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Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide

Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide
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  1  Journal of Toxicology and Environmental Health, Part B , 10:1–269, 2007Copyright © Taylor & Francis Group, LLCISSN: 1093-7404 print / 1521-6950 onlineDOI: 10.1080/10937400701597766 HUMAN HEALTH RISK ASSESSMENT FOR ALUMINIUM, ALUMINIUM OXIDE,  AND ALUMINIUM HYDROXIDE Daniel Krewski 1,2 , Robert A Yokel 3 , Evert Nieboer 4 , David Borchelt 5 , Joshua Cohen 6 ,  Jean Harry 7 , Sam Kacew  2,8 , Joan Lindsay 9 , Amal M Mahfouz 10 , Virginie Rondeau 11 1 Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, 2 McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada, 3 College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Kentucky, USA, 4 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada, Institute of Community Medicine, University of Tromsø, Norway, 5 SantaFe Health Alzheimer’s Disease Research Center, Department of Neuroscience, McKnight Brain Institute, University of Florida, USA, 6 Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, USA, 7 National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA, 8 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada, 9  Aging-Related Diseases Section, Surveillance Division, Public Health Agency of Canada, Ottawa, Ontario, Canada, 10 United States Environmental Protection Agency, Washington DC, USA, 11 INSERM E0338 (Biostatistic), Université Victor Segalen Bordeaux 2, Bordeaux, France Guest Editors: Vic Armstrong and Michelle C. TurnerKeywords: aluminium, aluminium oxide, aluminium hydroxide, speciation, human health,neurotoxicity, exposure, toxicokinetics, toxicology, epidemiology, Alzheimer’s disease, risk assessment  DISCLAIMER  Although the present report is based primarily on peer-reviewed scientific literature, severalabstracts of work in-progress have been cited along with some personal communications that wereconsidered by the authors to be of relevance to their task. The authors included all relevant peer-reviewed scientific literature as of September 1, 2006 in their work. However, the conclusionsdrawn and the assessment of the health risks of aluminium are restricted to information appearing in the scientific peer-reviewed literature. All doses cited in the report are the doses as the alumin-ium form administered according to the srcinal study.The manuscript has been reviewed and approved for publication by internal review at the U.S.Environmental Protection Agency. Approval does not signify that the contents necessarily reflect theviews and policies of the Agency nor does mention of trade names or commercial products consti-tute endorsement or recommendation for their use. The views expressed in the current SpecialIssue of the  Journal  are solely those of the authors.Prior to embarking on the assessment, the authors were asked to identify any potential conflictsof interest. None was declared.  ACKNOWLEDGMENTS The McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa con-ducted a comprehensive review of the potential human health risks associated with exposure toaluminium, aluminium oxide, and aluminium hydroxide; this study was co-sponsored by the Inter-national Aluminium Institute (IAI) and the U.S. Environmental Protection Agency (EPA). The  Address correspondence to Daniel Krewski, Professor and Director McLaughlin Centre for Population Health Risk Assessment,University of Ottawa, Room 320, One Stewart Street, Ottawa, Ontario, Canada K1N 6N5. Tel: 613-562-5381, Fax: 613-562-5380.E-mail:cphra@uottawa.ca  2D. KREWSKI ET AL. McLaughlin Centre convened a 10-member international Expert Panel to conduct an independent assessment of aluminium health risks. The full assessment, which was authored by the Panel,appears in this Special Issue of the  Journal . An international Scientific Advisory Committee wasformed to provide independent oversight to the assessment. The Scientific Advisory Committeecomprised Jose L Domingo, Rovira i Virgili University, Spain, Anders Glynn, Swedish National Food Administration, Vesa Riihimaki, Finnish Institute of Occupational Health, and Thomas Wisniewski,New York University School of Medicine. The Scientific Advisory Committee reviewed the assess-ment for major omissions and also provided detailed comments in specific areas of expertise. Vic Armstrong and Michelle C. Turner, in serving as Guest Editors for the Special Issue, integrated theauthors’ contributions to the assessment and handled all aspects of the peer-review. None of thestudy participants received funding directly from either sponsor.The authors met two times during the period from November 2004 to April 2005 to review thescientific literature on the health risks of aluminium. Following peer-review and acceptance forpublication by the  Journal of Toxicology and Environmental Health , the sponsors were given theopportunity to provide comments related to technical issues requiring clarification. There was noobligation on the part of the authors to accept any of the changes suggested by the sponsors, how-ever, as a result of the comments, the authors were able to correct some minor errors, following which the report underwent a second peer-review.The authors wish to acknowledge Ian Arnold, Eirik Nordheim, Chris Bayliss and Ed O’Hanianfor providing helpful scientific background information on aluminium and Mari Golub and WesleyHarris for providing comments on the manuscript. The assistance of Nicole Boom and NataliyaKaryakina who served as research assistants, contributing to the development of background mate-rial on toxicological and epidemiological aspects is also gratefully acknowledged. Finally, Fan Mohelped to create a database of reference material, Nagarajkumar Yenugadhati provided editorialassistance, and Robert Clarke helped with organizational aspects of the work.D. Krewski is the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at theUniversity of Ottawa.  ABBREVIATIONS aerodynamic diameters (d ae ), alum-treated water (ATW), alveolar macrophages (AM), Alzheimer’s disease (AD), American Conference of Governmental Industrial Hygienists (ACGIH),amyloid precursor protein (APP), amyotrophic lateral sclerosis (ALS), apoliprotein E gene (ApoE),atomic absorption (AA), bacillus calmette-guerin (BCG), blood-brain barrier (BBB), bromodeoxyuri-dine (BrdU), bronchoalveolar lavage fluid (BALF), body content (B τ ), central nervous system (CNS),cerebrospinal fluid (CSF), Chemical Abstracts Service (CAS), clara cell protein 16 (CC16), clockdrawing test (CDT), coal-tar-pitch volatiles (CTPV), computerized tomographic (CT), confidenceinterval (CI), desferrioxamine (DFO), dialysis associated encephalopathy (DAE), dinitrophenol(DNP), diphtheria toxoid, tetanus toxoid, and pertussis (DTP), electroencephalogram (EEG), electro-thermal atomic absorption spectrometry (EAAS), energy dispersive (electron probe) x-ray microanal-ysis (EDX), energy dispersive x-ray spectrometry (EDXS), erythroid colony forming units (CFU-E)ethylenediaminetetraacetic acid (EDTA), European Economic Union Council (EEC), European Inven-tory of Existing Commercial Substances (EINECS), event-related potential (ERP-P300), extracellularfluid (ECF), fatty acid (FA), flammable (F), Food and Agriculture Organization (FAO), forced expira-tory volume (FEV 1 ), forced vital capacity (FVC), gastric intubation (i.g.), gastrointestinal (GI), glomer-ular filtration rate (GFR), glucose-6-phosphate dehydrogenase (G6PDH), glutathione (GSH), half life( t ½ ), hepatitis B virus (HBV), histamine provocation test (HPT), immunoglobulin (Ig), inductively-coupled plasma mass spectrometry (ICP-MS), intelligence quotient (IQ), interleukin (IL), Interna-tional Agency for Research on Cancer (IARC), International Programme on Chemical Safety (IPCS),intramuscular (i.m.), intraperitoneal (i.p.), intravenous (i.v.), job-exposure matrix (JEM), lactatedehydrogenase (LDH), laser microprobe mass analysis (LAMMA), laser microprobe mass spectros-copy (LMMS), limit values for average exposure (VME), macrophagic myofasciitis (MMF), manualmetal (MMA), margin of exposure (MOE), mass median aerodynamic diameter (MMAD), maximum   ALUMINIUM AND HUMAN HEALTH3 contaminant level (MCL), maximum workplace concentration (MAK), mega tonnes (Mt), metalinert-gas (MIG), micro-beam proton-induced X-ray emission (PIXE µ beam), micronucleated poly-chromatic peripheral erythrocyte (mnPCE), mini-mental state exam (MMSE), minimal risk level(MRL), monocarboxylate-1 (MCT-1), National Institute for Insurance Against Occupational Acci-dents (INAIL), National Institute for Occupational Safety and Health (NIOSH), neurofibrillarydegeneration (NFD), neurofibrillary tangle (NFT), neutron activation analysis (NAA), odds ratio(OR), oxidized glutathione (GSSG), parathyroid hormone (PTH), parathyroidectomy (PTX), Parkin-sonism-dementia (PD), particulate matter (PM), permissible exposure limit (PEL), physiologicallybased pharmacokinetic (PBPK), area under the concentration x time curve (AUC), polycyclic aro-matic hydrocarbons (PAH), presenile dementia of the Alzheimer type (PDAT), provisional tolerableweekly intake (PTWI), reactivity limit (RL), recommended exposure limit (REL), reconstituted soft water (RSW), relative risk (RR), risk phrase (R), safety phrase (S), scanning electron microscopy(SEM), secondary ion mass spectrometry (SIMS), short term exposure limit (STEL), sodium alumin-ium phosphate (SALP), standardized incidence ratio (SIR), standardized mortality ratio (SMR), sub-cutaneous (s.c.), tetanus toxoid (TT), thiobarbituric acid reactive substances (TBARS), threshold limit value (TLV), thyroparathyroidectomized (TPTX), time-weighted average (TWA), total parenteralnutrition (TPN), total suspended particles (TSP), toxic (T), transferrin (Tf), transferrin-receptor medi-ated endocytosis (TfR-ME), transmission electron microscopy (TEM), tungsten inert-gas (TIG), tumornecrosis factor (TNF), U.S. Environmental Protection Agency (EPA), U.S. Occupational Safety andHealth Administration (OSHA), volume of distribution (V d ), wavelength dispersive X-ray microanaly-sis (WDX), World Health Organization (WHO), zirconium aluminium glycinate (ZAG). EXECUTIVE SUMMARY Identity, Physical and Chemical Properties, Analytical Methods  A compendium is provided of aluminium compounds used in industrial settings, and as phar-maceuticals, food additives, cosmetics and as other household products. Most aluminium com-pounds are solids exhibiting high melting points. The solubility of aluminium salts is governed bypH, because the aluminium(III)-cation (Al 3+ ) has a strong affinity for the hydroxide ion, which pro-motes precipitation. Like Mg  2+  and Ca 2+  ions, Al 3+  in most situations seeks out complexing agentswith oxygen-atom donor sites such as carboxylate and phosphate groups, including in biologicalsystems. Aluminium oxides, hydroxides and oxyhydroxides occur in numerous crystallographicforms, which exhibit different surface properties. Few compounds of aluminium are classified in Annex 1 of the European Economic Union Council (EEC) Directive 67/1548, with aluminium powderand sodium aluminium fluoride (cryolite) as examples of exceptions, as well as compounds inwhich the anion renders them reactive such as aluminium phosphide. And finally, the more recent analytical methods available for the study of chemical speciation in solids and solution, and forquantitative analysis, have been applied to the determination of aluminium and the identificationof its various forms. Sources of Human Exposure  Aluminium and its compounds comprise about 8% of the Earth’s surface; aluminium occursnaturally in silicates, cryolite, and bauxite rock. Natural processes account for most of the redistri-bution of aluminium in the environment. Acidic precipitation mobilizes aluminium from naturalsources, and direct anthropogenic releases of aluminium compounds associated with industrialprocesses occur mainly to air. Certain uses lead to the presence of aluminium in drinking waterand foodstuffs.Bauxite is the most important raw material used in the production of aluminium. Bauxite isrefined to produce alumina from which aluminium metal is recovered by electrolytic reduction;aluminium is also recycled from scrap. Aluminium hydroxide is produced from bauxite. In 2004,primary aluminium was being produced in 41 countries, the largest producers being China, Russia,Canada and the United States. In that year, worldwide production of primary aluminium, alumina  4D. KREWSKI ET AL. and aluminium hydroxide reached about 30, 63, and 5 million tonnes per annum, respectively.More than 7 million tonnes of aluminium is recovered annually from recycled old scrap.The largest markets for aluminium metal and its alloys are in transportation, building and con-struction, packaging and in electrical equipment. Transportation uses are one of the fastest growing areas for aluminium use. Aluminium powders are used in pigments and paints, fuel additives,explosives and propellants. Aluminium oxides are used as food additives and in the manufacture of,for example, abrasives, refractories, ceramics, electrical insulators, catalysts, paper, spark plugs, light bulbs, artificial gems, alloys, glass and heat resistant fibres. Aluminium hydroxide is used widely inpharmaceutical and personal care products. Food related uses of aluminium compounds includepreservatives, fillers, colouring agents, anti-caking agents, emulsifiers and baking powders; soy-based infant formula can contain aluminium. Natural aluminium minerals especially bentonite and zeolite are used in water purification, sugar refining, brewing and paper industries. Aluminium has not been classified with respect to carcinogenicity; however, “aluminium pro-duction” has been classified as carcinogenic to humans by the International Agency for Research onCancer (IARC) (for further explanation, please see Effects on Humans, Effects from OccupationalExposure, Cancer ). Occupational limits exist in several countries for exposures to aluminium dust and aluminium oxide. For non-occupational environments, limits have been set for intake in foodsand drinking water; the latter are based on aesthetic or practical, rather than health, considerations. Environmental Levels and Human Exposure  Aluminium may be designated as crustal in srcin, and thus surface soils at uncontaminated sitesconstitute a source of soluble aluminium species in surface water and aluminium-containing partic-ulates in sediments and ambient-air aerosols. Not surprisingly, the latter are present extensively inair samples in agricultural communities and when road dust is extensive. Environmental acidifica-tion is known to mobilize aluminium from land to aquatic environments. Interestingly, aluminiumlevels and its various forms (species) are often similar in source water and after its treatment withpotassium alum as a flocculent during drinking water purification.Workers in the aluminium production and user industries, as well as aluminium welders, expe-rience considerable exposures to the metal and/or its compounds. In the absence of occupationalexposures and chronic use of aluminium-containing antacids and buffered aspirin, food is the majorintake source of aluminium, followed by drinking water. When considering bioavailability, namelythe fraction that is actually taken up into the blood stream, food is again the primary uptake sourcefor individuals not occupationally exposed. However, chronic use of antacids, buffered aspirins andother medical preparations would likely constitute the major uptake source, even when exposed at work. Kinetics and MetabolismHumans The use of 26  Al as a tracer and accelerator mass spectrometry has enabled safestudies of aluminium toxicokinetics with real exposure-relevant doses in humans. Aluminium bio-availability from occupational inhalation exposure is ~2% whereas oral aluminium bioavailabilityfrom water has been reported to be 0.1 to 0.4%. Oral aluminium bioavailability is increased bycitrate, acidic pH, and uraemia and may be decreased by silicon-containing compounds. Oralaluminium bioavailability is also inversely related to iron status.Oral aluminium bioavailability is greater from water than from aluminium hydroxide or sucral-fate. Oral aluminium bioavailability from aluminium hydroxide is ≤ 0.1%, and is less with higherdoses. Increased oral aluminium absorption has been suggested in Alzheimer’s disease (AD) andDown’s subjects. Oral aluminium bioavailability from the diet has been estimated to be ~0.1 to0.3%, based on daily aluminium intake and urinary elimination. Results of a few studies with acontrolled diet and tea are consistent with this estimate.Steady state serum to whole blood aluminium concentrations are ~equal. Slightly >90% of plasma aluminium is associated with transferrin (Tf), ~7 to 8% with citrate, and <1% with phos-phate and hydroxide. Normal plasma aluminium concentration is believed to be 1 to 2 µ g/L.   ALUMINIUM AND HUMAN HEALTH5 Normal tissue aluminium concentrations are greater in lung (due to entrapment of particles fromthe environment) than bone than soft tissues. Approximately 60, 25, 10, 3 and 1% of the aluminiumbody burden is in the bone, lung, muscle, liver and brain, respectively. Higher concentrations areseen in uraemia and higher still in dialysis encephalopathy.Tissue aluminium concentration increases with age. Some studies have reported that the alu-minium concentration in the bulk brain samples, neurofibrillary tangles (NFT) and plaques washigher in AD subjects than controls. Other studies have found no difference. Hair aluminium con-centration has been described but its value as an indicator of aluminium body burden has not beendemonstrated.Greater than 95% of aluminium is eliminated by the kidney; ~2% in bile. Occupational alu-minium exposure increases urinary more than plasma aluminium concentration above their normallevels. Depending on the type and route of exposure, aluminium clearance has been characterizedas having multiple half-times and are estimated in hours, days, and years. Most of the Al was elimi-nated within the first week; the terminal half-life probably represents <1% of the injectedaluminium.Biological monitoring of human aluminium exposure has been conducted with urine, which isthought to indicate recent exposure, and plasma, which is thought to better reflect the aluminiumbody burden and long-term exposure. However, neither is a very good predictor of the aluminiumbody burden, which is better estimated by bone aluminium, the desferrioxamine challenge test, orcombined measurement of serum iPTH (parathyroid hormone) and the desferrioxamine test.Serum aluminium >30 µ g/L in dialysis patients has been associated with osteomalacia andrelated disorders and >80 µ g/L associated with encephalopathy. Up to 5 mg/kg of parenteral des-ferrioxamine once or twice weekly has been shown to be safe and effective for long-term treatment of aluminium overload.  Animals In studies of animals, pulmonary deposition of fly ash was 2 to 12% and wasinversely related to particle size. Oral aluminium bioavailability from water appears to be ~0.3%.The very limited data available suggest oral aluminium bioavailability from food is less than fromwater.Oral aluminium bioavailability is increased by citrate, and to a lesser extent, other carboxylicacids, increased solubility of the aluminium species, acidic pH, uraemia, increased dose of solublealuminium species, and perhaps fluoride. Oral aluminium bioavailability is decreased by silicon-containing compounds. Oral aluminium bioavailability is also inversely related to iron, calcium andsodium status. Absorption of aluminium from the gastrointestinal tract (GI) appears to be primarily in the distalintestine. There is evidence supporting several mechanisms of intestinal aluminium absorption,including sodium transport processes, an interaction with calcium uptake, and paracellular diffusion. Aluminium penetration of the skin is very shallow. Aluminium may be able to enter the brain fromthe nasal cavity by a direct route, bypassing systemic circulation, but convincing evidence is lacking. Absorption of aluminium from intramuscularly (i.m.) injected aluminium hydroxide and aluminiunphosphate adjuvants is significant, and may eventually be complete. Tissue aluminium concentra-tion increases with age.The volume of distribution (V d ) of aluminium is initially consistent with the blood volume, andthen increases with time. Steady state serum to whole blood aluminium concentrations are ~equal.Greater than 90% of serum aluminium is bound to Tf. Although aluminium has been reported inmany intracellular compartments, concentrations were often greater in the nucleus. Ferritin canincorporate aluminium.Following i.v. injection, ~0.001 to 0.01% of the aluminium dose enters each gram of brain and~100-fold more each gram of bone. Brain aluminium uptake across the blood-brain barrier (BBB)may be mediated by Tf-receptor mediated endocytosis (TfR-ME) and a Tf-independent mechanismthat may transport aluminium citrate. There appears to be a transporter that effluxes aluminiumfrom the brain into blood. Aluminium distributes into the placenta, foetus, milk, hair, and can bequantified in all tissues and fluids. Greater than 95% of aluminium is eliminated by the kidney,probably by glomerular filtration. Less than 2% appears in bile.
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