and in staple foods Cadmium (chemical symbol Cd) is a to sediments and become immobilized like potatoes and grains. Naturally high transition metal element. Although (Faroon et al., 2012). levels of Cd can be found in peanuts, the pure metal is not typically found in soybeans and sunflower seeds (Faroon et nature, it is associated with zinc ores, and al., 2012). to a certain extent to the ores of lead According to data collected in the and copper. For this reason, it is difficult European Union (EU), it is estimated that to eliminate the by-product of Cd from 90% of Cd exposure in non-smokers Smokers showed an overall high mean the metallurgy of the aforementioned occurs from food, particularly cereals blood Cd compared to non-smokers. This elements. Other industrial sources of and vegetable crops. Plants can take could be measured as high as 1.58µg/L, Cd include smelting of other metals, up Cd salts from the soil. This uptake compared to the average value for adults, combustion of fossil fuels, incineration depends on factors such as the type 0.38µg/L. The reason for this markedly of waste and the utilization of phosphate of soil, the solubility of Cd in it and the high value is the fact that tobacco leaves and sewage sludge fertilizers (Alexandar species of the plant in question. Other naturally accumulate Cd more readily than et al., 2009). sources of exposure include meat and other plants. It was also noted that non- fish, although these are less significant. smokers exposed to second-hand smoke However, consumption of organs such as were also at risk for Cd accumulation The uses of Cd in industry include the liver and kidneys from exposed animals (Faroon et al., 2012). production of coatings, pigments, plastics, contributes a more noteworthy source of plastic stabilizers, batteries, photovoltaic Cd, as the element tends to accumulate devices and nonferrous alloys. When Cd biomarkers are typically detected in in these organs. For non-smokers, air and it is released in the environment it can blood, urine, hepatic tissue, faeces, renal water pose negligible threats in terms of contaminate the air, water and soil. Cd tissue, hair and other tissues (Faroon et exposure as very low levels are present is released from natural mechanisms al., 2012). Blood Cd levels tend to be more (Alexandar et al., 2009). including forest fires, marine aerosol closely related to recent Cd exposure, production and volcanic eruptions whereas urine Cd levels reflect body among other natural phenomena (Faroon Data collected in the United States (US) burden over lengthy exposure, and tend et al., 2012). complies with the report issued by the to increase with renal tubular dysfunction. European Food Safety Authority. Exposure Liver Cd levels are also related to duration to non-smokers in the US is largely from and intensity of exposure regardless of Typically found in its +2 oxidation state, the diet, with females exhibiting a larger renal function (Roels et al., 1981). Cd ions exist in their hydrated forms as uptake of Cd from their gastrointestinal well as complexed to organic or inorganic 26 Minima Cadmium Toxicity cysteine, which typically bind metal pathway Cd causes Fanconi syndrome, ions in the body; with the example which is the damage of the renal proximal of haemoglobin. These chelators tubule resulting in loss of calcium and This metal ion can pose numerous health have numerous important functions phosphate in the urine and the subsequent risks. Cd2+ does not have any known use including transport, detoxification, development of osteomalacia. Although in animal or human biology, however sequestering and metabolism of metal the study does not entirely dismiss the its divalent nature can assimilate roles ions. Metallothioneins bound to Cd direct pathway, histopathological analysis performed by other essential metals. are reabsorbed in kidney tubules showed that osteomalacia development It can cross membranes using metal (Nordberg & Nordberg 2009). Renal was linked to the Cd concentration in transporters. When it gains entry within cortex Cd accumulation results in tubular the renal cortex but not in bone. Figure the cell, Cd2+ can bind ligands with proteinuria with measurable loss of low 1.1 shows the damage caused by Cd; in a particularly high affinity. Clearance molecular weight proteins. These include comparison to the normal subjects, there is difficult, explaining the long term retinol binding protein, β-1-microglobulin is notable atrophy in the renal cortex of storage of Cd in intestinal, hepatic and and β-2-microglobulin. Progression of IID patients, as well as osteoid lesions in renal tissues. The biological half life of renal damage results in glucose, amino their bones (Baba et al., 2014). this metal is estimated to vary from 10 acids and minerals being lost in the urine. to 30 years. Its toxicity stems from its Long term exposure eventually damages interference with iron, calcium or zinc Cd exposure by inhalation has been the renal glomeruli and results in a drop homeostasis, which are necessary for linked to lung cancer in studies based in glomerular filtration rate. Uraemia can basic cellular functions (Alexandar et al., on men who were exposed to Cd at develop in serious cases. Reversibility 2009). their workplace; however, these studies of Cd-induced tubular dysfunction did not account for other significant depends on the severity of proteinuria, factors such as the possibility of other The acute effects of Cadmium which is quantified by the amount of β-2- carcinogens or the smoking habits of the microglobulin (B2M) in the urine (Table subjects. Considering different studies, it 1.1) (Nordberg 1998). Metal fume fever is a condition which was concluded that Cd was not a cause develops within 48h of exposure to metal of lung cancer; rather, cigarette smoking fumes and is typically caused by cadmium Itai-Itai disease (IID) is a painful disease and exposure to arsenic were to blame oxide, although other metal oxides can which presents with multiple distortions (Faroon et al., 2012). also cause it. Patients present with flu-like and fractures of the long bones. It is the symptoms, with resolution within 24-48h most severe form of chronic Cd poisoning Treatment for Cadmium Toxicity of onset. The pathogenesis is not fully by ingestion. Due to a zinc mine located understood; however it is hypothesized upstream from Toyama Prefecture, that upregulation of protein release in the Jinzu River was contaminated with Treatment of Cd exposure is largely response to stress occurs. An example Cd. People who lived in the river basin symptomatic. Patients exposed to oral could be heat shock proteins, which are showed the symptoms of Itai-Itai (Baba et Cd salts should be given a gastric lavage chaperone proteins released in response al., 2014). or induced to vomit. Inhalation exposure to hypothermia and other environmental treatment consists of removing the stresses. The advised treatment is subject from exposure and giving oxygen A study was conducted on post- immediate removal from the source of as necessary. Chelating agents are menopausal women living in this Cd exposure, bed rest, antipyretics and contraindicated as they are nephrotoxic area. The aim of the study was to link treatment for osteoporosis (Malaguarnera in combination with Cd (Nordberg, 1998). osteomalacia with renal tubulopathy. et al., 2013). Two methods for cause of development of osteomalacia were considered; a direct In a study using a rat model, administration The chronic effects of Cadmium and an indirect pathway. In the direct of Chlorella vulgaris was observed to pathway, osteomalacia is thought to be increase excretion of Cd in the urine and caused by the direct interference of Cd faeces, as well as preventing its uptake Metallothioneins are sulfur-containing with bone metabolism. In the indirect from the gastrointestinal tract. The proteins rich in the amino acid

Table 1: Levels of B2M in the urine compared with the level of damage achieved and the possibility for reversal (Nordberg 1998).

Medicamenta 27 precise mechanism by which excretion is liquid, and phenylmercury, a white solid they are being inserted, removed, as they increased is unknown. Prevention of Cd (Risher & DeWoskin, 1999). deteriorate with time and from the buried uptake is thought to be due to dietary or cremated remains of people who had fibre found in Chlorella, which traps Cd these fillings. According to the final report In nature the commonest forms of Hg are in the intestinal epithelium. Epithelial prepared for the European commission, elemental, mercuric chloride, cinnabar ore cells are then lost in the faeces by the phasing out of Hg-containing dental and methylmercury. Liquid elemental Hg desquamation (Shim et al., 2009). amalgam would be difficult for a number has multiple uses, such as the production of reasons, including the expense of of caustic soda, gaseous chlorine, as dental amalgams that do not contain Overview on Mercury well as the extraction of gold from it Hg. Also, dentists would require training ore or gold-containing items. Elemental to insert these amalgams as well as new Hg is used in measuring devices like Mercury (chemical symbol Hg) is a equipment with it. Health services in thermometers and barometers, and also transition metal which occurs in three the EU do not always cover these costs; batteries and electric switches. Inorganic variations; the elemental form and in dental fillings are not covered by the Hg is used in fungicides, skin-lightening inorganic and organic compounds. In national health insurance schemes in creams, paints, tattoo dyes, topical its elemental form Hg is a liquid at room Malta (Mudgal et al., 2012). antiseptics as well as disinfecting agents. temperature. Depending on how high the Prior to 1991, organic Hg compounds temperature, colourless and odourless were used in antifungal agents, but this Mercury Toxicity vapours are emitted (Risher & DeWoskin, use was discontinued after it became 1999). known that Hg vapours were released Hg poisoning in the clinical setting from these products (Risher & DeWoskin, is largely due to suicide attempts by In its inorganic form, Hg occurs as 1999). ingestion of mercury cyanide or other salts of chloride, sulfide or oxides. A compounds. Accidental poisoning is large majority are white salts, with Hg constitutes about 50% of the unusual, although reports of Hg exposure the exception of cinnabar. Cinnabar is components of dental amalgam. Other by youngsters from broken mercury mercury sulfide, a red salt which converts metals include silver, copper, tin and thermometers and barometers have been to black following light exposure. trace metals. Dental amalgam is used to reported. Inorganic Hg compounds in Organic Hg compounds are also known treat dental cavities. Its continued use their pure powder form are the cause of as organomercurials. The most common till today is mainly due to its quality and non-fatal poisoning in adults (Triunfante organomercurial is methylmercury, a the fact that most dentists are trained et al., 2009). crystalline white solid. Other compounds to use it, as opposed to other modern include dimethylmercury, a colourless substitutes. These fillings leach Hg when Chronic exposure of methylmercury from bioaccumulation in fish is a cause of concern (Triunfante et al., 2009). Hg in trace amounts dissolves in water and is converted into toxic methylmercury, which is absorbed by fish through the gills and by consuming smaller aquatic organisms contaminated by Hg. Larger fish carry the largest amounts of Hg due to predation. A study conducted in Ghana analysed the content of heavy metals including Hg in several canned fish products. Canned tuna brands showed the highest Hg levels from the fish analysed (Okyere et al., 2015).

Intoxication from inhalation of metallic Hg vapour typically results in respiratory distress, which can result in death if severe (Triunfante et al., 2009). When Hg is inhaled, 74-80% of the dose is absorbed via the alveolar membrane in the lungs. It is then transported to a number of tissues including the liver, Figure 1: Histological sections of normal renal cortex (a), IID patient renal cortex (b), normal iliac central nervous system and especially the bone (c) and IID patient iliac bone (d). Renal cortex atrophy in (b) and iliac bone osteoid lesions kidneys. In a case report by Gul Oz et al. in (d) can be observed following prolonged exposure to Cd (Baba et al., 2014). (2012), a family of four suffered varying 28 Minima degrees of Hg poisoning after one of the children brought home a minute piece of Hg in a glass from school, which broke and was vacuumed up by the mother in a non-aerated room.

Nephrotic syndrome due to Hg intoxication developed in the mother following 3 months from exposure. Kidney malfunctions present with proteinuria, which can be for one of two reasons: antigen-antibody complexes that form as a result of excess Hg are not effectively cleared and result in damage to the glomeruli (Figure 2.1); alternatively Hg ions cause direct damage in renal tubules (Gul Oz et al., 2012).

The initial effects of Hg poisoning are flu-like symptoms within 1 to 3 days of exposure. These effects include excess salivation, oedematous gingiva, fever, Figure 2: Histological section showing depositions on the capillary walls of glomeruli made up dry cough, diarrhoea, nausea and of granules formed by antibody-antigen complexes that did not clear successfully, (Gul Oz et al., vomiting. Later effects include non- 2012). cardiogenic pulmonary oedema as well as pneumothorax. In post-mortem analyses of Hg-exposed lungs, damage such as Treatment for Mercury intoxication as their effectiveness decreases with time. intense corrosion of the bronchiolar In chronic intoxication, DMPA and DMSA epithelium and necrotizing bronchiolitis chelation appears to reduce the inorganic British Anti-Lewisite, also known as with fluid accumulation in the alveoli and Hg burden on some organs. However, BAL, was developed in warfare as the interstitium. Dysfunctions in other in morbidity and mortality terms, the an antidote to lewisite, which is an systems such as the kidneys, liver, blood benefit has not yet been concluded. arsenical vesicant. BAL’s chemical name and skin have also been reported (Gul Oz Some observed side effects of DMPS is 2,3-dimercaptopropanal, and it is an et al., 2012). and DMSA include allergic reactions with oil which is freely absorbed by the skin. It widespread rashes in 1 to 10% of subjects binds lewisite to form a stable compound, in certain studies. Other effects include The final phase of Hg poisoning is typically therefore removing this toxin’s effect gastrointestinal issues and reversible a progressing hypoxic state which can on the enzyme pyruvate. BAL can also rises in hepatic transaminases and drops lead to death. If the patient survives prevent the vesicant effects of lewisite if in white blood cell count (Kosnett 2013). the intoxication, there may be residual applied before exposure, but can reverse damage in the form of gingivostomatitis, the initial symptoms up to two hours after tremors as well as erethrism, which can exposure. The resulting compound is then Conclusion manifest as loss of memory, emotional excreted in the urine. This drug was also instability, insomnia, depression and used to treat Hg poisoning. (Peters 1949). Diagnosis of heavy metal intoxication is shyness (Gul Oz et al., 2012). not one of the first which comes to mind In rats, intravenous BAL proved effective in when presented with a case, and therefore Injection of metallic Hg with the intent preventing the acute systemic poisoning achieving a good standard of care requires of suicide is also reported. Intravenous caused by mercury chloride. When BAL understanding the sources of exposure of injection leads to pulmonary embolization was supplied by injection as well as oral each metal as well as the pathophysiology by globules of Hg, and patients present dosage, it also safeguarded the rats from of poisoning. This is also true from the with chest pain, dyspnoea, fever and fatal doses (Stocken 1946). point of view of researchers looking for cough. Other signs include changes in the possible prevention treatments. patient’s electrocardiogram, impairment In the 1950s, chemically similar dithiols of renal function and dermatological which could also dissolve in water Exposure can occur from medication, diet, symptoms. Subcutaneous Hg injections were produced; unithiol (DMPS) and the environment and on the workplace. results in inflammation that is localised, succimer (DMSA). Treatment with For this reason, a thorough history of granulation tissue and the formation of these substances is required as early as possible heavy metal intoxication cases abscesses. Eventual systemic involvement possible following Hg exposure, as their should be gathered and scrutinized is also expected (Alhamad et al., 2012). Medicamenta 29 before any attempt at a diagnosis is Registry, US. kidney cadmium in workers exposed to made. When multiple patients present this metal: Its significance with respect to with similar symptoms, it can be advisable cadmium in blood and urine. Environ Res Gul Oz, S., Tozlu, M., Siddika Yalcin, S., to further investigate any linking factors. 26, 217-240. Sozen, T. & Sain Guven, G. 2012. Mercury The possibility of intentional poisoning as vapor inhalation and poisoning of a a means of suicide or murder cannot be family. Inhal Toxicol 24, 652-658. Shim, J., Son, Y., Park, J. & Kim, M. 2009. excluded. Effect of Chlorella intake on Cadmium metabolism in rats. Nutr Res Pract 3, 15- Kosnett, M. 2013. The Role of Chelation The primary treatment is removing the 22. in the Treatment of Arsenic and Mercury patient from the source of exposure Poisoning. J Med Toxicol 9, 347-354. as soon as possible. Further follow-up Triunfante, P., Soares, M., Santos, A., depends on the type of metal poisoning; Tavares, S., Carmo, H. & de Lourdes Bastos, chelating agents discussed in the essay Malaguarnera, M., Drago, F., Malaguarnera, M. 2009. Mercury fatal intoxication: Two are used at the discretion of the physician G., Li Volti, G., Salomone, S., Caraci, F., case reports. Forensic Sci Int 184, e1-e6. in charge, due to side effects and the Galvano, F., Vacante, M., Bucolo, C. & chance of nephrotoxicity especially when Malaguarnera, M. 2013. Metal fume fever. the kidneys have already been implicated. Lancet 381, 2298.

Future research should be based on the Mudgal, S., Van Long, L., Mitsios, A., Pahal, prevention as well as treatment. New S., De Toni, A. & Hylander, L. 2012. Study and better chelators are a good avenue, on the potential for reducing mercury however other studies have focused on pollution from dental amalgam and substances like Vitamin E and NAC, as batteries. BIO IS 07.0307/2011/594114/ well as organisms like Chlorella vulgaris SER/C3, 10-20. for preventing the toxic effects of specific metals when administered concomitantly. Nordberg, G. 1998. METALS: CHEMICAL More studies would be required before PROPERTIES AND TOXICITY. In: J. Stellman any conclusions can be reached; however, (ed) Encyclopaedia of Occupational Health current studies are showing promise. and Safety: Chemical, industries and occupations, pp. 63.2-63.45. International References Labour Organization, Geneva.

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