{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:49:50Z","timestamp":1790401790050,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2015,4,28]],"date-time":"2015-04-28T00:00:00Z","timestamp":1430179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Metallic elements, ions and compounds produce varying degrees of toxicity in organisms with which they come into contact. Metal speciation is critical to understanding these adverse effects; the adjectives \u201cheavy\u201d and \u201ctoxic\u201d are not helpful in describing the biological properties of individual elements, but detailed chemical structures are. As a broad generalization, the metallic form of an element is inert, and the ionic salts are the species that show more significant bioavailability. Yet the salts and other chelates of a metal ion can give rise to quite different toxicities, as exemplified by a range of carcinogenic potential for various nickel species. Another important distinction comes when a metallic element is organified, increasing its lipophilicity and hence its ability to penetrate the blood brain barrier, as is seen, for example, with organic mercury and tin species. Some metallic elements, such as gold and platinum, are themselves useful therapeutic agents in some forms, while other species of the same element can be toxic, thus focusing attention on species interconversions in evaluating metal-based drugs. The therapeutic use of metal-chelating agents introduces new species of the target metal in vivo, and this can affect not only its desired detoxification, but also introduce a potential for further mechanisms of toxicity. Examples of therapeutic iron chelator species are discussed in this context, as well as the more recent aspects of development of chelation therapy for uranium exposure.<\/jats:p>","DOI":"10.3390\/toxics3020170","type":"journal-article","created":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T04:42:57Z","timestamp":1430282577000},"page":"170-186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Speciation in Metal Toxicity and Metal-Based Therapeutics"],"prefix":"10.3390","volume":"3","author":[{"given":"Douglas","family":"Templeton","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,4,28]]},"reference":[{"key":"ref_1","unstructured":"International Agency for Research on Cancer (1990). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, IARC."},{"key":"ref_2","unstructured":"Apostoli, P., Cornelis, R., Duffus, J.H., Hoet, P., Lison, D., and Templeton, D.M. (2006). Elemental Speciation in Human Health Risk Assessment. IPCS, Environmental Health Criteria 234, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/ajim.4700140303","article-title":"Acute nickel toxicity in electroplating workers who accidently ingested a solution of nickel sulfate and nickel chloride","volume":"14","author":"Sunderman","year":"1988","journal-title":"Am. J. Ind. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1016\/j.ccr.2013.02.022","article-title":"Nickel binding sites in histone proteins: Spectroscopic and structural characterization","volume":"257","author":"Peana","year":"2013","journal-title":"Coord. Chem. Rev."},{"key":"ref_5","unstructured":"Chang, L.W. (1996). Toxicology of Metals, CRC Lewis Purlishers."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0048-9697(94)90401-4","article-title":"Isotope-specific analysis of Ni by ICP-MS: Applications of stable isotope tracers to biokinetic studies","volume":"148","author":"Templeton","year":"1994","journal-title":"Sci. Total Environ."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1006\/taap.1998.8577","article-title":"Absorption and retention of nickel from drinking water in relation to food intake and nickel sensitivity","volume":"154","author":"Nielsen","year":"1999","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1351\/pac200072081453","article-title":"Guidelines for terms related to chemical speciation and fractionation of elements: Definitions, structural aspects, and methodological approaches","volume":"72","author":"Templeton","year":"2000","journal-title":"Pure Appl. Chem."},{"key":"ref_9","first-page":"3837","article-title":"Toxicity of nanoparticles","volume":"22","author":"Zoroddu","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s002160051234","article-title":"Biomedical aspects of trace element speciation","volume":"363","author":"Templeton","year":"1999","journal-title":"Fresenius J. Anal. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Caroli, S., and Z\u00e1ray, G. (2012). Analytical Techniques for Clinical Chemistry: Methods and Applications, John Wiley and Sons.","DOI":"10.1002\/9781118271858"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5964","DOI":"10.1039\/C2DT32222F","article-title":"Interaction of divalent cations with peptide fragments from Parkinson\u2019s disease genes","volume":"42","author":"Remelli","year":"2013","journal-title":"Dalton Trans."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/j.1432-1033.1985.tb09013.x","article-title":"The symbiosis of metal and protein functions","volume":"150","author":"Williams","year":"1985","journal-title":"Eur. J. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1351\/pac200274050793","article-title":"\u201cHeavy metals\u201d\u2014A meaningless term?","volume":"74","author":"Duffus","year":"2002","journal-title":"Pure Appl. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1351\/pac200779071153","article-title":"Glossary of terms used in toxicology, 2nd ed.","volume":"79","author":"Duffus","year":"2007","journal-title":"Pure Appl. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/jhmas\/jrg042","article-title":"The history of gold therapy for tuberculosis","volume":"59","author":"Benedek","year":"2004","journal-title":"J. Hist. Med. Allied Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/BF03215464","article-title":"Medical uses of gold compounds: Past, present and future","volume":"29","author":"Fricker","year":"1996","journal-title":"Gold Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1351\/pac200476061255","article-title":"Mechanisms of immunosensitization to metals","volume":"76","author":"Templeton","year":"2004","journal-title":"Pure Appl. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1172\/JCI115569","article-title":"Gold-specific T cells in rheumatoid arthritis patients treated with gold","volume":"89","author":"Romagnoli","year":"1992","journal-title":"J. Clin. Invest."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/1523-1747.ep12372149","article-title":"The molecular basis of metal recognition by T cells","volume":"102","author":"Sinigaglia","year":"1994","journal-title":"J. Invest. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.4049\/jimmunol.155.3.1575","article-title":"The antirheumatic drug disodium aurothiomalate inhibits CD4+ T-cell recognition of peptides containing two or more cysteine residues","volume":"155","author":"Griem","year":"1995","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6519","DOI":"10.1021\/jm9012856","article-title":"Gold(I) Analogues of a platinum\u2013acridine antitumor agent are only moderately cytotoxic but show potent cctivity against Mycobacterium tuberculosis","volume":"52","author":"Eiter","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1039\/b907567d","article-title":"Inhibition of transcription by platinum antitumor compounds","volume":"1","author":"Lippard","year":"2009","journal-title":"Metallomics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1179\/joc.2008.20.3.348","article-title":"Participation of Omi Htra2 serine\u2013protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells","volume":"20","author":"Pruefer","year":"2008","journal-title":"J. Chemother."},{"key":"ref_25","first-page":"471","article-title":"Understanding and improving platinum anticancer drugs\u2014Phenanthriplatin","volume":"34","author":"Johnstone","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1039\/C3MT00357D","article-title":"Pt-based drugs: the spotlight will be on proteins","volume":"6","author":"Pinato","year":"2014","journal-title":"Metallomics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1515\/pac-2014-0504","article-title":"100 Years of metal coordiation chemistry: from Alfred Werner to anticancer metallodrugs","volume":"86","author":"Barry","year":"2014","journal-title":"Pur Appl. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ccr.2014.08.002","article-title":"Noble metals in medicine: Latest advances","volume":"284","author":"Medici","year":"2015","journal-title":"Coord. Chem. Rev."},{"key":"ref_29","first-page":"395","article-title":"Genetic defects in iron and copper trafficking","volume":"Volume 1","author":"Bruce","year":"2010","journal-title":"Endogenous Toxins: Target for Disease Treatment and Prevention"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/0003-2697(92)90435-A","article-title":"Speciation of tissue and cellular iron with on-line detection by inductively coupled plasma-mass spectrometry","volume":"205","author":"Xu","year":"1992","journal-title":"Anal. Biochem."},{"key":"ref_31","unstructured":"Baes, C.F., and Mesmer, R.E. (1986). The Hydrolysis of Cations, Robert E. Krieger."},{"key":"ref_32","first-page":"411","article-title":"An update on iron chelation therapy","volume":"10","author":"Poggiali","year":"2012","journal-title":"Blood Transfus."},{"key":"ref_33","first-page":"4546","article-title":"Specific iron chelators determine the route of ferritin degradation","volume":"114","author":"Ward","year":"2009","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/MOH.0000000000000031","article-title":"Iron chelation: an update","volume":"21","author":"Sheth","year":"2014","journal-title":"Curr. Opin. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.bcmd.2011.07.002","article-title":"Iron chelation therapy in thalassemia major: A systematic review with meta-analyses of 1520 patients included on randomized clinical trials","volume":"47","author":"Maggio","year":"2011","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/ana.24248","article-title":"Deferiprone in Friedreich ataxia: A 6-month randomized controlled trial","volume":"76","author":"Pandolfo","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.critrevonc.2014.01.006","article-title":"Iron overload and chelation therapy in myelodysplastic syndromes","volume":"91","author":"Temraz","year":"2014","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3390\/ijerph7010303","article-title":"The toxicity of depleted uranium","volume":"7","author":"Briner","year":"2010","journal-title":"J. Environ. Res. Public Health"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3390\/toxics2010050","article-title":"The chemistry and toxicology of depleted uranium","volume":"2","author":"Katz","year":"2014","journal-title":"Toxics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1515\/pac-2014-0109","article-title":"Uranium toxicity and chelation therapy","volume":"86","author":"Lawrence","year":"2014","journal-title":"Pure Appl. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/j.1600-0773.1989.tb00640.x","article-title":"Treatment of experimental acute uranium poisoning by chelating agents","volume":"64","author":"Ortega","year":"1989","journal-title":"Pharmacol. Toxicol."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/3\/2\/170\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:45:29Z","timestamp":1760215529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/3\/2\/170"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,28]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,6]]}},"alternative-id":["toxics3020170"],"URL":"https:\/\/doi.org\/10.3390\/toxics3020170","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,28]]}}}