A skin-lightening cream from Mexico that contained toxic mercury left a California woman with significant central nervous system damage, doctors report in a case study.
Many weeks after her initial hospitalization, the woman requires “ongoing tube feeding for nutritional support” and can’t speak or care for herself, according to the authors.
The cream contained a form of organic mercury called methylmercury.
This is the first known case of methylmercury poisoning in the United States in nearly 50 years.
“Most harmful skin-lightening creams are intentionally tainted with inorganic mercury. But in this case, the patient used a skin-lightening product containing organic mercury, which is far more toxic,” said study senior author Dr. Paul Blanc, of the University of California, San Francisco (UCSF), and California Poison Control System.
Organic mercury can cause “profound damage” to the central nervous system that may even worsen after use ends, he said.
The woman first sought medical help for involuntary muscle movement and weakness in her shoulders and arms, the case study reported.
After two weeks of outpatient care, she was admitted to a hospital with symptoms that included blurry vision, unsteady gait and difficulty speaking. Blood and urine tests confirmed mercury poisoning.
Her family told doctors that she had been using skin-lightening creams from Mexico twice a day for seven years, according to the case study published Dec. 19 in the U.S. Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report.
The woman underwent chelation therapy, a treatment for heavy metal poisoning, but her condition didn’t improve.
She was transferred to UCSF, where tests found that the skin cream she used contained methylmercury.
“Central nervous system toxicity, as in this case, is the hallmark of organic mercury – it typically comes on after weeks to months of exposure.
Once manifested, it quickly progresses and often worsens, despite removal of any further exposure,” Blanc said in a UCSF news release. “Unfortunately, chelation therapy, which is effective in inorganic mercury poisoning, has not been established to be efficacious for methylmercury.”
Consumers can take several steps to protect themselves, said study co-author Dr. Craig Smollin, of UCSF’s emergency department and medical director of the California Poison Control System’s San Francisco Division.
When buying skin creams, check that the product has a protective foil seal under the lid, Smollin advised.
“Purchase creams from well-known stores and avoid those with hand-made labels or without labels. Ingredients must be listed, and directions and warnings should be in English,” he said in the news release.
The US Agency for Toxic Substances and Disease Registry assembles a list of the substances that can cause the most significant problems to human health for their toxicity and potential for human exposure. It should be noticed that this priority list is not a list of “the most toxic” substances, but rather a prioritization of substances based on a combination of their frequency, toxicity, and potential for human exposure. This list is regularly revised to take into account any new information on toxic substances [1].
On these bases, lead (Pb), mercury (Hg), and cadmium (Cd) are classified not only as the most relevant toxic metals, but also as the most relevant toxic substances in general. Furthermore, the World Health Organization (WHO) has also included these three toxic metals in the top 10 chemicals of major public health concern [2].
Therefore, in the present review, we will take into consideration the chelating agents that can be useful for the clinical treatment of Pb, Hg, and Cd intoxication. In particular, since the sulfhydryl (SH) groups of proteins furnish the vehicle for both the toxicity and detoxification of the majority of heavy metal ions, we will take into consideration chelating agents characterized by thiol groups. The review aims to delineate principles that can be used in the search for improved antidotal treatments of these three toxic metals. We will start by recalling the hard–soft properties of these metal ions [3] reported in Table 1.
Table 1
Classification of the toxic metals, and the coordinating groups, according to their hard, intermediate (borderline), and soft character. The implied metal ions and coordinating groups are marked in red.
| Metal Ions | Coordinating Groups | ||||
|---|---|---|---|---|---|
| Hard | Borderline | Soft | Hard | Borderline | Soft |
| Li+, Na+, K+, Be2+ Mg2+, Ca2+, Sr2+, Mn2+, Al3+, Ga3+, Cr3+, Fe3+, Sn4+, (CH3)2Sn2+, UO22+, VO2+ | Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Pb2+, Sn2+, Sb3+, Bi3+ | Cu+, Ag+, Au+, Hg+, Pd2+, Cd2+, Pt2+, Hg2+, CH3Hg+, Pt4+ | H2O, OH−, F−, RCOO−, Cl−, RO−, NH3, RNH2 | C6H5NH2 | R2S, RSH, RS− |
It can be observed that Cd2+ and Hg2+, both belonging to group 12 in the periodic table of elements, are classified as soft metal ions, preferring the coordination by ligands characterized by soft groups such as R2S, RSH, and RS [4]. On the other hand, Pb2+, which belongs to group 14 in the periodic table, is classified as an intermediate metal ion, indicating that above all it will be coordinated by amino groups, even if the interaction with hard oxygen groups and soft thiol groups is observed in a number of complexes. Furthermore, different structural coordination modes characterize these metal ions, such as linear coordination for Hg with thiol groups, or tetrahedral for Cd, but these considerations will be further developed in the last sections of the present paper.
Exposure and Effects
Table 2 reports some exposure sources and target organs for Hg, Cd, and Pb, which will be discussed in the following lines.
Table 2
Some exposure sources and target organs for Hg, Cd, and Pb.
| Important Sources of Occupational Exposure | Routes of Exposure | Important Sources of Environmental Exposure | Routes of Exposure | Target Organs of Toxicity | |
|---|---|---|---|---|---|
| Elemental mercury | Coal-burning, waste incineration, gold extraction, dental amalgam handling, fluorescent lamp manufacturing | Inhalation | Dental amalgam in teeth | Inhalation | Central and peripheral nervous system |
| Inorganic mercury salts | – | – | Use of skin lightening products and medicinal use of mercury salts | Gastrointestinal ingestion, transdermal | Kidneys |
| Methyl mercury | – | – | Food (fish, seafood) | Gastrointestinal ingestion | Central nervous system |
| Cadmium | Production of nickel-Cd batteries, Cd plating, Cd-containing paint production | Inhalation | Food (rice, potato, and wheat, offal, seafood) Tobacco smoke | Gastrointestinal ingestion Inhalation | Kidneys Skeleton |
| Lead | Mining, smelting, battery manufacturing, traditional printing technology | Inhalation | Food, drinking water, dust and soil (in children) | Gastrointestinal ingestion | Central nervous system, hematopoietic system, kidneys |
Mercury
Environmental Hg exists in three chemical forms, viz. elemental Hg (metallic Hg0 liquid), inorganic mercuric salts (e.g., Hg chloride, HgCl2), and organic Hg compounds (e.g., methylmercury (MeHg, CH3Hg) and ethylmercury (EtHg, C2H5Hg)) [5,6].
Humans are exposed to low chronic levels of mercurial compounds via various routes: Oral, inhalation, and dermal [7], to MeHg mainly through fish, Hg vapor from dental amalgams, and EtHg through vaccines [8].
Although organic Hg is regarded as the most frequent and toxic one, elemental Hg is more volatile and, hence, more dangerous than generally perceived. Elemental Hg0 exists as liquid metal and can vaporize at room temperature due to high vapor pressure. For example, a worker who stays for about eight hours in a Hg-saturated place can inhale up to about 100 mg of Hg per day [9]. Major sources of elemental Hg emissions to the air are coal burning, metal smelting, crematoriums, waste incineration, and small-scale gold extraction [10].
Emitted Hg vapor is oxidized to ionic form (Hg2+) in the air layers, which falls to the ground with rain, often far from the emission point. This makes Hg exposure a global concern. In the soil layers and sediments, Hg has a very long half-life [11,12]. Also, Hg occurs naturally as a result of volcanic activities, forest fire, water movement, etc. [13].
Other important sources of Hg exposure is the use of Hg in measuring instruments and as a disinfectant. Regulatory measures during the last decades have reduced the Hg emissions to the environment significantly [12]. However, still, some hot spots of Hg pollution exist. Mainly in developing countries, Hg poses a threat to the environment and health of nearby living residents. Hence, environmental and human Hg exposure assessments are needed in these regions [11].
The main sources of elemental Hg in humans are Hg released from dental amalgams batteries, and incineration of medical waste [14,15]. In the 1830s, dental amalgam was introduced in the Western World and has since then been subject to recurrent concerns and controversies [16]. Today, many countries, including the Scandinavian countries and Italy, have in principle ceased the use of dental amalgam. However, this filling material is still in widespread use, particularly in developing countries [14].
Elemental Hg is oxidized to divalent inorganic Hg in red blood cells and tissues [17]. However, some Hg vapor passes the blood–brain barrier and enters the brain. Elemental Hg, which is highly diffusible and lipid-soluble, is oxidized and accumulated in the human brain. Its half-life in the brain is several years to several decades [18].
Numerous toxic effects and conditions have been linked to Hg vapor exposure. It has been suggested that inhaled Hg vapor from amalgam fillings is a predisposing factor to Alzheimer’s disease [19]. However, this hypothesis remains to be verified [20]. Research has also shown that Hg vapor passes the placenta and is taken up by the fetus.
The inorganic Hg concentrations in the placenta and umbilical cord have been found to correlate with the mother’s number of amalgam fillings [21,22]. Dental personnel who are occupationally exposed to Hg have a higher Hg body burden than unexposed individuals., Recently this was reviewed by Aaseth et al. [23] and Bjørklund et al. [24]. Also, dental personnel more often develop uncharacterized symptoms like fatigue, weakness, and anorexia than unexposed people [23]. A similar trend was shown for neurobehavioral effects, like idiopathic disturbances in cognitive skills, affective reactions, and motor functions [24].
In addition to dental personnel, occupational Hg exposure also occurs in the chloralkali industry (if Hg electrodes are used) and in the manufacture of fluorescent lamps and batteries. Adverse effects in the central nervous system of chloralkali workers may persist for ten years or more after high Hg vapor exposure has ceased. Mathiesen et al. [25] found that a group of 70 previously H-exposed chloralkali workers (time passed after the last exposure was on average 12.7 years) had decreased performance on a number of neuropsychological tests compared to an unexposed control group of 52 workers. Comparable results were shown in another study of high-level Hg vapor-exposed workers [26].
It has been demonstrated that adverse Hg effects in the peripheral nervous system are detectable even decades after cessation of exposure [27]. The major clinical feature of chronic elemental Hg poisoning is a triad of tremors, erethism, and gingivitis [28]. Long-term chronic Hg vapor exposure led to mercurial erethism, characterized by excessive shyness and social phobia [29].
In the 19th century, mercuric nitrate was commonly used in felt hat production. At that time in England and the US, the syndrome of erethism was common among exposed hatters. More on historical perspectives of Hg poisoning is given by Brooks et al. and Buckell et al. [30,31]. Apart from the central nervous system toxicity, elemental Hg can affect the human immune system or cause toxic pulmonary, reproductive, or cardiovascular effects [15].
Inorganic Hg2+ is absorbed from the gastrointestinal tract after ingestion and also through the skin [32]. The highest inorganic Hg levels are found in kidneys. In the kidneys, inorganic Hg can give many effects, including proteinuria and polyuria. This can further progress into nephritic syndrome [33]. Chronic inorganic Hg poisoning can also cause acrodynia, which is considered a hypersensitivity reaction, characterized by profuse sweating and erythematous rashes of the palms and soles [32].
Of serious concern is Hg exposure via fish and seafood. Mercury bioaccumulates and biomagnifies in the food chain, after biomethylation to MeHg [11,13]. Usually, the MeHg levels increase with the age of the fish [34]. Methylmercury has caused major environmental disasters [35]; the most serious happened in Minamata Bay, in Japan. In the 1950s, the plastic plant belonging to the Chisso Corporation group emitted wastewater containing Hg into this sea bay [36,37].
Over time, this caused a massive Hg accumulation in the food chain. Minamata disease is a neurological syndrome encompassing symptoms of sensory disturbances, ataxia, dysarthria, constriction of the visual field, auditory disturbances, and tremor. Another poisoning incident happened 20 years later in Iraq when the sensory, motor and visual disturbance were developed after ingestion of bread contaminated with organomercury fungicide [38].
After ingestion and rapid absorption of MeHg in the gastrointestinal tract, it circulates in the blood bound to SH-containing amino acid residues and distributed to the central nervous system and other parts of the organism [39,40]. By the use of molecular mimicry, MeHg, bound to the SH group of cysteine, crosses the blood–brain barrier and arrives at glial cells and neurons, where it is slowly converted to inorganic Hg [41].
Epidemiological studies have shown that pregnant women who are exposed to large MeHg concentrations give birth to children with severe brain damage even without having any poisoning symptoms themselves [11,42]. Furthermore, MeHg has been implicated in many neurodegenerative diseases, and a possible role in autism spectrum disorder has been suggested [20,41,43].
According to the International Agency for Research on Cancer, MeHg compounds are possibly carcinogenic to humans (group 2B), while metallic Hg and inorganic Hg compounds are not considered carcinogenic to humans [44].
Mercury compounds exert toxic actions through various mechanisms. Research indicates that toxic effects of organic Hg in the nervous system may be caused or worsened by the oxidized form, Hg2+, that binds to the thiol (-SH) groups and thereby alters protein structure and/or inhibits enzymatic functions [41]. Numerous studies have also suggested other mechanisms of Hg toxicity such as induction of oxidative stress, damage of Ca homeostasis, and changes in glutamate homeostasis [6].
Cadmium
Metallic Cd is, to a significant extent, a by-product of zinc (Zn) production and to some degree, also a by-product from copper (Cu) and Pb production [45]. Since 1990, the annual use of Cd is about 20,000 tons worldwide. Recycling accounts for ca. 18% of the production. A majority of Cd is used in nickel-Cd batteries. Also, Cd is used for corrosion protection of steel (cadmium plating), as a solder and weld metal in alloys, in polyvinyl chloride plastics, and as a pigment in paint colors, different types of paint, and glazes [46].
Numerous studies have reported health effects of Cd exposure in the general population, even in subjects without particular industrial exposure. The estimated Cd exposure in many areas, particularly industrial ones, is high enough to represent a human health threat [47,48,49]. Environmental Cd contamination is mainly a result of anthropogenic activities, but can also be of natural origin [50]. Due to high rate soil-to-plant transfer, Cd enters and accumulates in the food chain [51]. In most parts of the world, food is the primary Cd source for non-smokers [47].
Foods rich in Cd include offal, seafood, cocoa powder, and wild mushrooms. However, due to the larger consumption, 80% of Cd in food comes from staples (rice, potato, and wheat) [52,53]. The average daily Cd intake from food is 8–25 μg [50,52]. Currently, the Food and Agriculture Organization (FAO) and World Health Organization (WHO) Joint Expert Committee on Food Additives and Contaminants consider 25 µg Cd per kg body weight/month as a tolerable intake level [54].
However, certain subpopulations can have a much higher Cd intake than the average population (vegetarians, populations that consume rice as a dominant energy source) [52]. Tobacco leaves accumulate Cd. Therefore, cigarette smoke is a significant Cd source in the general population [55]. Cadmium in drinking water typically only contributes a few percent of the total Cd intake [53].
In the air, Cd is present in trace amounts [56]. Therefore, exposure from air generally provides less than a few percent of the total Cd body burden. However, Cd-polluted water and air and even house dust may occur in areas close to some metal industries. Itai-itai disease is the documented case of a mass Cd poisoning in Toyama Prefecture, Japan. What became the world’s first large Cd poisoning disaster started around 1912 and caused a crippling and very painful form of osteomalacia including severe kidney damage and multiple bone fractures [57] The disease got its name due to the pain moans.
After Cd uptake in the body, it is transported via the hepatic portal system to the liver, where Cd induces synthesis of metal-binding proteins, metallothioneins (MTs). Inhaled Cd induces MTs in the lungs, where CdMT complexes are formed directly. CdMTs are released from the liver, enterocytes, and lungs into the systematic circulation. Thus, Cd is transported primarily to the kidneys where it accumulates. A recent review by Satarug presents a detailed overview of Cd kinetics [51]. The half-life of renal Cd is 7–16 years [58] or longer [59]. However, the accumulation of Cd in the organism varies with age, gender, smoking status, and certain co-morbidities.
Long-term Cd exposure affects many organs. The kidneys have been considered the critical organ of Cd toxicity. Even low-level, long-term Cd exposure may induce various kidney dysfunctions [60].
Also, the liver is critical to Cd accumulation. In both sexes, both acute and chronic Cd exposure is linked to various liver-related diseases [60,61]. Recent epidemiological studies confirm the association between Cd exposure and increased risk of osteoporosis-related fractures [62], which originally was observed during the Itai-itai epidemic in Japan. Also, associations between Cd exposure and cardiovascular diseases [63], reproductive disorders in both sexes [64,65,66], thyroid disorders [67], gestational diabetes, and diabetes mellitus type 2 [68,69] have been shown. Also, Cd may produce hormesis phenomena [70]. IARC classifies Cd and Cd compounds as known human carcinogens [44], based on a causal relationship between exposure and lung cancer. New research has also shown positive associations between chronic Cd exposure and kidney and prostate cancers [71]. Studies have implied a possible role of Cd in pancreatic [72,73], bladder [74], prostate [75], and breast cancer [76].
The mechanisms of Cd toxicity are various and include binding to SH groups, oxidative stress induction [77,78], interactions with bioelements [79,80,81,82], mitochondrial toxicity [83], and altered microRNA expression [84].
Lead
For several decades, the use of Pb-containing gasoline was an environmental and human exposure source of organic Pb compounds [85,86]. Since the 1920s, Pb usually added as tetraethyl lead (TEL) to gasoline caused significant exposure via inhalation of car exhaust [87]. Since Pb is toxic, this gasoline was gradually phased out in most countries of the world. In the US, Pb in gasoline was banned from 1996, and in the EU, organolead was entirely phased out in 2000 [87].
The removal of Pb from gasoline is regarded as one of the major public health triumphs of the 20th century. Also, much work has been done to phase out Pb from various other products completely. To completely eliminate Pb from gasoline and water pipes took a long time but effectively reduced Pb pollution in the environment [86,88].
However, due to the persistence of Pb, it is still present in the environment. Although food generally contains low Pb levels, most of the Pb exposure in many countries nowadays occurs through food and drinking water [86,89]. In Europe, the average exposure via diet is about 0.50 µg Pb/kg body weight/day [90]. Cereal products contribute most to dietary Pb exposure, while Pb in dust and soil can be important sources for children.
Also, Pb in old paint dust and soil can be a source of increased Pb exposure for small children, due to their tendency for licking, chewing, and swallowing foreign bodies [91,92]. Residual paints that contain significant quantities of Pb is a problem in many countries of the world, especially for children [93].
Lead exposure mainly happens through the gastrointestinal and respiratory tract. Approximately 30%–40% of Pb from the respiratory tract is absorbed into the bloodstream while the gastrointestinal absorption depends mainly on age and nutritional status [86,94]. Hence, while adults absorb around 10%–15% of ingested Pb, this amount increases up to 50% in infants, young children, and pregnant woman [85,94,95].
Once absorbed, Pb is transported by the bloodstream mainly bound to erythrocytes and distributed to other tissues such as liver, kidneys, brain, lungs, spleen, teeth, and bones.
More than 95% of Pb is deposited in skeletal bones while in children, this percentage is less resulting in more Pb in soft tissues [85,86]. Furthermore, Pb passes the placental barrier during pregnancy and can cause damage to the fetus. Concentrations of Pb found in the umbilical cord blood are 80%–100% of the maternal blood levels [96].
Toxic effects of Pb have been detected in virtually every body system. Children are generally more vulnerable to Pb toxicity than adults, especially for neurological Pb toxicity. The most deleterious effects of Pb are detected on erythropoiesis, kidney function, and the central nervous system [85,86,97].
Other toxic effects of Pb include hypertension and hearing impairment, infertility, abdominal pain (“lead colic”), and anorexia [97]. Recent research has linked the level of Pb in drinking water to increased risk of cardiovascular pathologies [98]. For children, Pb exposure may impair cognitive abilities, attention, mental development, and skeletal growth [99]. Also, disturbed blood formation and renal effects may occur in children at relatively low Pb exposure [100].
A lower threshold for children that provides complete safety against Pb poisoning has not been established. The International Agency for Cancer Research classified inorganic Pb as probably carcinogenic to humans (Group 2A) [101].
Many in vivo and in vitro studies have been performed to identify the exact mechanisms of Pb toxicity. Some of them are oxidative stress induction [77,102], binding to sulfur ligands that can affect many enzymes and proteins [77], interaction with bioelements [102], changes in DNA structure, and inhibition of DNA repair [103].
More information: The U.S. National Library of Medicine has more on methylmercury poisoning.
