Metals play a crucial role in toxicology, with some being essential for life and others posing serious health risks. This topic explores the properties, exposure routes, and biological interactions of metals in the body, from absorption to excretion.

Understanding metal toxicity is vital for assessing environmental and occupational hazards. We'll examine how metals like lead, mercury, and cadmium affect various organ systems, their mechanisms of toxicity, and the resulting health effects from acute and chronic exposures.

Properties of metals

• Metals are a group of elements that share common physical and chemical characteristics
• Understanding the properties of metals is crucial for assessing their potential toxicity and essentiality in biological systems

Physical and chemical properties

• High electrical and thermal conductivity due to the presence of free electrons in their atomic structure
• Malleable (can be hammered into thin sheets) and ductile (can be drawn into wires) because of the metallic bonding between atoms
• High melting and boiling points resulting from the strong attractive forces between metal atoms
• Readily form alloys (mixtures of metals) with unique properties (stainless steel, brass)
• Participate in redox reactions by losing electrons to form cations (positively charged ions)

Toxic vs essential metals

• Some metals are essential for normal biological functions (iron, zinc, copper) while others have no known biological role and can be toxic (lead, mercury, cadmium)
• Essential metals are required in trace amounts and are incorporated into enzymes, proteins, and other biomolecules
  • Iron is a component of hemoglobin and is crucial for oxygen transport in the blood
  • Zinc is a cofactor for numerous enzymes involved in DNA synthesis, protein synthesis, and cell division
• Toxic metals can interfere with the functions of essential metals and disrupt normal biological processes
  • Lead can substitute for calcium in bones and interfere with neurotransmitter release
  • Mercury can bind to sulfhydryl groups in proteins and inhibit enzyme activity

Exposure to metals

• Exposure to metals can occur through various sources and routes, and the extent of exposure is influenced by multiple factors
• Understanding the sources, routes, and factors affecting metal exposure is essential for assessing the potential health risks

Sources of exposure

• Environmental sources include air (industrial emissions, vehicle exhaust), water (contaminated drinking water, industrial effluents), and soil (mining activities, agricultural practices)
• Occupational sources involve industries such as mining, smelting, battery manufacturing, and electroplating where workers are exposed to high levels of metals
• Consumer products containing metals include cosmetics (lead in lipsticks), toys (cadmium in paint), and food packaging materials (aluminum cans)
• Dietary sources of metal exposure include contaminated food (fish high in mercury) and supplements (iron, zinc)

Routes of exposure

• Inhalation of metal fumes, dusts, or vapors is a major route of exposure in occupational settings
• Ingestion of contaminated food, water, or soil can result in metal exposure, especially in children who have higher hand-to-mouth activity
• Dermal absorption of metals can occur through contact with contaminated soil, water, or products containing metals (cosmetics, jewelry)
• Parenteral exposure to metals can occur through medical procedures (dental amalgams, metal implants) or drug abuse (injection of metal-contaminated drugs)

Factors affecting exposure

• Duration and frequency of exposure influence the total dose of metal received over time
• Concentration of the metal in the exposure medium (air, water, food) determines the amount of metal available for absorption
• Chemical form of the metal affects its bioavailability and toxicity (inorganic vs organic, valence state)
• Individual susceptibility factors such as age, gender, nutritional status, and genetic polymorphisms can modulate the response to metal exposure

Absorption of metals

• Absorption refers to the process by which metals enter the systemic circulation from the site of exposure
• The extent and rate of metal absorption depend on the route of exposure and the physicochemical properties of the metal

Mechanisms of absorption

• Passive diffusion across cell membranes is the primary mechanism for the absorption of lipophilic metal compounds (organometallic compounds)
• Facilitated diffusion involves the use of transport proteins (divalent metal transporter 1) that bind to metals and facilitate their movement across cell membranes
• Active transport requires energy expenditure and is mediated by specific transporters (copper transporter 1) that pump metals against their concentration gradient
• Endocytosis is the process by which cells engulf metal particles or metal-protein complexes and internalize them into vesicles

Factors affecting absorption

• Solubility of the metal compound in biological fluids (water solubility favors absorption)
• Particle size of the metal influences the surface area available for interaction with biological membranes (smaller particles are more easily absorbed)
• Presence of other metals or nutrients can affect absorption through competition for transport proteins or formation of insoluble complexes
  • High calcium intake reduces the absorption of lead by competing for binding sites on transport proteins
  • Phytates in plant-based foods can bind to metals and reduce their absorption
• Physiological factors such as pH, mucus secretion, and gut motility can influence metal absorption in the gastrointestinal tract

Distribution of metals

• Once absorbed into the systemic circulation, metals are distributed to various tissues and organs in the body
• The pattern of metal distribution depends on the chemical properties of the metal and the presence of specific binding sites in tissues

Transport in the body

• Metals in the bloodstream can be present in the free ionic form, bound to small molecules (amino acids, citrate), or attached to transport proteins (transferrin, albumin)
• Red blood cells can also transport metals, particularly those that bind to hemoglobin (lead) or those that are essential for red blood cell function (iron)
• Metals can cross the blood-brain barrier and enter the central nervous system, leading to neurotoxic effects
  • Methylmercury readily crosses the blood-brain barrier and accumulates in the brain, causing neurological damage
• Metals can also cross the placental barrier and expose the developing fetus, resulting in developmental toxicity

Accumulation in tissues and organs

• Metals tend to accumulate in tissues and organs that have high affinity binding sites or active uptake mechanisms
• Bone is a major storage site for many metals (lead, cadmium) due to its high calcium content and the ability of metals to substitute for calcium in the hydroxyapatite matrix
• Liver and kidney are target organs for metal accumulation because of their role in metal metabolism and excretion
  • Cadmium accumulates in the liver and kidney, causing hepatotoxicity and nephrotoxicity
• Other tissues that can accumulate metals include the brain (mercury, manganese), lungs (beryllium, cobalt), and skin (nickel, chromium)

Metabolism of metals

• Metabolism refers to the biochemical transformations that metals undergo within the body, which can influence their toxicity and excretion
• The extent and nature of metal metabolism depend on the chemical properties of the metal and the presence of specific enzymes and cofactors

Biotransformation reactions

• Oxidation-reduction reactions involve the transfer of electrons between metals and biological molecules, altering the valence state of the metal
  • Chromium(VI) is reduced to chromium(III) by cellular reductants, generating reactive oxygen species in the process
• Methylation is the addition of methyl groups to metals, which can increase their lipophilicity and facilitate their distribution and elimination
  • Inorganic arsenic is methylated by arsenic methyltransferase to form monomethylarsonic acid and dimethylarsinic acid
• Conjugation reactions involve the attachment of polar molecules (glucuronic acid, sulfate, glutathione) to metals, increasing their water solubility and aiding in their excretion
  • Cadmium induces the synthesis of metallothionein, a cysteine-rich protein that binds and detoxifies cadmium

Factors affecting metabolism

• Genetic polymorphisms in enzymes involved in metal metabolism can influence individual susceptibility to metal toxicity
  • Polymorphisms in the arsenic methyltransferase gene are associated with differences in arsenic metabolism and toxicity
• Nutritional status can affect the availability of cofactors and substrates required for metal metabolism
  • Adequate intake of selenium is necessary for the activity of glutathione peroxidase, an enzyme that protects against mercury toxicity
• Interactions with other metals or xenobiotics can modulate metal metabolism through competition for metabolic enzymes or alteration of enzyme activity
  • Ethanol consumption induces cytochrome P450 enzymes, which can increase the activation of some metals (chromium) to their toxic forms

Excretion of metals

• Excretion is the process by which metals are eliminated from the body to maintain homeostasis and prevent accumulation
• The primary routes of metal excretion are through the urine, feces, and to a lesser extent, sweat, and breast milk

Routes of excretion

• Urinary excretion is the major route for the elimination of most metals (cadmium, mercury, arsenic) that are filtered by the kidneys and secreted into the urine
  • The extent of urinary excretion depends on the plasma concentration of the metal, the glomerular filtration rate, and the presence of specific transport proteins in the renal tubules
• Fecal excretion is important for metals that are poorly absorbed in the gastrointestinal tract (lead, aluminum) or those that undergo biliary excretion (manganese, mercury)
  • Biliary excretion involves the secretion of metals from the liver into the bile, which is then released into the small intestine and eliminated in the feces
• Sweat and breast milk are minor routes of metal excretion, but they can be significant for some metals (arsenic, mercury) and can pose a risk for nursing infants

Factors affecting excretion

• Renal function is a critical determinant of metal excretion, as impaired kidney function can lead to reduced elimination and increased accumulation of metals in the body
• Chelation therapy involves the administration of chelating agents (EDTA, dimercaprol) that bind to metals and form water-soluble complexes that are readily excreted in the urine
  • Chelation therapy is used to treat acute metal poisoning and chronic metal overload conditions (Wilson's disease)
• Age can influence metal excretion, as infants and older adults have reduced renal function compared to adults, making them more susceptible to metal accumulation
• Genetic variations in transport proteins involved in metal excretion (multidrug resistance-associated proteins) can affect individual differences in metal elimination

Toxicity mechanisms of metals

• Metals exert their toxic effects through various mechanisms that disrupt normal cellular functions and lead to tissue damage
• The primary toxicity mechanisms of metals include oxidative stress, enzyme inhibition, protein binding, and DNA damage

Oxidative stress

• Metals can generate reactive oxygen species (ROS) through redox cycling reactions, leading to oxidative stress and cellular damage
  • Iron catalyzes the Fenton reaction, which produces hydroxyl radicals that can oxidize lipids, proteins, and DNA
• Metals can also deplete cellular antioxidants (glutathione) and inhibit antioxidant enzymes (superoxide dismutase), exacerbating oxidative stress
• Oxidative stress can lead to lipid peroxidation, protein carbonylation, and DNA oxidation, resulting in cell death and tissue injury

Enzyme inhibition

• Metals can bind to the active sites of enzymes and inhibit their catalytic activity, disrupting critical cellular processes
  • Lead inhibits the activity of delta-aminolevulinic acid dehydratase, an enzyme involved in heme synthesis, leading to anemia
• Metals can also displace essential metal cofactors from enzymes, altering their structure and function
  • Cadmium can replace zinc in the zinc finger domains of DNA repair enzymes, impairing their ability to repair DNA damage

Protein binding

• Metals can bind to sulfhydryl groups, histidine residues, and other functional groups in proteins, altering their conformation and function
  • Mercury binds to the sulfhydryl groups of tubulin, disrupting microtubule assembly and causing neurological dysfunction
• Metals can also interfere with protein folding and induce the formation of protein aggregates, leading to cellular stress and toxicity
  • Aluminum promotes the aggregation of beta-amyloid protein, a key pathological feature of Alzheimer's disease

DNA damage

• Metals can directly interact with DNA, causing strand breaks, crosslinks, and other types of DNA damage
  • Chromium(VI) forms adducts with DNA bases, leading to mutations and chromosomal aberrations
• Metals can also interfere with DNA repair mechanisms, allowing the accumulation of DNA damage and increasing the risk of cancer
  • Nickel inhibits the activity of DNA repair enzymes, such as nucleotide excision repair enzymes, leading to the persistence of DNA lesions

Health effects of metal toxicity

• Metal toxicity can result in a wide range of adverse health effects, depending on the specific metal, the dose, and the duration of exposure
• Health effects can be acute (short-term) or chronic (long-term) and can target various organs and systems in the body

Acute vs chronic toxicity

• Acute metal toxicity occurs after a single or short-term exposure to high doses of a metal and is often characterized by rapid onset of symptoms
  • Acute lead poisoning can cause abdominal pain, vomiting, and encephalopathy
• Chronic metal toxicity develops after prolonged exposure to low doses of a metal and may have a gradual onset of symptoms
  • Chronic cadmium exposure can lead to kidney damage, osteoporosis, and lung cancer

Target organs and systems

• Nervous system: Metals can cause neurotoxicity by interfering with neurotransmitter synthesis, release, and uptake, and by inducing oxidative stress and neuroinflammation
  • Mercury exposure can lead to sensory and motor deficits, tremors, and cognitive impairment
• Cardiovascular system: Metals can affect the heart and blood vessels by inducing oxidative stress, altering lipid metabolism, and promoting atherosclerosis
  • Arsenic exposure is associated with an increased risk of hypertension, coronary heart disease, and peripheral vascular disease
• Respiratory system: Inhalation of metal fumes or particles can cause respiratory irritation, inflammation, and fibrosis
  • Beryllium exposure can lead to berylliosis, a chronic granulomatous lung disease
• Gastrointestinal system: Ingestion of metals can cause nausea, vomiting, diarrhea, and abdominal pain, and can also damage the liver and pancreas
  • Copper overload in Wilson's disease can cause hepatitis, cirrhosis, and liver failure
• Renal system: Metals can accumulate in the kidneys and cause tubular damage, glomerular dysfunction, and renal failure
  • Cadmium is a well-known nephrotoxicant that can cause proteinuria, glucosuria, and reduced glomerular filtration rate

Carcinogenicity of metals

• Some metals are classified as human carcinogens by the International Agency for Research on Cancer (IARC) based on epidemiological and experimental evidence
  • Arsenic is a known human carcinogen that increases the risk of skin, lung, bladder, and liver cancer
  • Chromium(VI) compounds are carcinogenic to humans and are associated with an increased risk of lung cancer in occupationally exposed workers
• Metals can promote carcinogenesis through various mechanisms, including DNA damage, oxidative stress, epigenetic alterations, and interference with DNA repair

Reproductive and developmental toxicity

• Metals can cross the placental barrier and affect fetal development, leading to birth defects, growth retardation, and neurodevelopmental disorders
  • Methylmercury exposure during pregnancy can cause microcephaly, cerebral palsy, and mental retardation in the offspring
• Metals can also impair reproductive function in both males and females by affecting hormone synthesis, spermatogenesis, and ovarian function
  • Lead exposure is associated with reduced sperm count and motility in men and with increased risk of spontaneous abortion and preterm delivery in women

Specific metal toxicants

• While there are numerous metals that can cause toxicity, some specific metals are of particular concern due to their widespread occurrence, high toxicity, and significant public health impact
• These metals include lead, mercury, cadmium, and arsenic, among others

Lead toxicity

• Lead is a ubiquitous environmental pollutant that can cause toxicity in multiple organ systems
• Children are particularly vulnerable to lead toxicity due to their higher absorption and developing nervous system
  • Lead exposure in children can cause intellectual disability, behavioral problems, and growth retardation
• Adults exposed to lead can experience hypertension, kidney damage, and reproductive problems
• Sources of lead exposure include lead-based paint, contaminated water, and occupational settings (battery manufacturing, lead smelting)

Mercury toxicity

• Mercury exists in three main forms: elemental, inorganic, and organic (methylmercury), each with distinct toxicity profiles
• Elemental mercury is neurotoxic and can cause tremors, emotional instability, and cognitive deficits upon inhalation exposure
• Inorganic mercury salts are corrosive and can cause gastrointestinal and renal damage
• Methylmercury is a potent neurotoxicant that bioaccumulates in the aquatic food chain and can cause sensory and motor deficits, as well as developmental abnormalities
  • Prenatal exposure to methylmercury, such as from maternal consumption of contaminated fish, can lead to congenital Minamata disease

Cadmium toxicity

• Cadmium is a toxic metal that accumulates in the body, primarily in the liver and kidneys, and has a long biological half-life
• Chronic cadmium exposure can cause kidney damage, characterized by proteinuria and reduced glomerular filtration rate
• Cadmium is also associate