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Arsenic

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JWH 10/23/06 Center for EnvironmentalHealth Sciences at DartmouthDartmouth TOXIC METALSResearch ProgramProjectProject 8 -8 - Bruce StantonBruce Stantonmolecular toxicology of arsenicmolecular toxicology of arsenicProject 2 - Joshua HamiltonProject 2 - Joshua Hamiltonmolecular toxicology of arsenicmolecular toxicology of arsenicProject 5 - Dean WilcoxProject 5 - Dean Wilcoxbiochemistry of arsenicbiochemistry of arsenicProject 4 - Margaret Project 4 - Margaret KaragasKaragasepidemiology of arsenicepidemiology of arsenicProject 7 - CarolProject 7 - Carol Folt Folt & Celia Chen& Celia Chenecotoxicology ecotoxicology of metalsof metalsProject 6 - Carl Project 6 - Carl Renshaw Renshaw & Ben & Ben BostickBostickenvironmental chemistry of arsenicenvironmental chemistry of arsenicArsenic as a human healthhazard: mechanisms of actionJoshua W. Hamilton Ph.D.Department of Pharmacology & ToxicologyDepartment of ChemistryDartmouth Superfund Basic ResearchProgram Project on Toxic MetalsCenter for Environmental Health SciencesJWH 10/23/06METALS:Toxic Metals, Heavy Metals, Essential Metals• three-fourths of all elementsare metals or metalloids• a “heavy metal” refers to itsatomic weight, not its toxicity• many metals are essential orplay a normal role in biology• many toxic metals that are notessential can mimic essentialmetals• like all chemicals, all metals aretoxic at high enough doses• like all chemicals, all metals arenon-toxic at very low dosesJWH 10/23/06Toxic metals in the environment• Toxic metals are a major concern at both Superfund / toxicwaste sites and in the environment in general• Eight of the top fifty substances on the CDC’s ATSDR prioritylist are metals, including the top three chemicals of concern inthe environment: arsenic, lead and mercury• Eight of the twenty-two substances on the EPA’s OSWER list ofchemicals of highest concern at Superfund sites are metals:arsenic, lead, mercury, cadmium, chromium, nickel, zinc andcopperJWH 10/23/06General chemical properties of arsenic group 5 element - “metalloid” most forms of arsenic are odorless, colorless andtasteless in water As+3 or As+5 inorganic forms:• arsenic trioxide AsIII2O3, arsenic pentoxideAsV2O5, sodium arsenite NaAsIIIO2, sodiumarsenate Na2HAsVO4, AsIII(OH)3, AsVO(OH)3 organic forms:• monomethylarsonic acid (MMAV) CH3H2AsO3,dimethylarsonic acid (DMAV, cacodylic acid)(CH3)2As(O)OH, arsenobetaine (fish)(CH3)3AsVCH2CO2As+3As+5As+3As+5in vivoenvironmentJWH 10/23/06iAsVArsenosugarsMMA fromgut microfloraArsenobetaine?iAsIIIMMAVMMAIIIDMAVDMAIIITMAVTMAIIISAMSAHSAMSAHSAMSAHadapted from D. Thomas et al. US EPACurrent scheme for metabolism of arsenic in vivoS-adenosyl-l-methionine:arsenicIIImethyltransferase41 kD protein, SAM, dithiol-req.Cyt19, GA no. AF393243JWH 10/23/06Arsenic as an environmental contaminant U.S. drinking water standard (MCL) for arsenic was 50parts per billion (ppb) from 1950’s through 2001 recently lowered to 10 ppb, 7-14 year implementation current WHO and EU arsenic standard is 10 ppb highly contaminated areas (India, South America) cancontain as much as 1800 ppb (180 times the WHOstandard); associated with significantly increased risk ofseveral cancers, vascular disease, and diabetes in New Hampshire, ~50% of households are on private wellsand 20% of all wells (10% of households, >120,000 people)are above 5 ppb; many are above 50 ppb (highest levels500-1400 ppb) approx. 25 million people in US with excessive AsJWH 10/23/06New Hampshire -The “arsenic state”natural arsenic in thegranite contaminatesprivate wells throughoutthe stateJWH 10/23/06Arsenic: Old History, New Concerns Known for thousands of years as an acute poison: “King ofPoisons and Poison of Kings” - still used (e.g., New Sweden ME) Also known for thousands of years as a medicinal agent (e.g.,Fowler’s Solution) - still used (e.g., curative for relapsed acutepromyelocytic leukemia) Revival of ancient belief over past thirty years: is arsenic anessential trace element? New concerns over past twenty years: low, non-overtly toxicenvironmental doses are associated with increased chronicdisease riskJWH 10/23/06Arsenic as a causative agent in human disease Chronic human exposure to inorganic arsenic (sub-clinical)has been linked to increased risk of:● Cancers- esp. lung, skin and bladder but also liver,kidney, and other malignancies● Non-cancer lung, kidney, liver diseases● Type 2 diabetes? (non-insulin-dependent, “adult-onset”)● Vascular and cardiovascular disease● Reproductive and developmental problems● Neurological and cognitive problems● Other emerging endpointsJWH 10/23/06Arsenic: mechanisms of carcinogenicity• At the cellular and molecular level, arsenic does many things, each ofwhich could contribute to disease processes• Possible mechanisms -• not a classic genotoxic mutagen -• generally negative for genotoxicity and mutagenicity• transforms cells in culture• alters DNA repair• co-genotoxin and co-mutagen• tumor promoter and tumor progressor• alters cell proliferation (cell division)• alters cell signaling, cell-cell communication• alters DNA methylation, protein phosphorylation• potent endocrine disruptor• all of the above?• Emerging hypothesis - arsenic doesn’t “cause” anything, it increasesrisks from other factors: other chemical exposures (occupational,smoking, etc.), genetic predisposition, age, diet, lifestyle, etc.JWH 10/23/06The toxicology paradigm and -omics approachesexposure internaldoseearlybiologicaleffectbiologicallyeffectivedosealteredstructure /functiondiseaseindividual susceptibilitytoxicogenomics: + ++ ++ + +toxicoproteomics: ± + ++ ++ ++Changes in gene / protein expression can reflect: transient alterationsphenotypic changes cell population changesgenetic changes (mutations)epigenetic changes (e.g., DNA methylation)JW Hamilton. Toxicogenomic and toxicoproteomic approaches for biomarkers. In: Toxicologic Biomarkers (APDeCaprio, Ed) Marcel Dekker, NY, 2006.JWH 10/23/06Model for effects of arsenic on glucocorticoid receptorRC Kaltreider et al. Environ. Hlth. Perspect. 109:245, 2001JWH 10/23/06Arsenic has opposite effects on steroid receptor functionat lower (0.01-1.0 µ M) and higher (2-3 µM) dosesJE Bodwell et al. Environ. Chem. Res. Toxicol. 17:1064, 2004No Observed Effect Level(NOEL)No Observed Effect Level(NOEL)“The FirstNOEL”50-90% suppression -2-3 µM,140-210


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