Metal Toxicology PDF

METAL TOXICOLOGY Assoc. Prof. ChM. Dr Normah Awang  Introduction CONTENT Overview of Metal Definition Toxicology Heavy Metals Sources of Heavy Metals Properties of Heavy Metals Common Toxic Hea...

METAL TOXICOLOGY Assoc. Prof. ChM. Dr Normah Awang  Introduction CONTENT Overview of Metal Definition Toxicology Heavy Metals Sources of Heavy Metals Properties of Heavy Metals Common Toxic Heavy Metals Common Toxic Mechanisms & Sites Of Action Exposure to Toxic Heavy Metals INTRODUCTION Many of the metals are essential Substances are toxic with for proper functioning of excess exposure. biological systems where they are usually required in trace amounts. Metals such as Na, K, and Ca operate as essential charged molecules (ions) critical for Blood, urine, and hair are neurotransmission and muscle contraction. the most accessible tissues for measuring metal exposure.  Definition METALS METALLOIDS HEAVY METALS Any opaque, fusible, ductile, and typically Elements with features A metal having an atomic weight lustrous substances that are good greater than sodium, a density conductors of electricity and heat, form intermediate between metals and non-metals. greater than 5 g/cm3 Arsenic 5.7; cations by loss of electrons, and yield basic cadmium 8.65; lead 11.34; mercury oxides and hydroxides. Example: arsenic 13.54  HEAVY METALS 23 out of 35 metals (that Natural geogenic High density (5 g/cm3) concern us due to or anthropogenic occupational or residential and high relative exposure) are heavy metals. source. atomic weight. Non-degradable Antimony, arsenic, bismuth, cadmium, cerium, chromium, cobalt, copper, gallium, gold, iron, lead, manganese, mercury, nickel, platinum, silver, tellurium, thallium, tin, uranium, vanadium, and zinc. SOURCES OF HEAVY METALS IN THE ENVIRONMENT  They occur near the bottom of the periodic table Have high densities Toxic in nature Nondegradable PROPERTIES OF Note: Arsenic is not actually a metal but is a HEAVY METALS semimetal i.e. its properties are intermediate between those of metals and nonmetals.  COMMON TOXIC HEAVY METALS Arsenic Lead Cadmium Mercury Iron Zinc  Heavy Metals: GOOD or BAD??  1 Certain heavy metals (Eg: Fe, Cu, 1. Mn, Zn) are nutritionally essential for human health. HEALTHY Found naturally in fruits & vegetables. LIFE 2. Commercially available as multivitamin products. MEDICINE 2 ADVANTAGES Injection of gallium during radiological procedure. 3. Using lead as a radiation shield around x-ray equipment. INDUSTRIAL 3 Manufacture of pesticides APPLICATION Batteries Alloys Electroplated metal parts Textile dyes Steel (to improve the quality of life)  DISADVANTAGES not metabolized accumulate in the Heavy metals by the body soft tissues TOXIC How heavy metals can be exposed to human? Ingestion (eg: food, water) Agricultural activities Inhalation Absorption through the skin/eye contact Industrial activities (eg: manufacturing) Pharmaceutical Residential Common: Less Common: Adults – industrial exposure. Radiological procedure. Children – ingestion (contact with Broken thermometer. contaminated soil / eating objects). Suicide or homicide attempt.  If the metal is in lipid It readily soluble form (eg: penetrates the methyl mercury) membrane. For a metal to exert If the metal bound to Metal taken proteins (eg: cadmium- into the cell by toxicity, it must cross metallothionein) endocytosis. the membrane & enter the cell. Passive Other metals (eg: Pb) diffusion The toxic effects of metals usually involve interaction between free metal & the cellular target. The target tends to be specific biochemical processes and/or cellular and subcellular membranes.  Enzyme inhibition/ activation Endocrine & Subcellular reproductive organelles effects Common Toxic Respiratory Nervous system Mechanisms system & Sites Of Action Kidney Carcinogenicity Metal-binding protein Enzyme Inhibition / Activation Interaction of metals with enzymes Enzyme Enzyme inhibition activation Due to the interaction Metal displace an between metal with essential metal sulfhydryl (SH) groups cofactor of the on the enzyme. enzyme. Eg: Pb displace Zn in the zinc- dependent enzyme δ-aminolevulinic acid dehydratase (ALAD) and inhibit the synthesis of heme.  Subcellular Organelles Carcinogenicity Kidney Disrupt the structure & Some metals have been function of organelles. identified to be Common target organ carcinogenic in humans for metal toxicity due to and animals. its function as the main Eg: enzymes associated with endoplasmic reticulum may excretory organ. be inhibited, metals may be Example of human accumulated in lysosomes, carcinogens: As, chromium compounds, nickel. Example of respiratory enzymes in the nephrotoxicants: Cd mitochondria may be and Hg inhibited, & metal inclusion Example of probable bodies may be formed in the human carcinogens: Cd, nucleus. cisplatin, beryllium.  Endocrine & Nervous System Reproductive Effects Respiratory System Common target especially Male & female reproductive organs Occupational exposure (metal for organic metal are under neuroendocrine & dust). hormonal control, therefore any compounds. toxicants that can alters any of these processes will affect the reproductive Acute exposure: May cause irritations & inflammation of Eg: system. respiratory tract. Methylmercury – lipid Some metals can directly affect the soluble, able to cross sex organs. Chronic exposure: fibrosis BBB & enter nervous (aluminium), carcinogenesis (As, Eg: Cd can cause testicular injury system. after acute exposure, lead Cr, Ni). Organic Pb compounds accumulation in the testes (testicular – mainly neurotoxicants. degeneration), inhibition of spermatogenesis & Leydig-cell atrophy.  Metal-Binding Proteins The toxicity of most metals (eg: Cd, Pb Hg) depends on their transport & intracellular bioavailability. This availability is regulated to a degree by high-affinity binding to certain cytosolic proteins. Ligands usually possess many SH binding sites that can outcompete other intracellular proteins & mediate intracellular metal bioavailability & toxicity. Metallothionein (MT), a metal-binding protein is important in regulating the intracellular bioavailability of Cd, Cu, Hg, Zn and Ag.  Exposure to Toxic Heavy Metals Classification Acute: ≤ 14 days Intermediate: 15-354 days Chronic: > 365 days Acute exposure Chronic exposure Sudden/unexpected exposure. Repeated/ continuous exposure. Dose: Usually high Accumulation of the toxic substance in the body. Eg: accidental spill, careless handling. Dose: Usually low Eg: contaminated food, air, water, or dust, living near a hazardous waste site; working in contaminated area. OVERVIEW OF METAL TOXICOLOGY  Arsenic A metalloid (having both properties of a metal and a nonmetal). However, it is frequently referred to as a metal. Organic As – As combined with C and H. Inorganic As - As combined with other elements such as O, Cl & S. White / colorless powders Do not evaporate No smell Mostly have no special taste Hard to identify the presence of As in food, water, or air.  Arsenic is associated with ores containing metals, such as Cu and Pb. Released into the environment by the smelting process, manufacturing of chemicals and glasses, and semiconductor industry (AsH3). Also found in water supplies worldwide (exposure to aquatic organisms), paints, rat poisoning, fungicides, pesticides and wood preservatives. Cannot be destroyed in the environment but can change its form, or become attached to or separated from particles. As compounds occur in 3 forms: i. Pentavalent (As+5) – organic / arsenate compounds (eg: alkyl arsenates). ii. Trivalent (As+3) – inorganic / arsenate compounds (eg: Na3AsO4; As2O3); lipid soluble. iii. Arsine gas (AsH3) – most toxic form (TLV-TWA = 0.05 ppm).  Microorganisms in the Contamination of As environment convert As compounds in well to dimethylarsenate water Human Accumulate in fish and exposure shellfish It binds to SH groups of tissue protein. Within 24h of absorption, As distributes Crosses the blood-brain barrier (small amount). throughout the body Replace phosphorus in bone tissue and be stored for years.  Acute Chronic Sore throat from breathing Peripheral and central nervous Red skin at contact point changes (eg: sensory changes, numbness and tingling, and muscle Severe abdominal pain tenderness. Vomiting Symptoms Watery & bloody diarrhea (often within 1 hour after ingestion) Burning sensation ("needles and pins") in hands and feet. Neuropathy (inflammation and of Arsenic Anorexia Fever Renal failure wasting of the nerves) is usually gradual and occurs over several years. Poisoning Mucosal irritation Arrhythmia Hyperpigmentation in areas that are not exposed to sunlight. Cardiovascular changes (often subtle Excessive formation of skin on the palms and soles (hyperkeratosis). in the early stages but can progress to cardiovascular collapse). White bands of arsenic deposits Target organs: across the bed of the fingernails Blood Death (usually results from circulatory (usually 4-6 weeks after exposure). Kidneys failure within 24 h – 4 days. Central nervous system Birth defects. Digestive system Liver injury. Skin system Skin cancer.  Lead Applications Used in pipes, batteries and soldering materials for many years. Inorganic Pb may be absorbed via Homes built before 1940 mostly still GI tract, respiratory system & skin. contain lead (mostly in painted surfaces), thus cause chronic exposure due to The absorption of inorganic Pb in GIT is more efficient in children. It weathering, flaking, and dust. can also penetrates the BBB. It may crosses the placenta. Cable coverings, paint pigments, printing Pb distributed in kidney, blood & ink, gasoline, fertilizer, PVC plastics, X- liver. ray shielding, crystal glass production, Prolonged exposure – 95% of the pencils, and pesticides. body burden of Pb is in bone tissue.  Main Target Of Pb Hematopoietic System Nervous System Reproductive System Tend to affect infants & young Several enzymes involved in heme Male & female reproductive toxicity, children. miscarriages & degenerate offspring. synthesis are sensitive to inhibition by Pb (Eg: ALAD & heme Low level of exposure – synthetase (HS)). hyperactivity, mental deficiencies, impaired vision. Higher levels of exposure – encephalopathy (in children & Clinical anaemia mostly occurs adult). after moderate exposure to Pb. Pb damages arterioles & capillaries, thus cause cerebral edema & neuronal degeneration. Inhibition of ALAD or the presence of ALA in urine can be used as Clinical manifestations – ataxia, biomarkers to detect lead exposure coma, stupor, convulsions. at lower levels. Acute exposure to Pb is more likely to occur in the workplace. Target organs: Bones Brain Chronic exposure to Pb: Blood Birth defects Kidneys Mental retardation Thyroid gland Autism Allergies Dyslexia Hyperactivity Acute exposure to Pb: Loss of body weight Abdominal pain Shaky hands Convulsions Muscular weakness Hypertension Paralysis (beginning in the forearms) Renal dysfunction Arthritis Loss of appetite Numbness Fatigue Seizures Sleeplessness Lack of concentration Hallucinations Headache Numbness Arthritis  Cadmium Occurs in nature primarily in association with Pb & Zn ores & released near mines & smelters processing these ores. Industrially is used in nickel-cadmium batteries, PVC plastics, paint pigments & electroplating. Environmental exposure - mainly from contamination of groundwater (from smelting & industrial uses , the use of sewage sludge as a food-crop fertilizer). Main source of Cd in food – cereal products, grains & leafy vegetables. Consumption of Cd-contaminated rice in Japan = Itai-itai disease. Caused by Cd poisoning due to mining activities in Japan. Rice & cereals were contaminated with Cd2+. Severe kidney damage & osteomalacia (soft bone disease).  Target of Cadmium Lungs Kidney Liver Brain Bones s 1 Acute Cd Exposure Primary Ingestion – nausea, vomiting, effects abdominal pain Inhalation - breathing difficulty, pulmonary edema & chemical pneumonitis.  Cd is very slowly excreted from the body – chronic effects. Half-life of about 30 years. Low levels of exposure – Cd accumulation. Chronic exposure to Cd Chronic obstructive lung disease Renal disease Fragile bones Anaemia Arthritis Learning disorders Migraines Growth impairment Present the strategies your Osteoporosis company will implement to Loss of taste and smell reach crucial growth objectives. Poor appetite Cardiovascular disease  Subsequent Kidney Toxicity degradation of CdMT complex releases Cd2+ , thus inhibits lysosomal function & cause cell injury. Cd in circulatory system It accumulates within lysosomes Cd/MT re-absorbed efficiently by the proximal tubule cells  Mercury Example of Hg Applications Thermometers, thermostats, and dental amalgam. Generated naturally in the environment from the Elemental mercury degassing of the earth's crust, from volcanic emissions. In the form of mercury vapor. Almost completely absorbed It exists in three forms: by the respiratory system. i. elemental mercury (Hg0) Once absorbed, it can cross ii. inorganic mercurous (Hg+) & mercuric BBB into the nervous system. (Hg2+) salts Ingestion of elemental iii. Organic mercury (Eg: CH3Hg; CH3HgCH3) mercury – usually harmless.  Organic mercury Inorganic mercury may be converted to CH3Hg via the action of sulfate- reducing bacteria. CH3Hg – a highly toxic form of mercury that can across membranes. Environmental Organic Hg primarily affects nervous system – fetal brain more sensitive than adults. Contamination Large episode of Hg poisoning of Hg Minamata disease (1950s) Consumption of fish & shellfish from Minamata Bay, Japan. By 1970, at least 107 deaths & 800 cases of Minamata disease were confirmed. Many infants developed cerebral palsy-likes symptoms & mental deficiency.  Inorganic Mercury Inorganic Hg salts –primarily nephrotoxicants. Primary site of action – proximal tubular cells. Hg binds to SH groups of membrane proteins, affecting the integrity of membrane & resulting in aliguria, anuria & uremia.  Acute exposure Mary John Cough Account Executive Marketing Director Sore throat Shortness of breath Lorem ipsum dolor sit Abdominal pain amet, consectetur Nausea adipiscing elit, sed do Vomiting eiusmod tempor. Diarrhea Headaches Weakness Visual disturbances Ryan Tachycardia Natalie Hypertension Social Media Manager Chronic Exposure Permanent damage to the central nervous system and kidneys. Hg can cross placenta, thus may affect fetus. The effects are: Ava Jason Marketing Assistant mental retardation SEO Specialist brain Lorem ipsum dolordamage sit Lorem ipsum dolor sit cerebral palsy amet, consectetur amet, consectetur Blindness adipiscing elit, sed do Seizures adipiscing elit, sed do eiusmod tempor. inability to speak eiusmod tempor. THANK YOU!  ADDRESS: CENTER OF TOXICOLOGY AND HEALTH RISK STUDIES, FACULTY OF HEALTH SCIENCE, UKM KUALA LUMPUR CAMPUS EMAIL ADDRESS: [email protected] CONTACT NO: Office: 03-92897527 Handphone: 019-2268912