Lecture Notes-11-Metals PDF

Toxic Effects of Metals LECTURE NOTES WEEK 8  K E Y PO I N T S 1. Young children or elderly people, are more susceptible to toxicity from exposure to metal than most adults. 3. Complexation is the formation of a metal ion complex in which the metal ion 2. Metals that provoke immune is assoc...

Toxic Effects of Metals LECTURE NOTES WEEK 8  K E Y PO I N T S 1. Young children or elderly people, are more susceptible to toxicity from exposure to metal than most adults. 3. Complexation is the formation of a metal ion complex in which the metal ion 2. Metals that provoke immune is associated with a charged or reactions include mercury, gold, uncharged electron donor, platinum, beryllium, chromium, and referred to as a ligand. nickel.  K E Y PO I N T S Metal–protein interactions include binding to numerous enzymes, the metallothioneins, 4. Chelation occurs nonspecific binding to proteins such when bidentate ligands as serum albumin or hemoglobin, and form ring structures that include the metal specific metal carrier proteins ion and the two ligand involved in the membrane transport atoms attached to the of metals. metal. Chelated Molecules Structure of human hemoglobin. α and β subunits are in red and blue, respectively. The iron-containing heme groups in green.  Metals Metals are solids at room They are all naturally occurring temperature within the human environment. Except of Hg Metals are nonbiodegradable Common Physical properties: include high reflectivity (luster), Use of metals has influenced high electrical conductivity, their environmental levels in high thermal conductivity, air, water, soil, and food. mechanical ductility and strength. Human exposure is inevitable Chemical Properties: They become cations by losing  Metals in the Environment Environmental Cycle 1. Rainwater dissolves rocks and ores 2. Transports materials, including metals, to rivers and underground water (e.g., arsenic), 3. Eventually transporting them to  Metals in the Environment Biological cycles moving metals include Metal intoxication has been reported biomagnification in plants, aquatic organisms, by plants and animals and their invertebrates, fish, sea mammals, incorporation into food cycles. birds, and domestic animals. Human activities also Metal toxicity from naturally result in metal distribution in the occurring sources (As, Se, Th in global environment by discharge drinking water mainly) to soil, water, and air. Metal Toxicolog y FIGURE 23–1 Overview of metal toxicology. TABLE 23–1 Toxicity of several metals or metalloids. Metal Toxicology Metals in their ionic form can interact with biological systems Mimicry is the replacement of an essential metal ion by others Cell environment rich in DNA with and proteins is ideal metal similar properties binding ligands. (Zn with Cd, Cu or Ni) Enzyme inhibition is a toxic Metal mediated oxidative result damage. Catalysis of redox reactions generates  Metal Toxicology Exposure factors: dose, duration route and frequency of exposure Children and older people are more susceptible to Pb poisoning Host-based factors: Children GI absorbs higher Age at exposure, gender, calories/body weight, and metals and capacity or Smoking and diet also factors biotransformation.  Metal Toxicology Biomarkers of Metal exposure Metal Exposure Metal Exposure impacts genes that can induce concentrations in encode proteins that intracellular damage: blood, urine, or hair (1) remove the metal oxidative stress, from the cell via leading to chromium, chelation Lipid peroxidation, DNA–protein complexes Protein denaturation, or increased export, DNA damage, and biomarker for exposure organelle (2) reduce the level of and carcinogenic oxidative stress, and dysfunction. potential. (3) repair the metal- Metal Toxicology Metal-binding Proteins And Metal Transporters Protein binding essential Protein specific for toxic metal metal-binding is involved in the metabolism. trafficking of specific essential metals, Protein nonspecific binding acts in metal transport and tissue distribution. (serum albumin or hemoglobin) Metal Toxicology Ceruloplasmin is a copper-containing glycoprotein Transferrin (glycoprotein) binds oxidase in plasma. mostly Converts ferrous iron to ferric iron, the Ferric iron in plasma. which then binds to transferrin. It transports iron, aluminum and manganese across cell membranes. Metallothioneins with their thiol ligands Ferritin is primarily a storage bind to several essential and toxic protein metals such as zinc, cadmium, for iron. copper, MAJOR TOXIC METALS-Arsenic As Trivalent arsenic compounds: arsenic trioxide and sodium arsenite, Pentavalent compounds: sodium arsenate, arsenic pentoxide, and arsenic acid. Biotransformation leads to arsenilic acid, arsenosugars, and several methylated derivatives Arsine (AsH3) is an important gaseous arsenical. MAJOR TOXIC METALS-Arsenic As Exposure: Inorganic arsenic is absorbed Occupational (80% to 90%) Manufacture of pesticides, herbicides, from the gastrointestinal tract, and other agricultural products, in distributed throughout the body, smelting industries. often metabolized by methylation, and then excreted primarily in urine. Environmental from arsenic-contaminated drinking It is also excreted by desquamation water, and from the burning of coal of skin and in sweat containing naturally high levels of arsenic. Food, and seafood MAJOR TOXIC METALS-Arsenic As Arsenic exposure produces characteristic transverse white bands across fingernails (Mees’ line), Arsenic in the fingernails and hair has been used as a biomarker for exposure.  MAJOR TOXIC METALS-Arsenic As Symptoms of acute intoxication Toxicity fever, anorexia, hepatomegaly, Acute Poisoning melanosis, cardiac arrhythmia, and, in Ingestion of large doses fatal cases, eventual cardiac failure. (70 to 180 mg) of inorganic arsenic can be Acute arsenic ingestion can damage fatal. mucous membranes of the gastrointestinal tract, causing Sensory loss in the PNS irritation, vesicle formation, and even is the most common Anemiasloughing. and leucopenia, particularly neurological effect, granulocytopenia, occur a few days 1-2 weeks following high-dose arsenic exposure. They  MAJOR TOXIC METALS-Arsenic As Chronic Toxicity Mechanisms of Toxicity results in skin cancer, liver injury (jaundice), Trivalent As compounds are thiol- abdominal pain, and reactive hepatomegaly and thereby inhibit enzymes or alter may progress to cirrhosis proteins and ascites, even to by reacting with their thiol groups. hepatocellular carcinoma. Pentavalent As is an uncoupler of mitochondrial oxidative phosphorylation, MAJOR TOXIC METALS-Arsenic As Peripheral neuropathy at low dose chronic exposure Sensory changes, such as numbness in the hands and feet, developing later to painful “pins and needles” sensation. Sensory and motor nerves are affected. Dying-back axonopathy with demyelination may occur. Peripheral vascular disease was observed in persons with chronic exposure to inorganic arsenic in the drinking water.  MAJOR TOXIC METALS-Arsenic As Carcinogenicity DNA damage Treatment by oxidants and Fluid volume replacement and oxidative process, support of blood pressure. alteration in DNA methylation status The oral chelator penicillamine and genomic instability, or succimer (2,3-dimercaptosuccinic acid, DMSA) Impaired DNA damage repair, and enhanced cell proliferation. removes arsenic from the body.  MAJOR TOXIC METALS-Arsenic As Carcinogenicity Known human Skin cancers include carcinogen, basal cell and squamous associated with tumors cell of the skin, carcinomas, lung, and Mortality occurs from urinary bladder, lung cancer in young adults and possibly And following in utero kidney, exposure liver, and to arsenic. the developing prostate. fetus appears to be hypersensitive to arsenic  MAJOR TOXIC METALS-Cadmium Cd Exposure General population through Food Cd is accumulated in plants and animals absorbed from contaminated ground water Shellfish and animal liver and kidneys accumulate relatively high levels of Cd Smoking is another route of exposure (inhalation) 75% used in batteries, electroplating, galvanizing and paints. Byproduct of Zn and Pb smelting  MAJOR TOXIC METALS-Cadmium Cd Occupational exposure through inhalation for workers involved with refining zinc and lead ores, iron production, cement manufacture, fossil fuel combustion, manufacturing of paint pigments, cadmium–nickel batteries, and electroplating Cadmium is protein-bound in blood. It is rapidly taken up by tissues, and is deposited in the liver and kidney. Cadmium stored in hepatocytes is bound to metallothionine.  MAJOR TOXIC METALS-Cadmium Cd aa, amino acids; GSH, glutathione; MT, metallothionine; FIGURE 23–2 Cadmium transport, protein Cd-Alb, cadmium-albumin; Cd-LMWPr, binding, and toxicity. cadmium associated with low-molecular- MAJOR TOXIC METALS-Cadmium Cd Toxicity Chronic Toxicity ingestion of high concentrations Long term low-level cadmium (heavily contaminated beverages exposure or food) Effects are renal injury, obstructive causes severe irritation to the pulmonary disease, osteoporosis, gastrointestinal epithelium, and cardiovascular disease. leading to nausea, vomiting, and Cancer is primarily a concern in abdominal pain. occupationally exposed groups. Inhalation of cadmium fumes or Of greater concern than the other accidental exposure heated cadmium-containing MAJOR TOXIC METALS-Cadmium Cd Nephrotoxicity Skeletal changes Toxic to tubular cells and glomeruli, probably related to calcium loss include Impairs renal function leading to proteinuria. bone pain, The initial tubular cell necrosis and osteomalacia, and/or degeneration, progresses to an interstitial inflammation osteoporosis. and fibrosis. Great concern of dietary cadmium intake MAJOR TOXIC METALS-Cadmium Cd Chronic Pulmonary Disease Inhalation is toxic to the respiratory system: Related to the dose and duration of exposure. Cadmium-induced obstructive lung disease can be slow in onset, and results from chronic bronchitis, progressive fibrosis of the lower airways, and accompanying alveolar damage leading to emphysema. Pulmonary function is reduced with dyspnea, reduced vital capacity, and increased residual volume. MAJOR TOXIC METALS-Chromium Cr Most Common Cr(III). Na2Cr2O7 Used as a strong oxidizer in metal applications. Absorption of 2-10% of Cr(VI) and 0.5 – 2% of Cr(III). Cr(VI) readily crosses cell membranes via sulfate and phosphate transporters. Cr(VI) chromium is taken up by erythrocytes (blood); Cr(III) only loosely associated with erythrocytes. Chromium compounds distribute to all organs. Highest levels in the liver, spleen, and kidney. Chromium can remain in the lungs for years. Absorbed chromium is excreted primarily in urine MAJOR TOXIC METALS-Chromium Cr Toxicity Cr(VI) is corrosive. May cause chronic ulceration and perforation of the nasal septum, as well as chronic ulceration of other skin surfaces. Allergic contact dermatitis for previously sensitized individuals (type IV allergic reaction). Ingestion of high doses of Cr(VI) compounds may cause acute renal failure (proteinuria, hematuria, and anuria). MAJOR TOXIC METALS-Chromium Cr Carcinogenicity Cr(VI) in the chrome production and pigment industries increase the risk of lung cancer. Cr(VI)compounds are genotoxic, and can generate reactive oxygen radicals, inhibit protein synthesis, and arrest DNA replication. Cr(VI) can disrupt the p53 signaling pathway, alter the ATM/ATR cell cycle checkpoints, induce apoptosis, and interfere with DNA damage repair. Cr(VI) can also activate cell signaling enzymes, such as Src family kinases, to stimulate signal cascades leading to transcriptional repression of cellular protectant proteins. MAJOR TOXIC METALS - Lead Pb Exposure detectable practically in all phases of the inert environment and in all biological systems. MAJOR TOXIC METALS- Lead Pb Phased out of leaded gasoline Removed from paint, solder, and water supply pipes Results: Lowered blood lead levels in the general population. TABLE 23–1 Summary of lowest observed effect MAJOR TOXIC METALS-Lead Pb Toxicity Inhibition of enzymes leads to severe pathology or death. Children: impact on the central nervous system, Adults: peripheral neuropathy, chronic nephropathy, and hypertension Other target tissues: the gastrointestinal, immune, skeletal, and reproductive systems. Effects on the heme biosynthesis provide a sensitive biochemical indicator MAJOR TOXIC METALS-Lead Pb Neurologic, Neurobehavioral, and Developmental Effects Children: encephalopathy begins with lethargy, vomiting, irritability, loss of appetite, and dizziness, progressing to obvious ataxia, and a reduced level of consciousness, which may progress to coma and death. Recovery is often accompanied by sequelae including epilepsy, mental retardation, and, in some cases, optic neuropathy and blindness.  MAJOR TOXIC METALS-Lead Pb Indicators of Adverse Neurologic Effects Psychomotor tests or mental development indices, and broad measures of IQ. Lead may act as a surrogate for calcium and/or disrupt calcium homeostasis. Stimulation of protein kinase C may result in alteration of the blood–brain barrier. Lead affects virtually every neurotransmitter system in the brain, MAJOR TOXIC METALS-Lead Pb Neurotoxic Effects in Adults Abnormalities in a number of measures in neurobehavior. Peripheral neuropathy is a classic manifestation of lead toxicity in adults. Foot drop and wrist drop in workers with excessive occupational exposure Peripheral neuropathy is characterized by segmental demyelination and possibly axonal degeneration.  MAJOR TOXIC METALS-Lead Pb FIGURE 23–3 Lead interruption of heme biosynthesis. ALA, δ-aminolevulinatef; Pb, sites or lead effects. The major lead inhibition sites are ALA dehydrogenase and ferrochelatase.  MAJOR TOXIC METALS-Lead Pb Hematologic Effects Inhibition of ALAD results in increased urinary porphyrins, accumulation of ALA. coproporphyrins, Ferrochelatase catalyzes the δ-aminolevulinic acid (ALA), and zinc- insertion of iron into the protoporphyrin, anemia. protoporphyrin ring to form heme. Inhibition of δ-aminolevulinic acid Inhibition of ferrochelatase results dehydratase (ALAD) and in ferrochelatase. accumulation of protoporphyrin IX, ALAD catalyzes the condensation of which takes the place of heme in two units of ALA to form the hemoglobin molecule and, as Anemia only occurs in very porphobilinogen (PBG) the erythrocytes containing marked cases of lead toxicity. protoporphyrin IX circulate, zinc is  MAJOR TOXIC METALS-Lead Pb Renal Toxicity Lead nephrotoxicity impairs the renal Lead nephrotoxicity consists of synthesis of heme-containing proximal enzymes in the kidney, such as tubular dysfunction and can be heme-containing hydroxylase reversed by treatment with chelating involved in vitamin D metabolism agents. causing bone effects. Chronic lead nephrotoxicity Hyperuricemia with gout occurs consists Lead nephropathy can beprogressive a cause more frequently in the presence of interstitial fibrosis and of nephron hypertension. of lead nephropathy. loss, azotemia, and renal  MAJOR TOXIC METALS-Lead Pb Effects on Cardiovascular Alterations in calcium-activated System functions of vascular smooth Lead induced hypertension from muscle cells including Inactivation of endogenous nitric contractility by decreasing oxide and cGMP, possibly through Na+/K+ -ATPase activity and lead-induced reactive oxygen stimulation of the Na+ /Ca2+ species; exchange pump; and Changes in the renin–angiotensin– A possible rise in endothelin and aldosterone system, and increases thromboxane. in sympathetic activity, important humoral components of  MAJOR TOXIC METALS-Lead Pb Other Toxic Effects Lead can affect bone by As an immunosuppressive interfering with metabolic and agent, homeostatic mechanisms including Lead decreases parathyroid hormone, calcitonin, immunoglobulins, vitamin D, and other hormones that alters -cell subpopulations, influence calcium metabolism. and reduces polymorphonuclear leukocyte chemotactic activity. Lead substitutes for calcium in bone. Lead colic, although rare, is a major gastrointestinal symptom Lead is known to affect of severe lead poisoning, and is osteoblasts, osteoclasts, and characterized by  MAJOR TOXIC METALS- Mercury Hg vapor (Hg0) is much more hazardous than the liquid form. Binds to other elements (Cl, S, O) FIGURE 23–4 The movement o mercury in the MAJOR TOXIC METALS-Mercury Hg Atmospheric mercury, Methylmercury enters the originates from natural degassing aquatic of the earth’s crust, volcanic food chain starting with eruptions, evaporation from plankton, oceans and soils then herbivorous fish, and finally ascending to carnivorous From (anthropogenic sources) Tissue fish andmercury can rise to sea mammals metal mining and smelting (mercury, levels 1,800 to 80,000 times gold, copper, and zinc), coal higher than levels in the combustion, municipal incinerators, surrounding water and chloralkali industries MAJOR TOXIC METALS-Mercury Hg Exposure Occupational Accidental Dietary Exposure Exposure Exposure Inhalation (mercury From broken Consumption of fish vapor) from working elemental (methylmercury) in the chloralkali mercury containers, industry. medicinal devices, Other Foods Manufacturing of barometers, and (Inorganic mercury, scientific instruments, melting tooth usually below toxic electrical control amalgam levels). devices, dentistry fillings to recover Water and (mercury amalgams silver. atmospheric are used in tooth Inhalation of large MAJOR TOXIC METALS-Mercury Hg Toxicity Asthenic-vegetative Mercury Vapor syndrome or micromercurialism Inhalation at extremely high Identified by neurasthenic concentrations may produce symptoms and three or more of an acute, corrosive clinical findings: tremor, bronchitis and interstitial enlargement of the thyroid, pneumonitis and, increased uptake of radioiodine in the thyroid, labile pulse, if not fatal, may be tachycardia, dermographism, associated with CNS effects gingivitis, hematologic changes, such as tremor or increased or increased excretion of  MAJOR TOXIC METALS-Mercury Hg Inorganic Mercury Impacts the kidney Methylmercury High dose of mercuric chloride Is neurotoxic. is directly toxic to renal tubular Clinical manifestations: paresthesia (a cells, numbness and tingling sensation around the Chronic low-dose exposure to mouth and lips) and ataxia, (clumsy, mercury salts may induce an stumbling gait, and difficulty in swallowing immunologic glomerular disease. and articulating words). Exposed persons may develop Others: neurasthenia (a generalized proteinuria. sensation of weakness), vision and hearing Reversible after exposure loss, and spasticity and tremor. terminates. Possible progress to coma and death. cerebral edema, and cerebral atrophy MAJOR TOXIC METALS Mercury Hg Mechanism of Toxicity High-affinity binding of divalent mercury to sulfhydryl groups of proteins in the cells is an important mechanism for producing nonspecific cell injury or even cell death. Other general mechanisms include an increase in genes associated with oxidative stress, reduced glutathione levels, disruption of microtubules in neuritis, damage mitochondria, and MAJOR TOXIC METALS-Nickel Ni Used in metal alloys, including stainless steels, and in electroplating Occupational exposure: Inhalation of nickel-containing aerosols, dusts, or fumes, or dermal contact in workers engaged in nickel production (mining, milling, refinery, etc.) and nickel-using operations (smelting, electroplating, welding, nickel–cadmium batteries, etc.). The general population is exposed to MAJOR TOXIC METALS-Nickel Ni Toxicity Contact Dermatitis Nickel-induced contact dermatitis is the most common adverse health effect Is found in 10% to 20% of the general population. It results from exposure to airborne, liquid solutions, or prolonged skin contact with metal MAJOR TOXIC METALS-Nickel Ni More severe cases can progress Nickel Carbonyl Poisoning— to pneumonia, respiratory Metallic nickel combines with carbon failure, and monoxide to form nickel carbonyl finally to cerebral edema and (Ni[CO]4), Carcinogenicity: death. Respiratory tract carcinogen for On heating decomposes to Ni and CO nickel-refining industry workers. Nickel carbonyl is extremely toxic. Risks are highest for lung and nasal Intoxication begins with headache, cancers among workers heavily nausea, vomiting, and epigastric or exposed to nickel sulfide, nickel chest pain, followed by cough, oxide, and metallic nickel. hyperpnea, cyanosis, gastrointestinal TABLE 23–2 Toxicity of several metals or metalloids. ESSENTIAL METALS WITH POTENTIA L FOR TOXICITY cobalt, copper, iron, magnesium, manganese, molybdenum, selenium, and zinc. Essential METALS-Copper Cu Exposure Food, beverages, and drinking water for the general population. Industrial exposure from inhaled particulates in mining or metal, fumes in smelting operations, welding, or related activities. Essential METALS-Copper Cu Toxicity From excess oral copper intake are gastrointestinal distress. Nausea, vomiting, and abdominal pain have been reported shortly after drinking solutions of copper sulfate or beverages stored in containers that readily release copper. Ingestion of drinking water with > 3 mg Cu/L will produce gastrointestinal symptoms. Ingestion of large amounts of copper salts, most frequently copper sulfate, may produce hepatic necrosis and death.  Essential METALS-Copper Cu Hereditary Disease of Deficiencies in copper-containing Copper Metabolism proteins. Menkes Disease Bones are osteoporotic with flared Rare sex-linked genetic defect metaphases of the long bones and in bones of the skull. copper metabolism resulting in Extensive degeneration of the copper deficiency in male cerebral cortex and of white matter. infants. The gene for Menkes disease, ATP7A, belongs to the family of ATPases and is Peculiar hair, failure to thrive, a copper transporter. severe mental retardation, Deficiency of this blocks copper neurological impairment, transportation across the basolateral Essential METALS-Copper Cu Wilson’s Disease Autosomal recessive genetic Clinical abnormalities of the nervous system, disorder of copper liver, kidneys, and cornea are related to copper Excessive accumulation of accumulation. copper in liver, brain, Patients with Wilson’s disease have impaired kidneys, and cornea. biliary excretion of copper, which is believed to be Serum ceruloplasmin is low the fundamental cause of the copper overload. and serum copper not bound to ceruloplasmin is elevated. Reversal of abnormal copper metabolism is achieved by liver transplantation, confirming High urinary excretion of that the basic defect is in the liver. copper Clinical improvement can be achieved with chelation therapy. Essential METALS-Iron Fe (Fe2+, Fe3+) iron cycle Essential METALS-Iron Fe (Fe2+, Fe3+) Essential for Toxic conditions Doses of 0.5 g of Erythropoiesis, from: iron iron a key component deficiency, or 2.5 g of FeSO4 in of hemoglobin, accidental acute 1 to 6 h after myoglobin, exposures, ingestion heme enzymes, and chronic iron Cause toxic effects, metalloflavoprot overload death within Severe ein Accidental ingestion 24hours symptoms enzymes, and pallor or cyanosis, mitochondrial of iron-containing dietary supplements Symptoms metabolic acidosis, enzymes. abdominal pain,and cardiac is the most common cause of acute diarrhea, and collapse Essential METALS-Iron Fe (Fe2+, Fe3+) Chronic iron toxicity Possible connection to from iron accumulation cardiovascular disease (by (1) hereditary producing free radical damage hemochromatosis due to resulting in atherosclerosis and abnormal absorption of iron ischemic heart disease). from the intestinal tract, Aberrant iron metabolism (2) excess intake via the in the brain may induce diet or from oral iron neuroferritinopathy, preparations, and aceruloplasminemia, and manganism. (3) repeated blood transfusions or some form of Essential METALS-Magnesium Mg Mg plays a key role in a Essentiality Deficiency wide range of important Co-factor in many various disease states fundamental cellular enzymatic reactions such as reactions. Symptoms malabsorption syndromes, Absorbed through small neurological depression, neuromuscular irritability, renal dysfunction, and intestine. frank tetany, and even convulsions. endocrine disorder In competition with Ca If more Ca is present Magnesium deficiency induces an Hypomagnesia more less Mg is absorbed inflammatory syndrome, and is a common than 95% Mg is reabsorbed risk factor for diabetes mellitus, hypermagnesia during in the kidneys hypertension, hyperlipidemia, and MgO metal fume fever ischemic heart diseases.  Essential METALS-Molybdenum Mo Water-soluble Mo Essentiality compounds are readily Deficiency Co-factor for many absorbed when ingested. enzymes Chronic exposure to excess Mo in humans Highest Mo Symptoms is characterized by concentrations are found Molybdenum cofactor (Moco) high uric acid levels in the kidneys, liver, and deficiency is a pleiotropic genetic in serum and urine. bones. disorder (loss of theMo-dependent Very little Mo appears to enzymes) cross the placenta. This rare human disorder causes severe neurodegeneration and Excretion, primarily via childhood death. the urine, is rapid. Essential METALS-Zinc Zn Zinc is present in Essentiality Deficiency most foodstuffs, Over 300 active poor dietary zinc water, and air. zinc intake, metalloenzymes dietary phytate Occupational and 2000 zinc- intake, exposure to dusts and dependent chronic illness, fumes of metallic zinc Many metabolic transcription factors processes, or over Symptoms in zinc mining and supplementation growth retardation, appetite loss, smelting. healthy immune alopecia, with irondiarrhea, impaired or copper. High zinc content in system, immune galvanized essential for normal function, cognitive impairments, dermatitis, delayed healing of Copper or plastic growth wounds, pipes. and development taste abnormalities, and impaired Essential METALS-Zinc Zn Essential METALS-Zinc Zn Therapeutic uses Toxicity treatment of: gastrointestinal distress and Infant acute diarrhea from Diarrhea from drinking from galvanized zinc deficiency, cans common cold by its antiviral “metal- fume fever” from inhalation of and immunomodulatory ZnO effects, symptoms fever, chest pain, chills, Wilson’s disease to reduce cough, dyspnea, nausea, muscle soreness, copper burden and to induce fatigue, and leukocytosis metallothionein, ZnCl2 exposure (military use of “smoke prevention of blindness in bombs”) damages to the mucous age-related macular membrane including interstitial edema, Essential METALS-Zinc Zn Neuronal Toxicity— Pancreatic Toxicity Zn deficiency may Large amounts of Zn accumulate change antioxidant in secretory granules of pancreatic enzymes causing excess islet β-cells, Zn impacts the function free radicals damaging and survival of islet cells. Zn can cell membranes. cause β-cell death. Excess dietary zinc can damage to Zn Excess released by exocrine pancreas. oxidants can be a potent A single, Zn high dose injection neurotoxin, contributing increases plasma α-amylase activity to excitotoxic brain and can produce fibrosis and necrosis injury, and the later of pancreatic exocrine cells, but does development of MEDICAL THERAPYMETALS-Aluminum Al (Al3+) binds strongly to oxygen-donor Toxicity Lung and Bone Toxicity ligands persons with Occupational exposure such as citrate and chronic renal lung fibrosis in humans, phosphate. failure, and Osteomalacia from exposed to Al in excessive intake of Al Exposure from food the workplace, containing antacids. and Al may interfere with less from drinking Target organs intestinal phosphate water. lung, bone, and absorption. Also in uremic Pharmaceutical use central nervous patients exposed to Al of system, also from dialysis fluid. aluminum in antacids developmental May be direct effect on MEDICAL THERAPYMETALS-Aluminum Al (Al3+) MEDICAL THERAPYMETALS-Aluminum Al (Al3+) Neurotoxicity Neurotoxic to experimental Dialysis Dementia Animals (variety in age and Patients on long-term intermittent species), hemodialysis for chronic renal failure. In rabbits and cats, early develop first a speech disorder accumulation of neurofibrillary followed by dementia, convulsions, tangles (NFTs) in large neurons, and myoclonus. proximal axons, and dendrites 3 to 7 years of dialysis treatment of neurons in many brain may cause Al intoxication regions. Al content of brain, muscle, and bone Associated with loss of synapses increases from oral Al(OH)3 or from and atrophy of the dendritic dialysis fluid due to high parathyroid tree. hormone level MEDICAL THERAPYMETALS-Aluminum Al (Al3+) Alzheimer’s Disease-Is their a connection? High aluminum levels in Alzheimer’s brains may be a result but not the cause of the disease. The reduced effectiveness of the blood–brain barrier in Alzheimer’s might allow more aluminum into the brain. Also, there may be aluminum contamination. Studies are not conclusive However, other evidence suggest a link between aluminum in the brain and other neurodegenerative diseases. MEDICAL THERAPY METALS-Lithium Li (Li+) In batteries, alloys, catalysts, photographic materials, and the space industry. LiH + H2O LiOH + H2 used in manufacturing electronic tubes, in ceramics, and in chemical analysis. Groundwater contamination a risk factor for the aquatic environment. Lithium carbonate and lithium citrate are widely used for mania MEDICAL THERAPY METALS-Lithium Li (Li+) Toxicokinetics Readily absorbed from the gastrointestinal tract. Distributed to total body water Higher levels in kidney, thyroid, and bone Excretion mainly through the kidneys 80% of the filtered lithium reabsorbed. Lithium can substitute for sodium or potassium on several transport proteins. MEDICAL THERAPY METALS-Lithium Li (Li+) neurotoxicity, nephritis, and thyroid dysfunction Toxicity-Not considered highly Chronic lithium hazardous nephrotoxicity LiH is intensely corrosive and may and interstitial nephritis produce burns on the skin (hydroxide With long-term exposure formation). even when lithium levels in Intoxications mainly related to its the therapeutic Acute overdose range results in medicinal uses. neurological sequelae and Symptoms: neuromuscular changes cardiac toxicity, which can be (tremor, muscle hyperirritability, and ataxia) CNS fatal. disorders (blackout spells, epileptic seizures, Treatment with diuretics slurred speech, coma, psychosomatic retardation, (amiloride) and increased thirst), cardiovascular and lowering of blood levels via MEDICAL THERAPY METALS-Platinum Pt Used as automobile Toxicity Antitumor Effects of catalysts, Exposure to Pt dust Platinum Complexes in jewelry, in electronics, Hypersensitivity Important antitumor and in dental alloys. reactions. agents, (cisplatin, In medicine Urticaria, carboplatin, and (important antitumor contact dermatitis of oxaliplatin) Persons exposed to agents) skin, and respiratory Routinely used for the soluble compounds distress, ranging from treatment of advanced (sodium irritation to testicular cancer, chloroplatinate) suffer an asthmatic cancers from platinosis (skin syndrome. of head and neck, and respiratory bladder, esophagus, changes) MEDICAL THERAPY METALS-Platinum Pt MEDICAL THERAPY METALS-Platinum Pt Carcinogenic Effects of Toxicities of Platinum Antitumor Platinum Complexes— Complexes Cisplatin has antitumor Cisplatin produces proximal and distal activity in humans, tubular cell injury, mainly in the corticomedullary region, where the Also considered to be a concentration of platinum is highest. probable carcinogen in Hearing loss can occur and can be humans unilateral It is clearly carcinogenic in or bilateral. More frequent and severe rodents. with repeated doses. In mice deficient in Marked nausea and vomiting occur in metallothionein, it can induce most patients receiving the platinum MEDICAL THERAPY METALS-Platinum Pt Cisplatinum, platamin, neoplatin, cismaplat, Cis-diaminedichloro platinum(II) (CDDP) MEDICAL THERAPY METALS-Platinum Pt Oxaliplatin, Eloxatin Carboplatin Paraplatin MEDICAL THERAPYMETALS Platinum Pt Cisplatin Mechanism of action