Heavy Metal ToxicityMETALS AND DRUGS (CHELATORS) TO CONSIDERMETAL CHELATING AGENTS (DRUGS)Lead Ethylenediamine-tetraacetic acid (EDTA)2,3-dimercatosuccinic acid (Succimer)2,3-dimercatopropanol (BAL, Dimercaprol)PenicillamineCadmium Ethylenediamine-tetraacetic acid (EDTA)Mercury N-acetyl-penicillamine (NAP)Penicillamine2,3-dimercatopropanol (BAL, Dimercaprol)2,3-dimercatosuccinic acid (Succimer) Arsenic N-acetyl-penicillamine (NAP)Antimony Ethylenediamine-tetraacetic acid (EDTA)Iron DeferoxamineMetabolism after exposure to metals via skin absorption, inhalation, and ingestionEnvironmental Factors That Influence Lead Toxicity1. Pollution from air line industry- major cities like Atlanta, Chicago, New York2. Pottery related lead toxicity – associated with travelling3. School Children Projects-associated with handling clay4. Consumption of illicitly distilled liquor5. Old lead pipes corrode and contaminate drinking water6. Lead contamination associated with painting7. Gasoline tank cleaning associated organic lead toxicity 8. Recent recalls on “toys” (Made in China) due to excessive lead contaminationLead Toxicity Interferes With Heme BiosynthesisHeme Hemoglobin RBC functionMyoglobin Muscle functionCytochromes Mitochondrial RespirationMECHANISM OF LEAD TOXICITYHeme BiosynthesisSuccinyl CoA + Glycineδ-Aminolevulinate synthasePbδ-Aminolevulinateδ-Aminolevulinate dehydratasePbPorphobilinogenPorphobilinogen deminaseUroporphyrinogen III cosynthaseUroporphyrinogen IIIUroporphyrinogen decarboxylaseCoproporphyrinogen IIICoproporphyrinogen oxidaseProtoporphyrin IXFerrochelatase + Fe2+PbPbIncreasedin plasmaand urineIncreased in plasma and urineHemeLeadAbsorptiona. Skin- alkyl lead compounds (because of lipid solubility)b. Inhalation- up to 90% depending particle sizec. GI- adults 5 to 10%, children 40%Distribution: Initially carried in RBC and distributed to soft tissues (kidney and liver); redistributed to bone, teeth, and hairSource of exposure:a. GI- paint, pottery, moonshineb. Inhalation- metal fumesc. Skin- tetraethyl lead in gasolineMechanism of Toxicity:a. Inhibits heme biosynthesisb. Binds to sulfhydryl groups (-SH groups) of proteinsDiagnosis:a. History of exposureb. Whole blood lead level1. Children: >25 μg/dl treatments2. Adults: >50 μg/dl candidates for treatment c. Protoporphyrin levels in erythrocytes are usually elevated with lead levels> 40 μg/dld. Urinary lead excretion >80 μg/dle. Urinary δ aminolevulonic acidClinical SymptomsAcute: nausea, vomiting, thirst, diarrhea/constipation, abdominal painhemoglobinuria, oliguria leading to hypovolemic shockChronic: GI- lead colic (nausea, vomiting, abdominal pain)NMJ- lead palsy (weakness, fatigue, wrist-drop)CNS- lead encephalopathy (headache, vertigo, irritation, insomniaCNS edema)Treatmenta. Remove from exposureb. CaNa2EDTAc. 2,3-dimercaptopropanol (Dimercaprol, BAL)d. 2,3-dimercaptosuccinic acid (Succimer)e. D-penicillamineLiver CellCd-MTLysosomeRenal CellaaCdMT CdCd-MTdamageCd (200 μg/g)Cd-MTCdMTCdCd-GSHGSHTubularFluidGlomerular membranePlasmaCd-AlbCd-MT Cd-MTCd-GSHBileto urineCadmium (Cd++)Absorption:a. Inhalation 10 to 40%b. GI 1.5 to 5%Source of Exposure:a. GI-pigments, polishes, antique toysEnvironmental- electroplating, galvanization, plastics, batteriesc. Inhalation industrial, metal fumes, tobacco- 1 – 2 μg/packMechanism of toxicity:a. Inhalation: lung – local irritation and inhibition of α1-antitrypsinassociated with emphysemab. Renal:Mechanism of cadmium-induced renal toxicityDiagnosis:a, History of exposureb, Blood cadmium level >80 μg/dlClinical SymptomsAcute: Oral- vomiting, diarrhea, abdominal crampsInhalation- chest pains, nausea, dizziness, diarrhea, pulmonary edemaChronic: Oral- nephrotoxicityInhalation- emphysema-like syndrome and nephrotoxicityTreatmenta. Remove from exposureb. CaNa2EDTA(2,3 dimercaptopropanol (BAL) Cadmium complex extremelynephrotoxic and therefore is not used)Mercury (Hg)Source of exposure:a. environmental from electronics and plastic industryb. seed fungicide treatment, dentistry (dental amalgam fillings), wood preservatives, herbicides and insecticides, thermometers, batteries, and other products Absorption:a. GI- inorganic salts are variably absorbed (10%) but may be converted to organic mercury (methyl and ethyl in the gut by bacteria); organic compounds are well absorbed >90%b. Inhalation- elemental Hg completely absorbedMechanisms of toxicity:a. dissociation of salts precipitates proteins and destroys mucosal membranesb. necrosis of proximal tubular epitheliumc. inhibition of sulfhydryl (-SH) group containing enzymesDiagnosis:a. history of exposureb. blood mercury >4 µg/dlClinical SymptomsAcute: 1, (inorganic salts) degradation of mucosa- GI pain, vomiting, diuresis,anemia, hypovolemic shock, renal toxicity.2, (organic) CNS involvement- vision, depression, irritability, blushing,intention tremors, insomnia, fatigue, diuresisChronic: CNS symptoms similar to acute organic poisoning with gingivitis, tachycardia, goiter, increased urinary HgTreatmenta. remove from exposureb. Hg and Hg salts > 4 μg/dl: 2,3 dimercaptopropanol (BAL), penicillamine, N-acetyl-penicillamine (most effective)c. Methyl Hg- supportive treatment (non absorbable thiol resins can be givenorally to reduce Hg level in the gut)Minamata disease:Arsenic, As3+, As5+Sources of exposure:a. GI – well water, food b. Inhalation- fumes and dust from smelting Environmental: byproducts of smelting ore, AsGa in semiconductors, herbicides and pesticides Absorption:a. GI-inorganic: trivalent (arsenites) and pentavalent (arsenates) salts >90%organic: also bound as tri and pentavalent >90%Distribution: accumulates in lung, heart, kidney, liver, muscle and neural tissue. Concentrates in skin, nails and hair. Half life is 7 to 10 hoursMechanism of toxicity:a. Membranes: protein damage of capillary endothelium increased vascular permeability leading to vasodilation and vascular collapseb. Inhibition of sulfhydryl group containing enzymesc. Inhibition of anaerobic and oxidative phosphorylation (substitutes for inorganic phosphate in synthesis of high-energy phosphates)Clinical SymptomsAcute: damage to mucosa, sloughing, diarrhea (rice-water stools), hypovolemic shock, fever, GI discomport/pain, anorexia.Chronic: weakness, GI irritation, hepatomegaly, melanosis, arrhythmias, peripheral neuropathy, perivascular disease (blackfoot disease)Carcinogenicity: epidemilogic evidence; liver angiosarcoma,
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