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highly desirable properties: low melting point, malleability, durability, low cost, octane-boosting Lead poisoning (plumbism) is now considered one of the most common diseases of environmental origin Because of unique differences we will discuss lead poisoning in adults and then children separately. The earliest recorded lead mine reportedly existed in Turkey in 6500 BC widely used in the manufacture of brass and cosmetics in Greek Bronze Age lead geologically coexisted with silver as long as 2200 years ago, 25,000 tons of lead were produced annually Romans used lead in their plumbing, cooking utensils, and in the vessels that concentrated grape juice for wine In wine it enhanced color, wetness, and bouquet Hippocrates wrote descriptions of lead colic. Similar descriptions have been recorded throughout history by Benjamin Franklin and others Initial interest: 1839: clinical course of workers, primarily painters, who developed lead colic mean blood lead level has declined more than 80% since the performance of NHANES II (1976–1980), from 12.8 μg/dL to a current level of about 2 μg/dL The normal range is now considered to be less than 40 μg/dL. However, many clinicians continue to believe that lead poisoning in adults is defined only by the presence of clinical symptoms, not by any particular blood lead level. The increasing evidence of subclinical effects at low blood levels in adults argues for defining lead intoxication as a blood lead level of greater than 25 μg/dL Sources OCCUPATIONAL LEAD PAINT AIR WATER SOIL HOBBIES FOLK AND ALTERNATIVE MEDICINES FOOD OTHER Occupational lead standards were introduced by the Occupational Safety and Health Administration (OSHA) in 1978 the permissible exposure limit for lead is 50 μg/m3 for an 8-hour time-weighted average Workers with blood lead levels of 60 μg/dL or greater must be removed from the workplace; those with blood lead levels of 50 μg/dL or greater on three occasions at 1-month intervals in the prior 3 months must also be removed from work. Those with blood lead levels of 40 μg/dL or greater must undergo medical evaluation. Employers are responsible for paying the salaries of employees who are removed from work for lead-related reasons. Because of the reproductive effects of lead at lower lead levels, recommendations have been made that the permissible blood lead level in workers be reduced to 10 μg/dL the synthesis of methamphetamine may involve lead acetate. Sporadic reports have described lead intoxication from the injection of lead-contaminated methamphetamine Lead absorption from retained bullets can occur in those with gunshot wounds Lead absorption from pleura and synovial fluid is most efficient TOXICOKINETICS Lead is variably absorbed after ingestion Absorption is active, mediated by the same mucosal transport proteins that mediate calcium transport dependent on several factors, including the form of lead, particle size, gastrointestinal (GI) transit time, nutritional status, and chronologic age (30% to 50% vs 10%). increased lead absorption: Iron deficiency calcium deficiency High fat intake and inadequate calories half-life of about 30 days in adults 95% of lead is attached to (or within) the erythrocyte; thus, it is blood lead and not serum lead levels that are measured only 1% to 5% in the circulation Readily crosses the placenta; fetal blood lead levels are typically 30% to 35% higher than maternal blood levels Blood soft tissues, including the liver, kidneys, bone marrow, and brain hydroxyapatite lattice (inert and nontoxic) bone mobilization (e.g., zero gravity, complete bed rest, medications, advancing years, thyrotoxicosis, pregnancy) If not chelated only about 30 μg/day is excreted by the kidneys Therefore, declining blood lead levels in those with lead poisoning not undergoing chelation represent only lead’s distribution into soft tissues, not its excretion In occupational monitoring, urinary lead excretion of less than 50 μg/g of creatinine is within normal limits. Lead’s overall half-life is about 10,000 days (20–30 years) MECHANISMS OF TOXICITY toxic to enzymes, particularly zinc-dependent enzymes Kidneys: interferes with the heme-containing hydroxylase enzyme, which converts 25-vitamin D to 1,25-vitamin D (reversible) toxic action on the renal tubules tubulopathy selective proteinuria Levels > 40 μg/dL, lead produces dense intranuclear inclusion bodies in renal tubules More advanced interstitial fibrosis & tubular atrophy, with relative sparing of the glomeruli Hematopoietic: high affinity for sulfydryl groups, particularly those of metalloenzymes: heme synthetic pathway, particularly ○ δ- aminolevulinic acid dehydratase accumulation of δ-aminolevulinic acid, a putative neurotoxin ○ coproporphyrinogen oxidase, and ○ Ferrochelatase elevated levels of erythrocyte protoporphyrin (EP) Neurons: inhibit calmodulin, pyruvate kinase, and other enzymes essential to neuronal function inhibition of cellular functions requiring zinc and calcium Lead interferes with normal calcium metabolism, causing intracellular calcium buildup; it binds to most calciumactivated proteins with 100,000 times greater affinity CNS irritability, lethargy, insomnia, headache, difficulty concentrating, memory loss, Tremor abnormal auditory brainstem evoked potential encephalopathy characterized by depressed consciousness, seizures, and coma, in association with cerebral edema Life-threatening neurotoxicity usually develops with blood lead levels exceeding 150 μg/dL. PNS axonopathy that results in motor disturbances upper extremities more than the lower extremities, the extensors more than the flexors, and the dominant more than the nondominant arm The initial segmental demyelination eventually leads to injury of both the axon and cell body Kidneys lead, like cadmium, produces a renal injury characterized by excretion of β2-microglobulin and N-acetylglucosidase. (early markers of subacute lead-induced renal injury) chronic exposure to lead can result in hypertension (disturbances in vasomotor tone) hematopoietic system Basophilic stippling of erythrocytes, the precipitation of nuclearmaterial is a hallmark of severe lead exposure. Lead is also a potent suppressor of heme synthesis, producing anemia once lead levels exceed 50 μg/dL; the anemia can be either normochromic or hypochromic Reproduction a higher rate of spontaneous abortion and stillbirth Lead is one of the few toxins in which paternal exposure is also associated with adverse reproductive outcomes decreased sperm counts and a higher number of abnormal sperm others Other complications of lead intoxication include hypertension, GI disturbances, mild liver function abnormalities, gingival lead lines (blue discolorations of the gingiva), muscle and joint aches, and gouty arthritis diagnostic evaluation blood lead level: easy to obtain poor measure of total body burden atomic absorption spectrometry, anodic strip voltammetry, thermal- ionization mass spectrometry, and inductively coupled plasma–mass spectrometry (ICPMS) All of these, when performed with appropriate quality control measures, are extremely accurate x-ray fluorescence (XRF): difficult in children EP measurement remains important in the evaluation of lead exposure Less disturbance in adults lag behind lead exposure by several days Although investigators have suggested that Nacetylglucosidase can be used as a marker of lead-induced renal injury, the clinical utility of this test has not yet been proved measurement of auditory brainstem evoked potentials and nerve conduction velocity. Lumbar puncture should not be performed in patients with altered mental status from suspected lead poisoning because the underlying cerebral edema can lead to herniation Treatment Cessation of further exposure. The most important lead chelator developed is dimercaprol: British antilewisite (BAL) in addition mercury, arsenic, and gold 50% adverse effect preparation in a peanut oil only IM Can produce hemolysis in G6PD deficiency Other adverse effects: hypotension, rash, vomiting, and a metallic taste BAL should be administered to any patient with encephalopathy or a whole blood lead level greater than 100 μg/dL. The dose is 4 to 6 mg/kg per dose (maximum 300 mg per dose) Another effective lead chelator is calcium disodium ethylene diamine tetraacetic acid (CaNa2EDTA, calcium edetate) The resulting complex is excreted in urine. EDTA can be administered intravenously or intramuscularly; it is not administered orally, (less effective and possibly enhance GI absorption) EDTA has a very short half-life (about 65 minutes). it is ideally administered by continuous intravenous infusion. But intramuscular or intravenous administration two to three times dailyis acceptable. The dose of EDTA given to adults is 1 to 2 g daily. EDTA chelates nutrients, particularly zinc, in addition to lead. Therefore, in order to avoid zinc deficiency, courses of EDTA are limited to 5 days, followed by at least a 48-hour hiatus for nutritional recovery. EDTA courses are also limited to minimize its nephrotoxicity (manifested by proteinuria, hematuria, or glycosuria) A limitation of EDTA is its relative ineffectiveness with blood lead levels less than 30 to 35 μg/dL, which narrows its range of utility Oral chelators These include: succimer and D-penicillamine Chelation therapy is often withheld until blood lead levels exceed 70 μg/dL. EDTA chelation can exacerbate CNS toxicity when it is used alone when lead levels greater than 70 to 100 μg/dL; this CNS toxicity probably represents EDTA promotion of lead penetration into the brain. Thus dual therapy with EDTA and BAL should be considered for adults with blood lead levels greater than 100 μg/dL. BAL can be discontinued once the blood lead level has fallen below the range of 70 to 80 μg/dL Pregnant lead-poisoned women, unless their plumbism is severe, should not undergo chelation because of the possibility that the chelating agent will enhance lead movement across the placenta and be teratogenic CHILDHOOD LEAD POISONING Childhood lead poisoning was first reported in Brisbane, Australia, in 1899 of young children with the ingestion of paint in their homes studies have reported that lead poisoning in children can lead to subnormal intelligence, hyperactivity, aggression, and school failure According to the 1991 CDC guidelines, blood lead of 10 μg/dL or greater was demonstrable toxic. The peak onset of lead poisoning in children is the second year of life In children, lead paint and dust are the primary source of lead poisoning Lead paints: 1. relatively sweet 2. attractive to curious young children 3. 50% lead by weight 4. Pica A reported case of fatal childhood lead intoxication (blood lead level, 283 μg/dL) occurred after a child ingested a lead curtain weight, which was retained in the GI tract for several weeks Risk factors: oral habits of the child developmental delay e.g. Autism more prevalent in summer than winter. tendency for recurrent exposure despite environmental hazard reduction The half-life of lead in the soft tissues of children may be longer, probably because children have less bone available for lead incorporation. several studies indicate that the amount of lead excreted into breast milk is negligible unless maternal blood lead level is greater than 40 to 50 μg/dL Because lead freely crosses the placenta, the fetus invariably receives some amount of maternal lead, presumably in association with the degree of skeletal lead in the mother, reflecting her lifelong exposure Maternal bone lead has been correlated with fetal neurotoxicity encephalopathy appears in children at blood lead levels as low as 50 to 60 μg/dL Prominent features: irritability, anorexia, apathy, listlessness, abdominal pain, obtundation, if untreated, cerebral edema,seizures, and death Peripheral neuropathy can occur in children with lead intoxication children with sickle cell disease may be at higher risk for this complication subclinical peripheral neuropathy at lead levels as low as 30 μg/dL Lead can disturb bone development, leading to the formation of growth arrest, or “lead lines.” Lead lines are best identified at the metaphyses of long bones, particularly the distal radius and proximal fibula. These lines generally appear 3 to 6 weeks after a period of significant lead exposure and generally correlate with a peak blood lead level of greater than 45 to 50 μg/dL. because of the risk for CNS deterioration or death when EDTA alone is given to children with severe lead intoxication, dual therapy with both BAL and EDTA should be instituted for children with blood lead levels of 70 μg/dL or greater. EDTA is begun about 4 hours after the first dose of BAL. BAL is given every 6 to 8 hours until the blood lead level is less than 70 μg/dL. EDTA is given in a daily dose of 35 to 50 mg/kg per day (1000 to 1500 mg/m2) A “rebound” blood lead level measurement should be obtained 2 to 3 days after the EDTA is discontinued for those in whom an immediate second course of EDTA chelation is anticipated It is not uncommon for children with blood lead levels of 60 μg/dL or greater to require two or more courses of EDTA. not every child with lead intoxication has a gratifying response to EDTA chelation, particularly children with blood levels less than 45 μg/dL, EDTA mobilization test greater than 0.6 D-Penicillamine incompletely understood chelating properties Effective even in children with blood lead levels of 20 to 35 μg/dL. Blood lead levels as low as 3 μg/dL can be achieved is given in a dose of about 15 mg/kg daily The tablets must usually be crushed or the capsules opened and placed in food or drink. Iron supplementation should be discontinued 65% decrease Children must be monitored every 2 to 4 weeks for evidence of adverse effects. Penicillamine has an overall adverse effect rate of 5% to 10%, GI upset Rash WBC deppresion Monitoring laboratory tests include CBC, urinalysis, blood lead, and EP determinations. Typical courses of D-penicillamine therapy are 2 to 3 months in length. Dimercaptosuccinic acid (DMSA) or Succimer has been approved for use in children with blood lead levels exceeding 45 μg/dL. its safety and efficacy extend to children with blood lead levels between 25 and 45 μg/dL it is prudent to use conventional, dual parenteral therapy (EDTA and BAL) in children with blood lead levels of 70 μg/dL or greater The current treatment protocol is administration of 10 mg/kg per dose. For the first 5 days of succimer therapy, it is given three times daily. For the next 14 days, treatment is twice a day. A complete course of DMSA chelation is therefore 19 days. An alternative regimen is 10 mg/kg/dose, given twice a day for 28 days. Succimer, unlike BAL, does not produce hemolysis in those with G6PD deficiency. Also, succimer can be administered concomitantly with iron therapy. Side effects: rash and minor elevations in hepatic transaminases in contrast to penicillamine, succimer discontinuation is followed by a robust rebound in blood lead level, appearing 2 to 4 weeks after completion of therapy Because lead rebounds can be confused with reexposure to lead, it is important to monitor EP levels. Lead reexposure is associated with increases in EP values; lead rebound is not.