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Lead and Arsenic Toxicity

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Lead Poisoning Physical Properties Lead (Pb) has been used by humans for at least 7000 years, because it is widespread, easy to extract, and easy to work with. It is highly malleable and ductile as well as easy to smelt. Leads elemental symbol Pb, is an abbreviation of its Latin name plumbum. Metallic lead (Pb0) is resistant to corrosion and can combine other metals to form various alloys(Lead alloys are used in batteries, shields from radiation, water pipes, and ammunition) Inorganic Lead Organic Lead Lead has no known biological function.

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Uses and Sources of Lead: Lead paint: Food containers(painted with lead-based paint or lead-containing glaze, canned foods) Petrol (tetraethyl lead) Toys and Jewelry Herbal remedies from India, China, and other parts of Asia may be potential sources of lead exposure.

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Uses and Sources of Lead: Soil: Exposure to soil that contains particulate lead has been shown to be significantly hazardous for children, who are more commonly exposed by ingestion of house dust or soil than by paint chips. Water: Drinking water is also a major source of lead Exposure. Occupational sources: Remodeling construction Smelters Battery factories Ammunition. Soil: Exposure to soil that contains particulate lead has been shown to be significantly hazardous for children, who are more commonly exposed by ingestion of house dust or soil than by paint chips. Water: Drinking water is also a major source of lead Exposure. Occupational sources: Remodeling construction Smelters Battery factories Ammunition factories Ceramic glazes.

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Contribution of Sources

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Toxicokinetics Absorption of Lead: GI: Children absorb lead well orally (~50%) adults poorly (~10%). Lead absorption is enhanced if diet is poor in iron or calcium. High fat intake and inadequate calories have also been associated with enhanced lead absorption. Respiratory: Inorganic lead Skin: Organic lead

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Toxicokinetics Distribution: 95% in bone (%70 in children) 4% in soft tissue (brain, liver, kidneys, bone marrow) 1% blood Lead readily crosses the placenta

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Toxicokinetics Half-life Of Lead 25 DAYS -- BLOOD 40 DAYS -- SOFT TISSUE 20 YEARS -- BONE

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Toxicokinetics Hepatic Metabolism/Excretion Inorganic lead is not metabolized but is excreted unchanged. Organic or alkyl-lead,(leaded gasoline, also identified as tetraethyl- and tetramethyl-lead) undergoes oxidative dealkylation to the highly neurotoxin metabolites, triethyl- and trimethyl-lead. The major route of excretion of absorbed lead is the kidney. Urine: %65 Bile: %35 Children excrete less of their daily uptake than adults, with an average retention in adults of %1-4 versus %33 in children.

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Toxic Effects of Lead Nervous System Neurological, Neurobehavioral, and Developmental Effects in Children Clinically overt lead encephalopathy may occur in children with high exposure to lead, probably at BLL of 70 g/dL or higher. Symptoms of lead encephalopathy: Lethargy Vomiting Irritability Loss of appetite Dizziness Progressing to obvious ataxia, and a reduced level of consciousness, which may progress to coma and death

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Toxic Effects of Lead Neurological, Neurobehavioral, and Developmental Effects in Children The pathological findings at autopsy are severe edema of the brain due to extravasations of fluid from capillaries in the brain. This is accompanied by the loss of neuronal cells and an increase in glial cells. Recovery is often accompanied by sequelae including epilepsy, mental retardation, and, in some cases, optic neuropathy and blindness. Most studies report a 2- to 4-point IQ deficit for each g/dL increase in BLL within the range of 5 35 g/dL.

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Toxic Effects of Lead Neurological, Neurobehavioral, and Developmental Effects in Children Lead can affect the brain by multiple mechanisms: Lead may act as a surrogate for calcium and/or disrupt calcium homeostasis. Lead affects virtually every neurotransmitter system in the brain, including glutamatergic, dopaminergic, and cholinergic systems. (All these systems play a critical role in synaptic plasticity and cellular mechanisms for cognitive function, learning, and memory.)

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Toxic Effects of Lead Neurotoxic Effects in Adults CNS : Fatigue, irritability, lethargy, insomnia, headache, difficulty concentrating, memory loss and tremor. Sever lead intoxication can result in an encephalopathy characterized by depressed consciousness, seizure, and coma, in association with cerebral edema. PNS: More than a half-century ago, foot drop and wrist drop characterized the house painter and other workers with excessive occupational exposure to lead. Axonopathy motor disturbance Upper extremities, extensor

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Toxic Effects of Lead Hematologic Effects Lead has multiple hematologic effects,ranging from increased urinary porphyrins, coproporphyrins, -aminolevulinic acid (ALA), and zinc- protoporphyrin to anemia.

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Toxic Effects of Lead Renal Toxicity Acute lead nephrotoxicity consists of proximal tubular dysfunction and can be reversed by treatment with chelating agents. Chronic lead nephrotoxicity consists of interstitial fibrosis and progressive nephron loss, azotaemia and renal failure. Fanconlike syndrome A characteristic microscopic change is the presence of intranuclear inclusion bodies.

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Toxic Effects of Lead Effects on Cardiovascular System The most important manifestation of lead toxicity on the cardiovascular system is hypertension. The pathogenesis of lead-induced hypertension is multifactorial including: (1) Inactivation of endogenous nitric oxide and cGMP, possibly through lead-induced reactive oxygen species. (2) Changes in the renninangiotensinaldosterone system, and increases in sympathetic activity, important humoral components of hypertension. (3) Alterations in calcium-activated functions of vascular smooth muscle cells including contractility by decreasing Na+/K+-ATPase activity and stimulation of the Na+/Ca++ exchange pump. (4) Possible rise in endothelin and thromboxane.

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Toxic Effects of Lead Reproductive system Impairment of both male and female reproductive function is associated with over plumbism. Gastrointestinal Lead colic is a major gastrointestinal symptom of severe lead poisoning, and is characterized by abdominal pain, nausea, vomiting, constipation, and cramps. It is rarely seen today.

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Toxic Effects of Lead Bone Effects Lead has an extremely long half-life in bone, accounting for over 90% of the body lead in adults. Lead can affect bone by interfering with metabolic and homeostatic mechanisms including parathyroid hormone, calcitonin, vitamin D, and other hormones that influence calcium metabolism. Lead substitutes for calcium in bone. Lead is known to affect osteoblasts,osteoclasts, and chrondrocytes and has been associated with osteoporosis and delays in fracture repair. In children exposed to lead, a higher bone mineral density (BMD) was observed.

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Carcinogenicity 2B. Agent is possibly carcinogenic to humans Human epidemiology data weak Animal data positive

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Children Vulnerability CHILDREN are more vulnerable exposure than ADULTS Size Consume More Food Inhale More Air Developing Nervous System Increased need for Calcium

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Recommended Lead level 0.48mol/l (10g/dl) = elevated. >0.72mol/l (15g/dl) =substantially elevated. Notifiable level. >1.20mol/l (25g/dl) = dangerously elevated. >2.20mol/l (45g/dl)= Symptomatic

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Clinical Presentation Blood lead concentration (g/L) Children: 1000 GI Tract NilAbdominal pain Constipation Abdominal pain, constipation, weight loss, loss of appetite Abdominal colic, vomiting Blood Subclinical inhibition of RBC enzymes Mild anaemiaSevere anaemia CNS Effects on IQ in children? Mild fatigue, irritability, slowed motor neurone conduction Fatigue, poor concentration [Peripheral neuropathy] Encephalopathy - delirium - ataxia - fits - coma Other NilMuscle pain Hypertension, nephrotoxicity, lowered Vit D metabolism Hypertension, nephrotoxicity, lowered Vit D metabolism

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IDENTIFY & REMOVE from SOURCE Nutrition Therapy: Diets high in iron and calcium Examples of foods high in iron are: *Cheese, fish, meat, eggs, beans, spinach, raisins Examples of foods high in calcium are: * Milk, cheese, ice cream, yogurt, bread, fish, meat, broccoli, fruit, nuts

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Consider the use of chelation therapy - Chelaton terapy is wildely recomended for asymptomatic children with BLL >450g/l Increase lead excretion,reduce blood cocentration,and reverse hemotologic markers of toxcity.

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EDTA - Sodium Calcium Edetate 1000-1500 mg/m2/d, IV,IM IV for severe toxicity, particularly encephalopathy Well tolerated,

Chelation Therapy Guidelinesa Condition, BPb ( g/dL)DoseRegimen/Comments Adults EncephalopathyBAL 450 mg/m2/d75 mg/m2 IM every 4 h for 5 d CaNa2EDTA 1500 mg/m2/d Continuous infusion or 2-4 divided IV doses for 5 d (start 4 h after BAL) Symptoms suggestive of encephalopathy or >100 BAL 300-450 mg/m2/d50-75 mg/m2 every 4 h for 3-5 d CaNa2EDTA 1000-1500 mg/m2/d Continuous infusion or 2-4 divided IV doses for 5 d (start 4 h after BAL) Base dose, duration on BPb, severity of symptoms Mild symptoms or 70-100 Succimer 700-1050 mg/m2/d 350 mg/m2 tid for 5 d, then bid for 14 d Asymptomatic and

Children Encephalopathy BAL 450 mg/m2/d75 mg/m2 IM every 4 h for 5 d CaNa2EDTA 1500 mg/m2/d Continuous infusion or 2-4 divided IV doses for 5 d (start 4 h after BAL) Symptomatic or > 69 BAL 300-450 mg/m2/da50-75 mg/m2 every 4 h for 3-5 d CaNa2EDTA 1000-1500 mg/m2/da Continuous infusion or 2-4 divided IV doses for 5 d (start 4 h after BAL) Base dose, duration on BPb, severity of symptoms Asymptomatic: 45-69 Succimer 700-1050 mg/m2/d 350 mg/m2 tid for 5 d, then bid for 14 d or CaNa2EDTA, 1000 mg/m2/d Continuous infusion or 2-4 divided IV for 5 d (or rarely, D-penicillamine) 20-44 Routine chelation not indicated If succimer used, same regimen as per above group Attempt exposure reduction