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UNC-Chapel Hill ENVR 132 - Toxic effects of inorganic salts notes

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Toxic effects of inorganic saltsElaine [email protected], 962-0089Room 2308 Kerr HallSource Material (not reading assignments)Klassen CD. Heavy metals and heavy metal antagonists. In: Hardman JG, Limbird LL (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10thedition, Chapter 67. McGraw Hill (2001).Bhattacharyya MH et al., Biochemical Pathways in Cadmium Toxicity. In: Zalups RK and Koropatnick J (eds). Molecular Biology and Toxicology of Metals, Chapter 2. Taylor and Francis (2000).Tchounwou et al., (2003) Environmental Exposure to Mercury and Its Toxicopathologic Implications for Public Health. Envirn Toxicol 18:149-175.Metals and other inorganicsWhy are they of such concern ?• Widely distributed in the natural environment• Non-biodegradable• Persistent in the environment• Neither created nor destroyed by humans• Concentrated due to industrial use• Global dispersion due to human useHuman Industry and Environmental Metals; Lead in Greenland Ice1750 1800 1850 1900 1950 2000050100150200250Lead Content (ng/kg snow)Date of Samples(Modified From: Clarkson et al)What is a Metal?• Physical properties:– electrical conductivity– thermal conductivity– luster– deformed without cleavage under stress• Chemical properties:– tendency to donate electrons (cationic)– formation of basic oxidesMetalloidsTransition (heavy)metalsInner transition metals(rare earths)Other metalsAlkali metalsAlkalineearth metalsTypes of “Metals”Metals as Toxic Agents• The “toxic” metals often follow “essential” metal metabolic pathways (atomic or molecular mimicry)• Metal compounds can also mimic organic compounds• Metals often accumulate in biological systems• Metals as elements are indestructible– cannot be broken down into less toxic subunitsMolecular Mimicry with Metals: Uptake of Ionic CadmiumControl NEM KCN Zinc024681012Cellular Cadmium UptakeATPZn (+2)Cd (+2)CellSHSHCdZnHighly Toxic Inorganics• Several metals/metalloids are considered to be high priority hazardous substances• Metals considered highly toxic include:– arsenic, beryllium, cadmium, chromium, lead, mercury, and nickel • Many are potent neurotoxins– eg., lead• Out of ~ 30 known human carcinogens, 5 are metalsCdAsNiCrBeExample: Metals/Metalloids Considered Human CarcinogensCarcinogenic Metals/Metalloids• Known human carcinogenic metals:– arsenic (skin, bladder, lung, liver)– beryllium (lung)– cadmium (lung, possibly prostate) – chromium (lung, sino-nasal cavity)– nickel (lung, sino-nasal cavity)Metals/Metalloids as Toxic Agents• Many metals are essential • Essential metals have intentional accumulation, transport and storage mechanisms to allow safe use• Examples:– metallothionein for copper or zinc storage– transferrin and ferritin for iron transport and storageEssential Metals• Examples of essential metal nutrients: Co, Cr, Cu, Fe, Zn• Other possible essential metals: As, Ni• Examples of metal functions that are essential to life:– regulation of gene expression– DNA synthesis and repair– enzyme activity and structure– oxygen transport• Life could not continue without metalsFactors Influencing Metal Toxicity• Standard factors – exposure related: dose, route, duration, frequency – subject related: age, sex, species, biotransformation– agent related: speciation, form• Essentiality– essential metals have safe transport, storage utilization systems • Sensitive subpopulations• Acquired toleranceToxicMetalExposure sitePresystemic eliminationDeliveryExcretionDetoxicationDistribution away from targetToxicmetalUltimateToxicantTarget SiteTargetMoleculeAbsorptionTarget distributionReabsorptionToxicationUltimatetoxicantFactors Influencing Metal Toxicity: Sensitive Subpopulations and Environmental Exposure• Sensitive subpopulations have been observed in several diseases induced by environmental metal exposure• Examples:– Minimata disease: in utero exposed populations most affected– Itai-Itai disease: post-menopausal, multiparous women most affected– Lead toxicity: children much more vulnerableFactors Influencing Metal Toxicity: Acquired Tolerance•Examples:– enhanced sequestration:• activation of MT gene and cadmium sequestration– reduced uptake or enhanced excretion:• arsenic, nickel, cadmium– altered metabolism:• arsenic and upregulation of glutathione-S-transferase– facilitates effluxGeneral Mechanisms of Metal Toxicology• Several general mechanisms of metal toxicity– extensive overlap• General mechanisms include:– osmotic cell death • not trivial• usually at a point of locally high metal concentrations– inhalation of metal particles– metal fragments or devices in chronic contact with tissuesGeneral Mechanisms of Metal Toxicology (continued)• disruption of normal cellular metabolism• leading to aberrant metabolism or altered homeostasis• frequently occur through atomic or molecular mimicry•examples: – disruption of essential metal metabolism– depletion of cofactors (e.g., S-adenosyl methionine)– depletion of GSH (could result in altered cellular redox status)–etc.General Mechanisms of Metal Toxicology(continued)• direct binding to cellular components:• direct binding leading to dysfunction – enzyme inhibition, DNA adduction, etc.• direct binding through mimicry leading to aberrant function– gene activation, receptor activation, etc.• direct binding through mimicry leading to displacement of essential metal:– adverse effect of released essential metal – disrupted homeostasisGeneral Mechanisms of Metal Toxicology(continued)• indirect attack on cellular components: • generation of radicals that attack cellular components– directly with redox active metals (eg. Ni, Cr, Cu, etc)– indirectly with metals that displace redox active essential metals (eg. Fe, Cu)• adverse effects of radical attack:– disruption of protein conformation leading to dysfunction» diminished or enhanced » oxidative DNA damage or base modification leading to aberrant gene expression or mutation» lipid peroxidation and membrane disruptionInorganics of highest environmental concern:cadmium, mercury, lead and arsenicCadmium• Relatively rare metal present in the earth’s crust • Occurs in only one valency state Cd2+•Used as– Protective coating on steel– Colored pigments in paints and plastics (bright yellow, orange and red)–


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