Toxic Metals: Mechanisms and Health Effects

Background

• Many metals have been reported to produce toxicity in humans
• Major toxic metals include lead and cadmium
• Essential metals include zinc and copper
• Medicinal metals include platinum and bismuth
• Minor toxic metals include indium and uranium
• Toxic metalloids include arsenic and antimony
• Non-metallic elemental toxicants include selenium

Metals as Toxicants

• Metals are naturally occurring and ubiquitous in the human environment
• Human exposure to metals is unavoidable
• Metals cannot be created nor destroyed
• Human activities have influenced environmental levels of metals in air, water, soil, and food
• Metals are non-biodegradable, and their bioaccumulation causes concern

Chemical Mechanisms of Metal Toxicity

• Cells presents metal binding ligands
• Inhibition of biologically critical enzymes is an important molecular mechanism of metal toxicity
• Metals can mimic essential ones and bind to reserved physiological sites
• Mimicry or replacement of zinc can happen with cadmium, cooper, and nickel
• Metals can act as catalysts for redox reactions and cause oxidative modification of biomolecules, leading to carcinogenicity
• Metal mediated oxidative damage is key in metal toxicology
• Carbon and sulfur-based radicals may also occur
• Metals in their ionic form can be reactive, forming DNA and protein adducts
• Metals can induce aberrant gene expression which produces adverse effects

Factors Impacting Metal Toxicity

• Exposure-related factors include dose, route, duration, and frequency of exposure
• Host-based factors include age, gender, and capacity or biotransformation
• Younger subjects are often more sensitive to metal intoxication, such as neurotoxicity of lead in children
• The exposure pathway to toxic metals in children is food
• Children have higher gastrointestinal absorption of metals, like lead
• Elderly persons are generally more susceptible to metal toxicity
• Smoking or alcohol ingestion may impact metal intoxication levels

Molecular Responses to Metal Exposure

• Exposure to high levels of essential and nonessential metals induces intracellular damage
• The damage includes oxidative stress that leads to lipid peroxidation, protein denaturation, DNA damage, and organelle dysfunction
• Elevated metal exposure can disrupt the function of proteins by binding directly or displacing metals in metalloproteins
• Metal exposure is associated with increased expression of genes that encode proteins to:
  • Remove the metal from the cell via chelation or exporting
  • Reduce the level of oxidative stress
  • Repair metal-induced intracellular damage

Metal-Binding Proteins and Metal Transporters

• Protein binding of metals is critical for essential and toxic metal metabolism
• Proteins play roles in the disposition of metals
• Non-specific binding proteins like serum albumin or hemoglobin aid in metal transport and tissue distribution
• Specific metal-binding proteins facilitate trafficking of essential metals
• Toxic metals can interact with metal-binding proteins through mimicry
• Metallothioneins are known metal-binding proteins with thiol ligands for high affinity binding sites for zinc, cadmium, copper and mercury
• Transferrin is a glycoprotein that binds ferric iron in plasma and transports iron across cell membranes, while also transporting aluminum and manganese
• Ferritin is primarily an iron storage protein to detoxify cadmium, zinc, beryllium, and aluminum
• Ceruloplasmin is a copper-containing glycoprotein oxidase in plasma that converts ferrous iron to ferric iron, and promotes iron uptake

Major Toxic Metals

• Occupational arsenic exposure occurs in the manufacturing of pesticides, herbicides, and agricultural products
• High arsenic exposure occurs in smelting industries
• Environmental arsenic exposure comes from drinking water, burning arsenic-dense coal, and seafood

Toxicokinetics of Arsenic

• Inorganic arsenic is absorbed from the gastrointestinal tract at (80-90%)
• Absorbed arsenic is distributed throughout the body, metabolized by methylation, and excreted in urine
• Low solubility arsenic compounds are absorbed less efficiently after oral exposure
• Arsenic is excreted by desquamation of the skin, in sweat, and concentrates in fingernails and hair
• Arsenic exposure produces white bands across fingernails after six weeks, known as Mees' line used as a biomarker

Toxicity of Arsenic

• Acute arsenic poisoning can be fatal with ingestion of large doses (70-180mg)
• Acute poisoning may result in fever, anorexia, hepatomegaly, melanosis, cardiac arrhythmia, and cardiac failure
• Acute arsenic ingestion damages mucous membranes of the gastrointestinal tract causing irritation, vesicle formation, and sloughing
• Sensory loss in the peripheral nervous system occurs
• High-dose arsenic exposure induces anemia and leucopenia that are reversible

Toxicity of Arsenic - Chronic

• Skin is a major target organ
• Skin cancer is prevalent with high arsenical exposure
• Liver injury, jaundice, abdominal pain, and hepatomegaly may progress to cirrhosis and hepatocellular carcinoma
• Low arsenic levels can induce peripheral neuropathy
• Peripheral vascular disease presents with chronic arsenic through drinking water

Mechanisms of Arsenic Toxicity

• Trivalent compounds of arsenic are thiol-reactive
• Trivalent compounds inhibit enzymes or alter proteins by reacting with proteinaceous thiol groups
• Pentavalent arsenate is an uncoupler of mitochondrial oxidative phosphorylation
• Pentavalent arsenate mechanism is like to arsenate competing with phosphate to forming adenosine triphosphate
• Arsenic produces oxidants and oxidative DNA damage
• Arsenic alters DNA methylation status, genomic instability, impairs DNA damage repair, and enhances cell proliferation

Cadmium Toxicity

• Around 75% of cadmium is used in nickel-cadmium batteries
• The noncorrosive properties of cadmium are used in electroplating or galvanizing alloys for corrosion resistance
• Cadmium is a color pigment for paints and plastics
• Cadmium is a produced as a by-product of zinc and lead smelting

Sources of Cadmium Exposure

• Food is the major source of cadmium
• Plants accumulate cadmium through soil, fertilizers, and cadmium-containing water for irrigation
• Shellfish and animal liver and kidneys accumulate cadmium
• Air from cigarette smoke contaminates through inhalation

Acute Cadmium Toxicity

• Ingestion of high cadmium concentrations causes severe irritation to the gastrointestinal epithelium, leading to nausea, vomiting, and abdominal pain
• Inhalation of cadmium fumes can produce acute pneumonitis with pulmonary edema

Cadmium Toxicity - Long Term

• Major long-term toxic effects of cadmium include renal injury, obstructive pulmonary disease, osteoporosis, and cardiovascular disease
• Cancer is primarily a concern for occupationally exposed groups
• Chronic effects of cadmium are of greater concern than acute toxic exposures

Lead Toxicity

• Lead-containing paint is a primary source of lead exposure in children
• Hand-to-mouth transfer of paint chips and dust from older housing is the major environmental source of lead for infants and toddlers
• Lead in household dust can come from outside the home from soil
• Food and water are routes of exposure for the general population
• Dietary intake of lead has decreased in recent years.

Mercury Toxicity

• Inhalation of mercury vapor produces corrosive bronchitis and interstitial pneumonitis
• Mercury vapor inhalation can be associated with central nervous system effects such as tremor or excitability
• Asthenic-vegetative syndrome or micromercurialism include neurasthenic symptoms, tremor, enlargement of the thyroid, elevated radioiodine uptake, labile pulse, tachycardia, dermographism, gingivitis, hematologic changes, or increased mercury in urine
• Kidney is the major target organ to inorganic mercury
• High dose mercuric chloride is directly toxic to renal tubular cells
• Chronic mercury exposure induces immunologic glomerular disease which leads to proteinuria that is reversible after removing exposure
• Methyl mercury produces neurotoxicity which results in paresthesia, ataxia, difficulty in swallowing and articulating words as clinical manifestations
• Methyl mercury poisoning can have symptoms such as neurasthenia, vision and hearing loss, and spasticity and tremors
• Methyl mercury poisoning leads to coma, death, and cerebral edema

Mechanism of Toxicity Mercury

• High-affinity binding of divalent mercury to sulfhydryl groups of proteins in the cells produces nonspecific cell injury and death
• Mercury increases genes associated with oxidative stress, reduces glutathione levels, disrupts microtubules in neuritis, damages mitochondria, and disrupts intracellular calcium homeostasis

Nickel Toxicity

• Nickel-induced contact dermatitis is common and affects 10%-20% of general population
• Nickel-induced contact dermatitis results from exposure to airborne nickel, liquid nickel solutions, or metal items containing nickel
• Nickel Carbonyl Poisoning results with metallic nickel combines with carbon monoxide
• Nickel carbonyl is extremely toxic
• Nickel carbonyl poisoning leads to headache, nausea, vomiting, epigastric pain, cough, hyperpnea, cyanosis, gastrointestinal symptoms. and weakness
• Nickel carbonyl poisoning can cause fever, leukocytosis, pneumonia, respiratory failure, cerebral edema and death
• Nickel is a respiratory tract carcinogen in nickel refining industry workers with higher risk to nasal and pulmonary cancer with nickel sulfide, nickel oxide and metallic nickel

Essential Metals with Potential for Toxicity

• Included in essential metals: cobalt, copper, iron, magnesium, manganese, molybdenum, selenium, and zinc
• Essential metals can all produce target organ toxicity

Copper Toxicity

• Food, beverages, and drinking water are major sources of population exposure
• Industrial copper exposure is from inhaled particulates in mining, smelting operations, and welding
• Excess oral copper intake causes gastrointestinal distress with nausea, vomiting, and abdominal pain
• Drinking solutions of copper sulfate or beverages in containers with copper can cause toxic effect
• Drinking water with > 3 mg Cu/L will produce gastrointestinal symptoms
• Copper salts, copper sulfate ingestion, can produce hepatic necrosis and death

Iron Toxicity

• Is an essential metal that is a key component of hemoglobin, myoglobin, heme enzymes, metalloflavoprotein enzymes, and mitochondrial enzymes
• Iron exists as ferrous (+2) and ferric (+3) forms
• Iron is considered in circumstances of iron deficiency, accidental acute exposures, and chronic iron overload from dietary or blood transfusions
• Acute iron poisoning is from iron-containing dietary supplements
• Iron toxicity occurs after ingestion of more than 0.5 g o or 2.5 g of ferrous sulfate which induce symptoms like abdominal pain, diarrhea, and vomiting occuring at 1-6h after ingestion
• Severe iron poisoning can result in pallor, cyanosis, metabolic acidosis, and cardiac collapse, and death is possible in severely poisoned children within 24 hours

Zinc Toxicity

• Zinc deficiency has severe health consequences
• Zinc toxicity is relatively uncommon and occurs at very high exposure levels
• Zinc is present in most foodstuffs, water, and air
• Occupational exposure of Zinc is through metallic zinc mining and smelting
• Zinc content in substances in contact with galvanized copper or plastic pipes may be high
• Zinc toxicity gastrointestinal distress and diarrhea have been reported after beverage ingestion while Beverages stand in galvanized cans causing Toxicity
• Zinc oxide inhalation creates "metal fume fever", characterized by fever, chest pain, chills, cough, dyspnea, nausea, muscle soreness, fatigue, and leukocytosis
• Military use of "smoke bombs" with Zinc chloride cause pronounced damage to mucous membrane
• Long-term exposure to lower doses of zinc causes copper deficiency with symptoms such as decreased erythrocyte number or hematocrit.