Heavy Metal Detoxification

Heavy Metal Detoxification

1 Overview

Summary and Quick Facts

  • Acute heavy metal intoxications may damage central nervous function, the cardiovascular and gastrointestinal (GI) systems, lungs, kidneys, liver, endocrine glands and bones. Chronic heavy metal exposure has been implicated in several degenerative diseases of these same systems and may increase the risk of some cancers.
  • This protocol will discuss the general features of heavy metal toxicity, with emphasis on the three metals that present the highest risk for environmental exposure and are most frequently implicated in acute toxicities: lead, mercury and cadmium, as well as the toxic metalloid arsenic. We will also present strategies for minimizing the risk of toxicity.
  • It’s not possible to completely avoid exposure to toxic metals. It is, however, possible to reduce metal toxicity risk through lifestyle choices that diminish the probability of harmful heavy metal uptake, such as dietary measures that may promote the safe metabolism or excretion of ingested heavy metals.

Heavy metals (including lead, cadmium, mercury, and the metalloid arsenic) are persistent in the environment and have documented potential for serious health consequences. Heavy metal toxicity may damage:

  • central nervous system
  • cardiovascular system
  • gastrointestinal system
  • lungs
  • kidneys
  • liver
  • endocrine glands
  • bones

Fortunately, integrative interventions like selenium and garlic have been shown to decrease the buildup and increase the excretion of toxic heavy metals.

Risk Factors for Toxic Metal Exposure

Lead:

  • Lead-containing plumbing
  • Lead-based paints (in buildings built before 1978 and is the predominant source for children)  
  • Foods grown in lead-rich soil

Mercury:

  • Eating fish or shellfish contaminated with methylmercury (includes shark, swordfish, king mackerel, tile fish, bass, walleye, pickerel)
  • Breathing contaminated workplace air or skin contact during use in the workplace
  • Release of mercury vapor from dental amalgam fillings

Cadmium

  • Tobacco smoke
  • Eating foods containing cadmium (levels are highest in grains, legumes, and leafy vegetables, fish and shellfish)
  • Contact with cadmium from household products (electric batteries and solar panels)

Signs and Symptoms

These can be similar to other health conditions and may not be immediately recognized as due to heavy metal toxicity:

  • Nausea
  • Vomiting
  • Diarrhea
  • Abdominal pain
  • Central nervous system dysfunction
  • Heart problems
  • Anemia

Diagnosis

  • Blood testing
  • Urine testing
  • Hair and nail analysis

Conventional Therapies

  • Chelation therapy, which enhances the elimination of metals (both toxic and essential) from the body, including:
    • DMPS, an oral medication for arsenic, cadmium, and mercury toxicity
    • Succimer (DMSA), an oral medication for mild-to-moderate lead, arsenic and mercury toxicity
    • Calcium-disodium EDTA for lead encephalopathy and lead poisoning

Novel and Emerging Therapies

  • Toxicogenomics, the study of gene expression changes by toxin exposure
  • New chelation therapies, including polygamma-glutamic acid-coated superparamagnetic nanoparticles that have a high specificity for metal toxins

Dietary and Lifestyle Changes

  • Avoid or replace mercury amalgam dental fillings with mercury-free composite material
  • Maintain nutrient sufficiency, as adequate intake of essential trace minerals may reduce toxic metal uptake
  • Limit consumption of high-mercury fish to no more than 1 serving/week

Integrative Interventions

  • Selenium: Selenium is an inhibitor of mercury accumulation and increases excretion of mercury and arsenic
  • Vitamin C: A free-radical scavenger that has been shown to reduce lead levels in humans
  • Folate: Higher blood folate levels in pregnant women were associated with lower blood mercury and cadmium levels
  • Garlic: Garlic lowered lead levels in the blood of industrial workers as effectively as the chelator d-penicillamine
  • Alpha-Lipoic Acid and Glutathione: In preclinical studies, these compounds reduced the adverse changes in blood parameters due to lead, cadmium, and copper

2 Introduction

Heavy metals with adverse health effects in human metabolism (including lead, cadmium, and mercury) present obvious concerns due to their persistence in the environment and documented potential for serious health consequences (ATSDR 2000; ATSDR 2004; ATSDR 2007a; ATSDR 2007b; ATSDR 2008a; ATSDR 2008b; ATSDR 2011).

Acute heavy metal intoxications may damage central nervous function, the cardiovascular and gastrointestinal (GI) systems, lungs, kidneys, liver, endocrine glands, and bones (Jang 2011; Adal 2013). Chronic heavy metal exposure has been implicated in several degenerative diseases of these same systems and may increase the risk of some cancers (Galanis 2009; Wu 2012). 

Heavy metals are ubiquitous in the environment (Pohl 2011). Humans risk overexposure from environmental concentrations that occur naturally (eg, arsenic-rich mineral deposits) or human activities (eg, lead or mercury release as a result of industrial pollution) (Orloff 2009; Hutton 1986).

It is not possible to completely avoid exposure to toxic metals (Singh 2011). Even people who are not occupationally exposed carry certain metals in their body as a result of exposure from other sources, such as food, beverages, or air (Washam 2011; Satarug 2010). It is, however, possible to reduce metal toxicity risk through lifestyle choices that diminish the probability of harmful heavy metal uptake, such as dietary measures that may promote the safe metabolism or excretion of ingested heavy metals (Peraza 1998).

This protocol will discuss the general features of heavy metal toxicity, with emphasis on the three metals that present the highest risk for environmental exposure and are most frequently implicated in acute toxicities: lead, mercury, and cadmium, as well as the toxic metalloid arsenic. We will also present strategies for minimizing the risk of toxicity.

3 General Background

The term “heavy metal” assumes a variety of different meanings throughout the different branches of science. Although “heavy metal” lacks a consistent definition in medical and scientific literature, the term is commonly used to describe the group of dense metals or their related compounds, usually associated with environmental pollution or toxicity (Duffus 2002). Elements fitting this description include lead, mercury, and cadmium. The rather broad definition of heavy metals may also be applied to toxic metalloids (a chemical element that has properties that include a mixture of those of metals and non-metals), like arsenic, as well as nutritionally-essential trace minerals with potential toxicities at elevated intake or exposure (eg, iron, zinc, or copper) (Duffus 2002; Bronstein 2012). 

Although “heavy metal” toxicities due to lead, mercury, and cadmium are generally considered rare in mainstream medicine, less well-recognized is that chronic accumulation that may not achieve classical acute toxicity thresholds may nevertheless contribute to adverse health effects.

Regarding acute toxicity, according to the 2011 National Poison Data System annual report, there were 7337 reported unintentional heavy metal exposures in the United States, resulting in 26 serious health outcomes and 2 deaths (Bronstein 2012). While data from the National Health and Nutrition Examination Survey (NHANES) shows a decade of encouraging year-over-year decreases in acutely toxic heavy metal exposure in the United States, there are still a significant number of people with blood levels that may put them at risk for chronic accumulation, and therefore toxicity, over time (CDC 2013a). For example, in the United States, children are exposed to lead in at least 4 million households. Children are particularly sensitive to lead intoxication, both acute and chronic, and there is no identified safe level of lead exposure in children (CDC 2013b; Koller 2004; Handler 2012; CDC 2012). Further, pregnant women risk toxic exposure to the developing fetus since the mobilization of stored lead from the mother’s bones can leach into the bloodstream, and this is more likely the result of chronic rather than acute lead exposure in the mother (Miranda 2010). With several toxic metals lacking robust pathways for elimination or otherwise remaining in the body for a long time, body burdens of some toxic metals (eg, lead, mercury, cadmium) may increase with age (Bjermo 2013).

While a specific toxic metal has the potential to exert detrimental effects by select mechanisms, there are several common features among toxic heavy metals. One of the most widely studied mechanisms of action for toxic metals is oxidative damage due to direct generation of free radical species and depletion of antioxidant reserves (Ercal 2001). Mercury, cadmium, and lead, for example, can effectively inhibit cellular glutathione peroxidase, reducing the effectiveness of this antioxidant defense system for detoxification (Reddy 1981). Many toxic heavy metals act as molecular “mimics” of nutritionally essential trace elements; as a result, they may compete with essential metallic cofactors for entry into cells and incorporation into enzymes (Jang 2011). For example, cadmium can compete with and displace zinc from proteins and enzymes; lead is chemically similar to calcium; and thallium is a potassium mimic in nerves and the cardiovascular system (Buchko 2000; Jang 2011; Thévenod 2013).​​

4 Development of Heavy Metal Toxicity

The severity and health outcomes of toxic heavy metal exposure depend on several factors, including the type and form of the element, route of exposure (oral/inhalation/topical/ocular), duration of exposure (acute vs. chronic), and a person’s individual susceptibility (CDC 2012).

Acute toxicities arise from sudden exposures to substantial quantities of some metals (such as from occupational exposure to aluminum dust or breaking a mercury-containing thermometer) and typically affect multiple organ systems, commonly the GI tract, cardiovascular system, nervous system, endocrine system, kidneys, hair, and nails (Jang 2011). Acute exposures to some metals (mercury, gold, nickel, and others) can also cause hypersensitivity (allergic) reactions (Sinicropi 2010).

Chronic toxicities are manifested as conditions that develop over extended periods from chronic exposure to relatively low concentrations (eg, sustained environmental exposure). Symptoms of chronic heavy metal toxicity (described later in this protocol) can be similar to other health conditions and may not be immediately recognized as intoxications. Increased cancer risk is a common feature of chronic exposure to certain metals; the exact mechanism of their carcinogenicity is not completely understood, although many are weak mutagens (cause DNA damage), can disrupt gene expression, and deregulate cell growth and development (Galanis 2009). They can also interfere with innate DNA repair systems (Koedrith 2011). In addition, certain metals may affect gene expression and alter gene function (Arita 2009; Martinez-Zamudio 2011).

The International Agency for Research on Cancer (IARC) has classified several metals based on their potential carcinogenicity to humans. Group 1 metals include arsenic and arsenic compounds, cadmium, gallium, and nickel compounds. Group 2B (possible carcinogens) include cobalt and cobalt compounds (Sinicropi 2010; Galanis 2009).

5 Common Heavy Metal Toxicants and Associated Health Risks

Mercury

Mercury has no known beneficial role in human metabolism, and its ability to affect the distribution and retention of other heavy metals makes it one of the most dangerous toxic metals (Houston 2011). Mercury toxicity can arise from ingestion of metallic mercury or mercury salts (which are generally poorly bioavailable) or by inhalation of mercury vapor (which is readily absorbed) (ATSDR 2001). The relatively high solubility and stability of certain mercury salts in water enables them to be readily taken up and biotransformed to methylmercury by certain fish; these forms are readily absorbed through the GI tract and are becoming a major source of mercury exposure in humans (Houston 2011). Dimethylmercury, a mercury compound chemically synthesized in the laboratory, can also be absorbed through the skin, and several cases of fatal exposure among laboratory workers have been reported (Nierenberg 1998; Bernhoft 2012).

Although humans can excrete small amounts of mercury in urine or feces as well as via exhalation or sweating, they lack an active robust mechanism for mercury excretion, allowing levels to accumulate with chronic exposure (Houston 2011; Sällsten 2000; Houston 2011). Mercury, particularly when inhaled as mercury vapors, can distribute to many organs, but may concentrate in the brain and kidneys (ATSDR 2001). It can also cross the placenta and be found in breast milk (Yang 1997).

Mercury exerts its toxic effects by competing with and displacing iron and copper from the active site of enzymes involved in energy production; this induces mitochondrial dysfunction and oxidative damage (Houston 2011). Mercury can also directly accelerate the oxidative destruction of cell membranes and LDL cholesterol particles as well as bind to and inactivate the cellular antioxidants N-acetyl cysteine, alpha-lipoic acid, and glutathione (Houston 2011). Because of its effect on cellular defense and energy generation, mercury can cause widespread toxicity and symptoms in several organ systems: nervous system (eg, personality changes, tremors, memory deficits, loss of coordination); cardiovascular system (eg, increased risk of arterial obstruction, hypertension, stroke, atherosclerosis, heart attacks, and increased inflammation); GI tract (eg, nausea, diarrhea, ulceration); and kidneys (failure) (Houston 2011; ATSDR 2001). Mercury may also accumulate in the thyroid and increase the risk of autoimmune disorders (Gallagher 2012), and may cause contact dermatitis (Caravati 2008).

Lead

Lead toxicity is one of the most frequently reported unintentional toxic heavy metal exposures and the leading cause of single metal toxicity in children (Bronstein 2012). Lead has no known beneficial function in human metabolism. Human environmental exposure is often through lead-containing paint, food stored in lead can liners, food stored in ceramic jars, or contaminated water (pipes cast in lead or soldered using lead solder). Inhalation of lead particulates is a primary route of occupational lead exposure, while oral ingestion is a primary form of exposure in the general population (ATSDR 2008a; Rodrigues 2010). Animal models also suggest that lead can be absorbed through the skin; lead acetate can be found in some cosmetic products (ATSDR 2008a; ATSDR 2007b). Children absorb lead up to 8-times more efficiently than adults (Abelsohn 2010). Ingestion of deteriorating lead-based paint chips or dust is the primary source of lead exposure in children (CDC 2009; Manton 2000). Also, toys and other children’s products may contain lead or be painted with lead-based paint; imported children’s products pose greater risk (Rossiter 2013; EPA 2013; Lipton 2007; DOH 2007). In 2009 and 2011, the Consumer Product Safety Commission began requiring lower lead levels in children’s products (as of 2011, allowing less than 100 ppm (parts per million) of lead in accessible parts of children’s products with some exceptions) (CPSC 2013); however, caution is still warranted. Because it mimics calcium, most absorbed lead is stored in the bones of children and adults where it can remain for decades. Conditions that cause release of calcium from the bones (fracture, pregnancy, age-related bone loss) will also release stored lead from bones, thus allowing it to enter into the blood and other organs. Lead can leave the body through feces or urine (ATSDR 2007b).

In addition to disrupting calcium metabolism, lead can mimic and displace magnesium and iron from certain enzymes that construct the building blocks of DNA (nucleotides) and disrupt the activity of zinc in the synthesis of heme (the carrier of oxygen in red blood cells) (Kirberger 2013). Chronic, low-level lead exposure (blood levels <10 µg/dL) is associated with increases in hypertension risk and reduction in kidney function. Higher levels of lead exposure affect the endocrine glands (changing the levels of thyroid hormones [at serum lead levels over 40-60 µg/dL] and reproductive hormones [at serum lead levels over 30-40 µg/dL] and lowering vitamin D levels), brain (causing conditions such as brain lesions, cognitive deficits, and behavioral changes), and can cause anemia. In children, low level (<10 µg/dL) lead exposure can result in several developmental disorders (accelerated skeletal growth, cognitive deficits and IQ decline, slowed growth and delayed sexual maturation) and higher levels (around 60-100 µg/dL) can manifest as colic (ATSDR 2007b).

Cadmium

Acute cadmium intoxication is a potentially fatal, but very rare event (Bronstein 2012); chronic exposure to cadmium presents a larger threat to human health (Thévenod 2013). Cadmium has no known beneficial role in human metabolism. Cadmium is found in soil and ocean water, and up to 10% of the cadmium ingested from dietary sources, such as food and water, is absorbed by the body. It is readily absorbed (40-60%) through the inhalation of cigarette smoke and can be absorbed through the skin. Following exposure, cadmium binds to red blood cells and is transported throughout the body where it concentrates in the liver and kidneys; significant amounts are also found in the testes, pancreas, and spleen (Sigel 2013). Cadmium is excreted slowly and may remain in the body for more than 20-30 years (Sigel 2013; Thévenod 2013). As it mimics zinc, cadmium is thought to exert its toxic activity by disrupting zinc metabolism; there are about 3000 different enzymes and structural proteins in human metabolism that require zinc for their activity and are potential targets of cadmium toxicity (Sigel 2013). Cadmium interferes with the cellular balance of zinc, and nutritional zinc or iron deficiencies can increase cadmium absorption (Sigel 2013; Thévenod 2013). Chronic cadmium exposure can result in the accumulation of cadmium complexes in the kidney (potentially leading to renal failure), decreased bone mineralization, and decreased lung function; it is also a known human carcinogen (Sigel 2013; ATSDR 2012a; ATSDR 2012b; Thévenod 2013; Sinicropi 2010).

Arsenic

Although arsenic is not technically a “heavy metal,” this metalloid (an element with both metal and non-metal chemical characteristics) nevertheless holds significant potential for adverse health outcomes.

In both 2007 and 2011, arsenic topped the Agency for Toxic Substances and Disease Registry (ATSDR) Priority List of Hazardous Substances, which ranks hazardous substances based on their frequency, toxicity, and potential for human exposure from hazardous waste sites (ATSDR 2011). It is one of the more commonly reported sources of unintentional intoxications (Bronstein 2012). Arsenic occurs naturally in the environment as both inorganic (the less abundant, more toxic form) and organic (the less toxic, more abundant form) arsenic. The most common route of exposure in humans is consumption of arsenic-containing food or drinking water. Seafood contains the highest concentrations of organic arsenic; cereals and poultry are also sources. Arsenic can also be inhaled (the predominant route for occupational exposure) or absorbed through the skin (ATSDR 2007a). Inorganic arsenic binds to hemoglobin in red blood cells once absorbed and is rapidly distributed to the liver, kidneys, heart, lungs, and to a lesser degree the nervous system, GI tract, and spleen; it can also cross the placenta (Ibrahim, Froberg 2006). Some inorganic arsenic can be converted to organic arsenic compounds in the liver (monomethylarsonic and dimethylarsinic acids) that have less acute toxicity (Ibrahim, Froberg 2006; ATSDR 2007a). Most inorganic and organic arsenic compounds are excreted by the kidneys, with a small amount retained in keratin-rich tissues (eg, nails, hair, and skin) (Ibrahim, Froberg 2006).

Arsenic binds and depletes lipoic acid in cells, interfering with the production of chemical energy (adenosine triphosphate -- ATP); it can also directly bind to and inactivate ATP (Ibrahim, Froberg 2006). Acute exposure to inorganic arsenic may cause nausea, vomiting, profuse diarrhea, arrhythmia, a decrease in red and white blood cell production, loss of blood volume (hypovolemic shock), burning or numbness in the extremities, and encephalopathy (Rusyniak 2010; ATSDR 2007a). Organic forms of arsenic have little acute toxicity compared to inorganic arsenic and arsine gas, the other two chemical forms of arsenic, which are more toxic  (Ibrahim, Froberg 2006). Chronic inorganic arsenic exposure can result in anemia, neuropathy, or liver toxicity within a few weeks to months (ATSDR 2004; Ibrahim, Froberg 2006). Longer exposure (3-7 years) can also result in characteristic skin lesions (areas of hyperpigmentation or keratin-containing lesions) on the palms and soles of the feet. Severe exposure can lead to loss of circulation to extremities, which can become necrotic and gangrenous (“black foot disease”) (Ibrahim, Froberg 2006; ATSDR 2007a). Chronic exposure to arsenic has been associated with several types of cancer (skin, lung, liver, bladder, and kidney) (Ibrahim, Froberg 2006). Chronic exposure to dimethylarsinic acid, a form of organic arsenic, may cause kidney damage (ATSDR 2007a).

Other Metals

There are several other metals with documented toxicities and varying risk of unintentional overexposure.

Iron. Iron toxicity is the most common metal toxicity worldwide (Crisponi 2013; Kontoghiorghes 2004). The classic symptom of iron overload, especially in the context of the disease hemochromatosis, is skin hyperpigmentation (to a bronze or grey color) due to deposits of iron and melanin complexes in the skin. The liver, as a primary source of iron storage, is particularly susceptible to overload and related damage (Siddique 2012). Iron toxicity is also associated with joint disease (arthropathy), arrhythmia, heart failure, increased atherosclerosis risk, and increases in the risk of liver, breast, gastrointestinal, and hematologic cancers (Araujo 1995; Nelson 1995; Sahinbegovic 2010; Ellervik 2012; Kallianpur 2004; Dongiovanni 2011; Kremastinos 2011). A comprehensive overview of iron overload is available in the Hemochromatosis protocol.

Aluminum. Aluminum is ubiquitous in nature (it is the most abundant metal in the earth’s crust) and naturally occurs in most foods and water; daily exposure through food, in most people, is 3-10 mg (Hewitt 1990; Crisponi 2013). However, occupational exposure to aluminum can cause significant toxicity, and aluminum toxicities are more frequently reported to poison control centers than are non-pesticide arsenic toxicities (Bronstein 2012). Elevated levels of aluminum in the brains of some Alzheimer’s patients is of unknown significance as to correlation and cause; data supporting the association is inconclusive, with more study required to determine if aluminum plays a causal role in Alzheimer’s disease pathogenesis (Becaria 2002; Lemire 2011; Percy 2011).

Copper. Although copper plays an important role in human nutrition, toxicity at elevated exposure has been reported. Excessive copper (through overexposure or from copper metabolism diseases like Wilson’s disease) can be neurotoxic (Wright 2007), and acute unintentional copper toxicities are more frequently reported than those of arsenic (Bronstein 2012).

Miscellaneous. Acute manganese intoxication has also been infrequently reported to U.S. poison control centers (Bronstein 2012). The release of depleted uranium into the environment (from armor-piercing ammunition) in regions like the Balkans and Middle East has been implicated in epidemics of leukemia, Kaposi sarcoma, and severe congenital defects (Shelleh 2012). ​

6 Risk Factors for Toxic Metal Exposure

Exposure of the general population to toxic metals may come from the environment or home and can be acute or chronic. It may result from contaminated food, air, water, or dust; living near a hazardous waste site or manufacturing plant that releases metal contaminants; overexposure to metal-containing pesticides, paints, or cosmetics; or improper disposal or cleanup of toxic metal-containing items (such as a broken thermometer).

Exposure risks for specific metals include:

Lead:

  • Lead-containing plumbing (lead pipes or plumbing solder; in 2007, it was estimated that less than 1% of the public water systems in the United States had lead levels above 5 µg/L) (ATSDR 2007b)
  • Lead-based paints (in buildings built before 1978; this is the predominant source for children) (EPA 2013)
  • Leaded gasoline (although banned in the United States in 1995 for automobiles, previous usage has widely dispersed it in the environment) (Miranda 2011)
  • Foods grown in lead-rich soil (ATSDR 2008a)

Mercury:

  • Eating fish or shellfish contaminated with methylmercury (the Food and Drug Administration [FDA] has set a maximum permissible level of 1 part of methylmercury in a million parts of seafood [1 ppm]) (ATSDR 2001). Ocean fish commonly high in mercury include shark, swordfish, king mackerel, and tilefish (Defilippis 2010). Levels of mercury above 1 ppm have also been found in predatory and bottom-dwelling freshwater fish (including bass, walleye, and pickerel) from mercury-contaminated waters (ATSDR 2001)
  • Breathing contaminated workplace air or skin contact during use in the workplace (certain medical and dental treatments as well as chemical or other industries that use mercury) (ATSDR 2000)
  • Release of mercury vapor from dental amalgam fillings (although the FDA deems amalgam fillings safe) (Bernhoft 2012; Jang 2011; Rusyniak 2010; FDA 2009)
  • Contact with elemental mercury from the following household devices: thermometers (the amount of elemental mercury from a broken thermometer spilled in a small, enclosed space can cause systemic toxicity if not properly cleaned up), fluorescent and mercury vapor lamps, thermostats, manometers/barometers, and wall switches manufactured before 1991 (Caravati 2008)
  • Skin-lightening products and antiseptics that contain mercury salts (Park 2012)

Arsenic:

  • Groundwater near arsenic-containing mineral ores
  • Wood preservatives (found in treated wood products manufactured before 2004) and antifouling paints
  • Some insecticides, herbicides (weed killers and defoliants), fungicides, cotton desiccants, paints and pigments
  • Seafood (shellfish, certain cold water and bottom-feeding finfish, and seaweed contain organic arsenic compounds with low acute toxicity) (ATSDR 2007a)

Cadmium:

  • Tobacco smoke (cadmium can concentrate in tobacco leaves)
  • Eating foods containing cadmium (levels are highest in grains, legumes, and leafy vegetables, and cadmium can bioaccumulate in fish and shellfish)
  • Contact with cadmium from household products (electric batteries and solar panels) (Nogué 2004; ATSDR 2012a)

7 Signs, Symptoms, and Diagnosis

Signs and Symptoms

Heavy metal toxicity can cause a variety of signs and symptoms. While manifestations of toxicity vary among the many toxic metals, several symptoms are often observed and may be indicative of heavy metal toxicity (Adal 2013):

  • Nausea
  • Vomiting
  • Diarrhea
  • Abdominal pain
  • Central nervous system dysfunction
  • Heart problems
  • Anemia
  • Fingernail or toenail discoloration (Mee’s lines; usually appearing as white stripes running horizontally across the nails)

Acute metal toxicity can be a life-threatening medical emergency that may require aggressive treatment in a hospital setting. If you suspect you have been exposed to a toxic metal, seek medical attention immediately.

Diagnosis

Diagnosing metal toxicities can be difficult; the symptoms and consequences of many, especially chronic toxicities, are non-specific and may resemble other diseases. A careful analysis of dietary, environmental, and occupational exposure history is one of the most important tools in evaluating a potential metal toxicity (Vearrier 2010). Metal testing can be an important aid to confirm or rule out a diagnosis of metal toxicity. Some metal tests include:

Blood testing. Commercial blood tests are available for many metals (universally toxic metals, such as lead and mercury, as well as essential metals that are toxic above certain thresholds, such as iron or copper). Blood levels of cadmium and lead are usually indicative of recent exposures and may not reflect whole body burdens (ATSDR 2007b; ATSDR 2012b). For example, in the case of lead, blood levels are only indicative of exposure over the previous 90 days (ATSDR 2007b). In the case of arsenic, which is cleared rapidly from the blood, blood tests may only be reliable during early stages of intoxication (< 7-10 days after exposure) (Rusyniak 2010). There is a poor correlation between blood levels and exposure for aluminum (ATSDR 2008b). Reference ranges for individual tests depend on the laboratory performing the analysis.

Urine testing. Because of differences in the rates of excretion for toxic metals, urine tests are indicative of cumulative exposure/total body burden for some metals (eg, cadmium) and recent exposure for others (eg, mercury) (ATSDR 2001; ATSDR 2012b). Urinary arsenic can be elevated following seafood consumption, limiting its diagnostic value in some cases (ATSDR 2007a). Post-challenge or post-provocation urine tests, which involve the measurement of urine metal concentrations following administration of a chelator, may reveal sources of stored toxic metals. However, since there are no broadly accepted reference ranges for urine metals determined by this technique, these tests are likely of limited diagnostic value and are not validated (Vearrier 2010; American College of Medical Toxicology 2010). Reference ranges for individual tests depend on the laboratory performing the analysis.

Hair and nail analysis. Hair and nail analysis can be used to determine cumulative exposure to cadmium, lead, arsenic, and methylmercury. While reliable for large body burdens, it may not be sensitive enough to resolve differences in lower exposures; it is also sensitive to external contamination (Suzuki 1989; Hughes 2006).

X-ray fluorescence (XRF). XRF is a non-invasive technique for assessing tissue deposits of metals (cumulative exposure). It can be used to detect cadmium in kidneys and lead in bones (Nilsson 1995; ATSDR 2007b). XRF is not a widely available technique.

8 Conventional Treatment

Removal of Exposure Source

The first step in mitigating the toxic effects of acute or chronic metal exposure is removal of the source of contamination. For acute exposures, this may involve (depending on the route of exposure) decontaminating the area of exposure, removing contaminated clothing, and/or removing the individual from the area where exposure occurred (Flora 2010).

Gastrointestinal Decontamination

Gastrointestinal decontamination techniques may be indicated for acute metal toxicities, although studies on their efficacy for this purpose are lacking and few consensus guidelines exist for their use in acute metal toxicity treatment. Gastric lavage (introduction of water into the stomach by a tube to wash out its contents) has been used in arsenic and lead poisonings (Tallis 1989; Rusyniak 2010; ATSDR 2007b; Caravati 2008). Emesis (induced vomiting) has also been suggested for removing metals within the stomach; however, some caustic metal compounds (mercuric oxide) may cause further damage by induced vomiting (ATSDR 2001), and emesis is not always effective for removing large amounts of solids (Manoguerra 2005). Bowel irrigation (introduction of water into the bowel to wash out its contents) may be useful for macroscopic particles of some metals (such as lead) that can easily transit through the intestines; larger particles may require surgery for removal (Roberge 1992; Rusyniak 2010; ATSDR 2007b). Activated charcoal may be effective for binding some ingested toxic metals or metal compounds (arsenic, thallium) but is ineffective for others (iron and mercury) (Worth 1984; Bateman 1999; Rusyniak 2002; Hoffman 2003; Rusyniak 2010; Manoguerra 2005).

Chelation Therapy

Chelators enhance the elimination of metals (both toxic and essential) from the body. Their use to ameliorate metal toxicity has been validated by several human case reports and animal models. They are most often used in cases of acute intoxications; the efficacy of chelation therapy in chronic metal intoxication is less clear, as chelation therapies are more effective when administered close to the time of exposure (Jang 2011). The decision to chelate should be made by professionals with experience using chelation therapy, preferably in consultation with a poison control center or medical toxicologist (Adal 2013).

Chelators currently used in the United States include:

Dimercaprol (BAL). BAL is indicated for the treatment of acute lead encephalopathy in children and adults as well as acute inorganic arsenic or mercury toxicosis. It has also been used for chronic arsenic toxicity, but currently there are no guidelines to evaluate its effectiveness (ATSDR 2004; Jang 2011). BAL is given by intramuscular injection, often several times per day for a period of 5-10 days. Side effects include vomiting, excess salivation, watery eyes, runny nose, injection site pain, and possible chelation of essential trace metals if given for extended periods (Jang 2011).

DMPS. DMPS, an analog of dimercaprol (Bernhoft 2012), is an oral medication studied for arsenic and cadmium chelation in animal models (Aposhian 1984; Patrick 2003) and mercury chelation in mine workers (Bernhoft 2012). The dosage used in the human trial was 400 mg/day for 14 days. At the end of two weeks, DMPS significantly increased urinary excretion of mercury and improved toxicity symptoms; however, it did not alter blood mercury levels. Allergic rash was the only side effect noted.

Succimer (DMSA). DMSA is an oral medication used to treat mild-moderate lead toxicosis (acute or chronic) in children and adults as well as acute arsenic or mercury intoxication. For both lead and mercury intoxication in adults, DMSA is dosed at 10 mg/kg three times daily for 5 days, followed by 10mg/kg twice daily for 14 days. Side effects are mostly gastrointestinal (diarrhea and vomiting), metallic taste, and mild increase in liver enzymes; rash, chills, and decreased white cell counts have also (rarely) been reported (Jang 2011).

Prussian blue. Prussian blue is an oral chelator for thallium or cesium poisoning in adults and children; it is dosed 3 times per day. Side effects include constipation, abdominal pain, and a blue color of the stool (Jang 2011).

EDTA. Calcium-disodium EDTA is used to treat lead encephalopathy and moderate lead poisoning (Jang 2011; Born 2013). It is given by slow, continuous intravenous infusion. Side effects include malaise, headache, fatigue, chills or fever, myalgia, anorexia, nasal congestion, watery eyes, anemia, transient hypotension, clotting abnormalities, and kidney failure (Jang 2011). EDTA, particularly after prolonged treatment, can also chelate essential trace metals, such as zinc, copper, and manganese (Flora 2010). Sodium EDTA (without calcium) can cause life-threatening hypocalcemia (Brown 2006).

Penicillamine (Cuprimine®). Penicillamine has been used as an oral treatment for lead, mercury, and copper poisoning; its use has fallen out of favor due to its potential for serious complications, which include allergic reactions (seen particularly in people allergic to penicillin), a severe form of anemia, severe lowering of white blood cell counts, and kidney failure (Jang 2011).

Iron chelators. There are several iron chelators that have found use in the treatment of metabolic iron overload (hemochromatosis) as well as acute iron intoxication (such as iron supplement overdose). Deferoxamine mesylate (Desferal®) is an injectable iron chelator that can remove iron from abnormal tissue stores but not sites of active metabolic iron usage (such as transferrin or hemoglobin) (Sinicropi 2010). Side effects include skin rash, hypotension, respiratory distress, and eye/ear toxicity; acute neurological toxicity is also possible (Crisponi 2013; Sinicropi 2010). Oral iron chelators include Deferiprone (Ferriprox®) and Deferasirox (Exjade®). They have better distribution than deferoxamine, which also increases their toxicity (Heli 2011). Long term (6-month) deferoxamine treatment has been used to treat aluminum intoxication (Sinicropi 2010) and aluminum-related osteomalacia (Crisponi 2013).

9 Novel and Emerging Therapies

Toxicogenomics. While elevated blood levels of metals are associated with adverse health outcomes, they are not necessarily indicative of clinical metal toxicity. Similarly, metal toxicities can occur in some individuals below levels that are predicted to be “safe.” Toxicogenomics, the study of gene expression changes by toxin exposure, may prove to be a useful tool for more sensitive and quick metal toxicity assessment. Several laboratories have already identified specific gene expression patterns in specific tissues arising from environmentally significant toxic metals (such as decreased expression of cytochrome P450 detoxification enzymes in response to arsenic exposure or induction of protective heat shock proteins by cadmium) (Yoon 2008).

New chelation therapies. Current chelation therapy uses chemical chelators that have several adverse effects, such as kidney overload, cardiac arrest, mineral deficiency, and anemia. This has motivated the search for safer heavy metal chelators, which have desirable properties, high specificity for metal toxins, and low affinity for nutritionally essential metals. Interesting candidates include polygamma-glutamic acid-coated superparamagnetic nanoparticles (Inbaraj 2012) and magnetic chitosan/graphene oxide composites (Fan 2013), which are both highly selective for lead. Magnetic chelators have the additional advantage that they can be magnetically directed to specific organs of interest (Inbaraj 2012).

10 Lifestyle Management for Reducing Metal Toxicity Risk

Maintain Good Occupational Hygiene

Occupational exposure can be reduced by modifying manufacturing processes to reduce worker contact with metal toxins, collecting and removing fumes, following proper hazardous waste management procedures, and substituting with safer materials/procedures when possible. In most countries, regulations limit employee exposure to toxins and establish worker and workplace health surveillance guidelines. Individuals can be proactive by learning about substances they are coming in contact with, limiting exposure by following safety procedures and wearing the required personal protective equipment, practicing proper skin and hand hygiene, and properly decontaminating before leaving the workplace (Coppotelli 2012).

Reduce General Exposure

Exposure to metal toxins can also be reduced by understanding the sources of metal exposure (see the section on risk factors) and adopting strategies to reduce contact with them. First, become familiar with symptoms of toxicity and first aid procedures for ingestion of substances containing toxic metals (Barsan 2008). Next, read product labels and know the potential hazards of products. Third, take advantage of established disposal programs and facilities for discarding metal-containing waste. Finally, avoid mercury amalgam dental fillings to reduce mercury exposure, especially when multiple fillings are needed. In one study, individuals with 7 or more mercury fillings had 30-50% higher urinary mercury levels compared to individuals without any amalgam fillings (Dutton 2013). Since studies have shown that exposure to mercury via dental amalgam fillings poses health risks (Geier 2013), removing and replacing existing dental fillings with mercury-free composite material should be considered. Individuals seeking to have their mercury amalgam fillings removed and replaced should seek out a dentist experienced in this procedure, as mercury vapor levels can rise in the surrounding environment if proper procedures are not followed during their removal, potentially exposing both the patient and dental staff to excessive mercury (Warwick 2013).

11 Integrative Interventions

In addition to the integrative interventions outlined in this protocol, readers are encouraged to review the Metabolic Detoxification protocol, as ensuring that the body’s general intrinsic detoxification pathways are functioning optimally may help avoid heavy metal accumulation and toxicity.

Several dietary constituents have been investigated for their ability to mitigate metal toxicity. They work by reducing or inhibiting metal absorption from the gut, binding up toxic metals in the blood and tissues to help draw them out of the body, or reducing free-radical damage (a significant contributor to the pathology caused by heavy metals). Most studies have been limited to animal and cell culture models, although the results of human studies have been encouraging.

For additional information on nutritional strategies to address iron toxicity, refer to Life Extension’s Hemochromatosis protocol.

Maintain Nutrient Sufficiency

Since many toxic metals mimic nutritionally essential metals, they compete for the same transport mechanisms for absorption from the intestines and uptake into cells. Therefore, adequate intake of essential trace minerals may reduce toxic metal uptake. For example, nutritional zinc or iron deficiency can increase cadmium absorption (Thévenod 2013), and lead absorption from the gut appears to be blocked by calcium, iron, and zinc (ATSDR 2007b; Patrick 2006). In animal models, selenium blocks the effects of lead when administered before exposure and reduces mercury toxicity (Patrick 2006). It also increases its excretion in humans (Li 2012; Zwolak 2012).

Choose Fish Oil Supplements over High-Mercury Fish

Most toxicology data support the recommendation, in non-pregnant adults, to limit consumption of high-mercury fish (shark, swordfish, king mackerel, tilefish) to no more than one serving (7 oz.) per week. The Environmental Protection Agency recommends that pregnant women, nursing mothers, and young children avoid eating high-mercury fish because the fetal brain is more sensitive to mercury toxicity than the adult brain (Defilippis 2010). High-quality fish oil supplements represent a good alternative source of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) (Foran 2003).

The International Fish Oil Standards Program (IFOS) is an organization dedicated to differentiating high-quality fish oil products from those of lesser quality. In order to ensure your fish oil supplement does not contain dangerous concentrations of contaminants such as heavy metals, check the label to ensure your fish oil supplement achieves the rigorous IFOS 5-star rating (IFOS 2013).

Selenium

In addition to its role as a possible competitive inhibitor of mercury and lead absorption, selenium also increases toxic metal excretion. Moderate (100 mcg/day) increases in dietary selenium increased urinary excretion of stored mercury in long-term mercury-exposed Chinese residents (Li 2012), and 100-200 mcg/day reduced blood and hair levels of arsenic in Chinese farmers with arsenic poisoning (Zwolak 2012). Selenium also appears to mitigate the toxicity of some heavy metals, such as cadmium, thallium, inorganic mercury, and methylmercury, by modulating their interaction with certain biomolecules (Whanger 1992). In another study, supplementation with 100 mcg of selenium (in the form of selenomethionine) daily for 4 months led to a 34% reduction in levels of mercury detected in body hair. The authors of the study concluded that “… mercury accumulation in [… body] hair can be reduced by dietary supplementation with small daily amounts of organic selenium in a short range of time” (Seppanen 2000).

Modified Citrus Pectin

Three studies have investigated the use of modified citrus pectin (MCP) on the mobilization of metals from body stores. In the first, 8 healthy individuals were given 15 g of MCP daily for 5 days and 20 g of MCP on day 6. Significant increases in urinary excretion of arsenic, mercury, cadmium, and lead occurred within 1 to 6 days of MCP treatment. There was a 150% increase in cadmium excretion and a 560% increase in lead excretion on day 6 (Eliaz 2006). Essential minerals such as calcium, zinc, and magnesium were not noted to increase in the urinary analysis. Second, in a series of case reports, 5 patients with different illnesses took MCP alone or in combination with alginate for up to 8 months. The patients showed a 74% average decrease in toxic heavy metals after treatment (Eliaz 2007). In a third trial, 7 children with blood lead levels >20 µg/dL received 15 g/day of MCP for 2 to 4 weeks. Blood lead levels dropped an average of 161%, and urinary lead excretion increased by an average of 132% (Zhao 2008).

Silicon

Data from preliminary human studies reveal that naturally-occurring dissolved silicon from mineral waters appears to antagonize the metabolism of aluminum, potentially reduce Alzheimer's risk, and support cognitive function (Gillette Guyonnet 2007). In human subjects, soluble silicon (orthosilicic acid) decreases aluminum absorption from the digestive tract and decreases its accumulation in the brain (Jurkic 2013). In one study, Alzheimer’s patients drank up to 1 L of mineral water daily (containing up to 35 mg of silicon/L) for 12 weeks. Over the study period, urinary excretion of aluminum increased without affecting urinary excretion of the essential metals iron and copper. In addition, there was a clinically relevant improvement in cognitive performance in at least 3 out of 15 individuals (Davenward 2013).

Another source of orthosilicic acid studied for their metal reducing properties are compounds called zeolites. Zeolites are aluminum/silicon oxide-based crystalline compounds with adsorbent properties that have broad industrial applications and are finding applications in medicine (Montinaro 2013; Beltcheva 2012). Inclusion of zeolite (as the zeolite clinoptilolite) in high-lead diets of laboratory mice reduced tissue lead concentration by 77-91%, increased the percentage of healthy red blood cells, and reduced chromosomal damage (Topashka-Ancheva 2012; Beltcheva 2012). A clinical study on 33 men evaluated the ability of the zeolite clinoptilolite to increase heavy metal urinary excretion (Flowers 2009). To be included in the trial the men had to test positive, above a predetermined threshold, for at least four of the nine metals in a urinary test panel (ie, aluminum, antimony, arsenic, bismuth, cadmium, lead, mercury, nickel, and tin). The men were given either 15 drops of a clinoptilolite water suspension or placebo suspension twice daily for a maximum of 30 days. Significant increases in the urinary excretion of all 9 metals were observed in the men taking clinoptilolite as compared to placebo without a negative impact on electrolyte profiles. It has been hypothesized that the biological activity of some zeolites may be attributed to their orthosilicic acid releasing properties (ie, they are a source of orthosilicic acid) (Jurkic 2013).

Vitamin C

Vitamin C is a free-radical scavenger that can protect against oxidative damage caused by lead (Patrick 2006), mercury (Xu 2007), and cadmium (Ji 2012); it may prevent the absorption of lead as well as inhibit its cellular uptake and decrease its cellular toxicity (Patrick 2006). Observational data suggest an inverse relationship between serum levels of ascorbic acid and blood levels of lead; in other words, the higher the blood levels of vitamin C the lower those of lead (Simon 1999). Vitamin C supplementation (500 mg/day) in 12 silver refiners with high blood lead levels (mean of 32.8 µg/dL) demonstrated a 34% reduction in lead levels after 1 month (Tandon 2001). In a small study of 75 male smokers, vitamin C (1000 mg/day) reduced blood lead levels by 81% after one week of supplementation. Lower dose vitamin C (200 mg/day) had no effect (Dawson 1999).

Vitamin E

Through its antioxidant action, vitamin E mitigates some of the toxic damage caused by heavy metals, which are strong inducers of oxidative stress in tissues. In one study, rats were fed a diet containing lead acetate and subsequently developed sings of toxicity such as oxidative damage to lipids and alterations in blood chemistry parameters. When either vitamin E or garlic oil were administered in conjunction with the lead, the toxic effects were ameliorated. The researchers who conducted the study noted that the protective effect of vitamin E was probably due to its ability to support detoxification and scavenge tissue-damaging free radicals (Sajitha 2010). In another animal study, one group of mice were given toxic heavy metals (lead, mercury, cadmium, and copper) in their drinking water for 7 weeks, while another group underwent the same treatment but, in addition, received vitamin E five times weekly. The scientists found that the mice not receiving vitamin E exhibited evidence of oxidative injury to their kidneys and testis, whereas those organs appeared normal in mice receiving vitamin E. Also, the mice not receiving vitamin E showed changes in plasma levels of creatinine, urea, and uric acid while these blood parameters did not change significantly in the vitamin E group (Al-Attar 2011). Vitamin E has also been shown to counter the deleterious effects of heavy metals in humans. In several groups of workers regularly exposed to airborne heavy metal toxicity due to the nature of their work, daily supplementation with 800 mg vitamin E and 500 mg vitamin C for 6 months led to improved markers of intrinsic antioxidant defenses and decreased markers of oxidative damage. In fact, following the period of supplementation, the activity of certain intrinsic antioxidant systems reached levels comparable to those observed in control subjects not exposed to the toxicants (Wilhelm Filho 2010).

Folate

Folic acid is a cofactor in sulfur-containing amino acid metabolism. Sulfur-containing amino acids (cysteine and methionine) are precursors to known heavy metal chelators (alpha-lipoic acid and glutathione). In a study of 1105 pregnant women, 841 of which were followed through late pregnancy or delivery, higher blood folate levels were associated with lower blood mercury levels during mid- and late-pregnancy (Kim 2013). A similar study in Australia on 173 pregnant non-smokers demonstrated that the failure to use folic acid or iron supplements during pregnancy was associated with higher blood cadmium levels (Hinwood 2013).

Garlic

Garlic contains many active sulfur compounds derived from cysteine with potential metal-chelating properties; these garlic constituents may also protect from metal-catalyzed oxidative damage. Rats fed garlic as 7% of their diet (either a week before, after, or during exposure to heavy metal toxins) for 6 weeks demonstrated significantly reduced lead, cadmium, or mercury accumulation in their livers (Nwokocha 2012). Garlic treatment also reduced the frequency of metal-related lesions in the livers of rats in the same study. Garlic may also increase the bioaccessibility of iron and zinc (both antagonists of cadmium and lead absorption) from dietary cereal grains (Gautam 2010). In a study of 117 car battery industry workers with occupational lead poisoning, garlic (1200 mg dried powder) daily for 4 weeks lowered blood lead as effectively as D-penicillamine (by approximately 18%). Additionally, treatment with garlic showed less adverse effects and more clinical improvement as compared to D-penicillamine (Kianoush 2012).

Cilantro

Cilantro (Coriandrum sativum) can bind and immobilize mercury and methylmercury from contaminated water  (Karunasagar 2005). In mouse models, cilantro suspensions significantly reduced the deposition of lead into bones and reduced microscopic signs of lead-induced kidney and testicular damage (Aga 2001; Sharma 2010). In a case report, a patient exposed to mercury during amalgam-based dental filling removal developed adverse effects, including abnormal ECG readings, which reverted almost back to normal by the administration of 400 mg/day of cilantro extract prior to and after removal for 2-3 weeks. Mercury deposits were reported to be absent following treatment, although the details of the treatment and mercury analysis in this report are unclear (Omura 1996).

Alpha-Lipoic Acid and Glutathione

Sulfur-containing compounds can complex with heavy metals, and the sulfur antioxidants alpha-lipoic acid (ALA) and glutathione have been demonstrated to chelate a number of metals in cell culture (mercury for glutathione; cadmium, lead, zinc, cobalt, nickel, iron, and copper for ALA) (Patrick 2002). In a rat model, ALA and glutathione reduced some of the adverse changes in blood parameters, including drops in red blood cell number and size as well as reductions in hemoglobin concentration brought about by intoxication with lead, cadmium, or copper (Nikolic 2013). ALA and glutathione in a rat model both reduced cadmium-associated oxidative stress and improved the activity of the antioxidant enzyme catalase in kidney tissue (Veljkovic 2012).

N-Acetyl Cysteine

N-acetyl cysteine (NAC) provides a source of sulfur for glutathione production and is effective at reducing oxidative stress due to heavy metal toxicity (Patrick 2006). As a sulfur-containing amino acid, it possesses two potential binding sites for metals and is capable of binding and sequestering divalent copper (II), trivalent iron (III), lead, mercury, and cadmium ions (Samuni 2013). Chronic exposure to toxic metals can decrease cysteine levels (Quig 1998). In animal models and cell culture experiments, NAC enhanced renal excretion of lead (Pb IV), lowered concentrations of mercury, and protected against cadmium-induced liver cell damage (Samuni 2013). Cysteine may also be useful as part of a complete protein (such as a whey protein), which provides additional essential amino acids that may block the entry of metals into nervous tissue (Quig 1998).

Glycine

Glycine is a conditionally essential amino acid found in plant and animal proteins. Chemically, glycine is the simplest of all amino acids. It combines with many toxic substances and converts them to less harmful forms, which are then excreted from the body. Glycine is also involved in the body’s natural synthesis of glutathione (Ruiz-Ramirez 2014), which itself is an important detoxifier of heavy metals (Patrick 2002). In a study of “Stronger Neo-Minophagen C,” a Japanese drug containing glycine, glycyrrhizin, and cysteine, which is said to be protective against chronic cadmium toxicity, the authors concluded that the reported beneficial effects were due to glycine. Glycine appeared to reduce the oxidative stress of chronic cadmium toxicity (Shaikh 1999).

Probiotics

Among their myriad functions, certain strains of probiotic bacteria may minimize toxin exposure by trapping and metabolizing xenobiotics or heavy metals. The probiotic bacterial strains Lactobacillus rhamnosus (LC-705 and GG), Lactobacillus plantarum (CCFM8661 and CCFM8610), and Bifidobacterium breve Bbi 99/E8 were all shown to bind both cadmium and lead in laboratory studies (Ibrahim, Halttunen 2006; Halttunen 2008). Binding was observed for both live and heat-killed cultures of LC-705. However, the efficiency of heavy metal binding by probiotics may decrease when multiple strains are combined (Halttunen 2008). In mouse models, two different Lactobacillus plantarum strains reduced tissue accumulation of cadmium and lead and protected against oxidative stress (Zhai 2013; Tian 2012).

Chlorella

Chlorella, a unicellular green algae with the ability to bind cadmium (in animal models) and zinc, copper, and lead (in vitro), has been used to detoxify wastewater of metal contaminants (Almaguer Cantu 2008; Shim 2008; Uchikawa 2010). In preclinical studies, chlorella lowered the bioavailability and accelerated the excretion of methylmercury (Uchikawa 2010) as well as cadmium (Shim 2009) and reduced lead-induced bone marrow toxicity (Queiroz 2011).

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