Heavy Metals in the Environment - Chapter 10 pps

10 Aluminum John Savory, R. Bruce Martin, and Othman Ghribi University of Virginia, Charlottesville, Virginia Mary M. Herman National Institutes of Health, Bethesda, Maryland 1. INTRODUCTION In 1856 Charles Dickens expressed enthusiasm about the newly discovered metal aluminum (Al), but it was not until 1886 that large-scale production was intro- duced. Since that time the use of Al has increased enormously and has become the focus of a major industry. A few studies on Al toxicity were carried out as early as 1888, but over the years, exposure to Al has generally been considered to be a minor problem. In a report in 1957, Campbell et al. expressed few con- cerns about hazards to human health presented by Al (1). The extensive literature that formed the basis of this report was published prior to the development of reliable analytical methods for the measurement of Al. Assessment of the hazard presented by certain forms of Al exposure to humans, animals, and plants has proved to be a difficult task. Aluminum is highly abundant in the environment and represents 8% of the earth’s crust, with only oxygen and silicon exceeding it in quantity, and is the most abundant metal. Copyright © 2002 Marcel Dekker, Inc. However, Al is complexed in minerals that conceal its abundance and, surpris- ingly, the concentration in the ocean is less than 1 µg/L. Most natural waters also have low concentrations of Al; any free Al 3ϩ is deposited in sediment as a hydroxide. It is with an increase in the acidity of fresh waters that Al can poten- tially pose a threat to living systems. Despite the abundance of Al in the environ- ment, it is present in relatively small amounts in healthy living systems. Nor- mally, the total body content of healthy humans is less than 30 mg. However, in certain human clinical conditions such as chronic renal failure, hyperalumi- nemia can occur, producing blood concentrations of Al that are as just as neuro- toxic as equimolar blood lead levels that result from excessive lead exposure. 2. ALUMINUM IN BIOLOGICAL SYSTEMS 2.1 Chemistry Appreciation of the toxicity of Al has been hindered by a general lack of under- standing of the chemical properties of this complex element. Al 3ϩ is a small ion with an effective ionic radius in sixfold coordination of only 54 pm. By way of comparison, other values are Fe 3ϩ , 65; Mg 2ϩ , 72; Zn 2ϩ , 74; and Ca 2ϩ , 100 pm (2). On the basis of ionic radii, Al 3ϩ is closest in size to Fe 3ϩ and Mg 2ϩ . High concentrations of Al colocalize with iron in brain cells (3). Ca 2ϩ is much larger, and in its favored eightfold coordination exhibits a radius of 112 pm, yielding a volume 9 times that of Al 3ϩ . In the mixed crystal Ca 3 Al 2 (OH) 12 , each hexacoordi- nate Al 3ϩ is surrounded by six hydroxide ions and each cubic Ca 2ϩ by eight hydroxide ions. Each metal ion adopts its own favored coordination number. The Al-O distances are 192 pm and the average of the Ca-O distances is 250 pm (4). The difference of 58 pm agrees exactly with the difference of ionic radii quoted above between six coordinate Al 3ϩ and eight coordinate Ca 2ϩ . Thus, the Al 3ϩ and Ca 2ϩ sites are distinctly different; one metal ion does not substitute for the other. For these reasons it is unlikely that Al 3ϩ binds strongly to the Ca 2ϩ sites of cal- modulin (5,6). With one-quarter of its amino acid residues bearing carboxylate side chains, calmodulin is an acidic protein that should bind multiply charged ions as a polyelectrolyte. When it does so, physical changes upon addition of Al 3ϩ are merely those of denaturation. It is, however, likely that Al 3ϩ interacts with calmodulin-regulated proteins that involve phosphate groups. By this route calmodulin-dependent reactions may exhibit an Al 3ϩ dependence (5,6). Martin has argued that in biological systems Al 3ϩ will be more competitive with Mg 2ϩ than with Ca 2ϩ (5,7). In both mineralogy and biology, comparable ionic radii frequently outweigh charge in determining behavior. More Al 3ϩ is accumulated by central nervous system tissue when the Mg 2ϩ concentration is low (8). Both Al 3ϩ and Mg 2ϩ favor oxygen donor ligands, especially phosphate groups (9). Al 3ϩ is 10 7 times more effective than Mg 2ϩ in promoting polymeriza- Copyright © 2002 Marcel Dekker, Inc. tion of tubulin to microtubules (10). In this study the free Al 3ϩ concentration was controlled near 10 12 M with nitrilotriacetate (NTA). Thus, wherever there is a process involving Mg 2ϩ , there exists an opportunity for interference by Al 3ϩ . The most likely Al 3ϩ binding sites are oxygen atoms, especially if they are negatively charged. Carboxylate, deprotonated hydroxy groups (as in cate- cholates, serine, and threonine), and phosphate groups are the strongest Al 3ϩ bind- ers. These binding characteristics differ sharply from those of the heavy metal ions that bind to sulfhydryl and amine groups. Even when part of a potential chelate ring, sulfhydryl groups do not bind Al 3ϩ . Amines bind Al 3ϩ strongly only as part of multidentate ligand systems, as in NTA and EDTA. Amino acids are weak binders, barely competing with metal ion hydrolysis (11). The nitrogenous bases of DNA and RNA do not bind Al 3ϩ strongly (5,6). The weakly basic phos- phate group of RNA and DNA also binds Al 3ϩ weakly (12), while the basic and chelating phosphate groups of nucleoside di- and triphosphates bind Al 3ϩ strongly (13). Within cells, Al 3ϩ is likely bound to nucleoside di- and triphosphates (13). In addition to stability of metal ion complexes, an important and often overlooked feature is the rate of ligand exchange out of and into the metal ion coordination sphere. Ligand exchange rates take on special importance for Al 3ϩ , because they are slow and systems may not be at equilibrium. The rate for ex- change of inner-sphere water with solvent water is known for many metal ions, and the order of increasing rate constants in acidic solutions for some biologically important metal ions is as follows: Al 3ϩ ϽϽ Fe 3ϩ ϽϽϽ Mg 2ϩ ϽϽ Zn 2ϩ Ͻ Ca 2ϩ . Each inequality symbol indicates an approximate 10-fold increase in rate constant from 1.3 s Ϫ1 for Al 3ϩ , increasing through 8 powers of 10 to Ͼ 108 s Ϫ1 for Ca 2ϩ at 25°C. Although these specific rate constants refer to water exchange in aquo metal ions, they also reflect relative rates of exchange of other ligands. Chelated ligands exchange more slowly, but the order remains. The slow ligand exchange rate for Al 3ϩ makes it useless as a metal ion engaged in enzyme active site reac- tions. The 10 5 times faster rate for Mg 2ϩ furnishes enough reason for Al 3ϩ inhibi- tion of enzymes with Mg 2ϩ cofactors. Processes involving rapid Ca 2ϩ exchange would be thwarted by substitution of the 10 8 -fold slower Al 3ϩ (4). Slow exchange of Al 3ϩ may be an important factor affecting the efficacy of administered Al 3ϩ compounds. Regardless of the type of ligand present, it is necessary to consider the hydrolysis equilibria of Al(III). At pH Ͻ 5, Al(III) exists as an octahedral hexahy- drate, Al(H 2 O) 6 3ϩ , usually abbreviated as Al 3ϩ . As a solution becomes less acidic, Al(H 2 O) 6 3ϩ undergoes successive deprotonations to yield Al(OH) 2ϩ and Al(OH) 2 ϩ (5,14). Neutral solutions give an Al(OH) 3 precipitate that redissolves, because of the formation of tetrahedral aluminate, Al(OH) 4 Ϫ , the primary soluble Al(III) species at pH Ͼ 6.2. Only two species dominate over the entire pH range, the octahedral hexahydrate Al(H 2 O) 6 3ϩ at pH Ͻ 5.5, and the tetrahedral Al(OH) 4 Ϫ at pH Ͼ 6.2, while there is a mixture of hydrolyzed species and coordination Copyright © 2002 Marcel Dekker, Inc. numbers between 5.5 Ͻ pH Ͻ 6.2 (distribution curves appear in the references) (11,14,15). If in addition other ligands are incapable of holding Al(III) in solution, it becomes necessary to include the solubility equilibrium with Al(OH) 3 (5,11,14). Inorganic Al(III) salts should not be added to neutral solutions in the absence of a solubilizing ligand. At pH 7.5, the maximum concentration of total Al(III) is about 8 µM, most of which is present as Al(OH) 4 Ϫ ; the free Al 3ϩ concentration is only 3 ϫ 10 Ϫ12 M. Unless the remainder of added Al(III) has been sequestered by other ligands, it will form insoluble Al(OH) 3 (5,6). 2.2 Al Speciation in Cerebrospinal Fluid and Brain Tissue Citrate is the main small-molecule binder of Al 3ϩ in the plasma compartment; 10% of the Al 3ϩ is bound to citrate and 90% to transferrin (6,12,16). Cerebrospi- nal fluid contains much less transferrin than plasma, and Al speciation studies (4) indicate that most of the Al is in the form of Al citrate. The pH of cerebrospi- nal fluid is 7.33, with concentrations of inorganic phosphate, transferrin, citrate, and amino acids of 0.49 mM, 0.25 µM, 0.18 mM, and 1.8 mM, respectively. Compared to plasma, cerebrospinal fluid has a higher citrate concentration (1.8 times), which favors Al citrate over Al transferrin, since the transferrin concentra- tion is about 0.5% of that in the plasma. The citrate/transferrin ratio is 2.0 in the plasma and Ͼ720 in the cerebrospinal fluid. Thus in cerebrospinal fluid Al(III) exists mainly as a citrate complex, with the free Al 3ϩ concentration comparable to that in plasma (4). 2.3 Where Is Al 3؉ Most Apt to Reside Within a Cell? Typical intracellular fluids contain about 10 mM total inorganic phosphate at pH 6.6. Analysis indicates that as for plasma and cerebrospinal fluid, the insoluble A1PO 4 in the presence of ligands such as transferrin and citrate, will become soluble, giving rise to a greater free Al 3ϩ concentration (4). For the purposes of metal ion binding, soluble phosphate groups may use- fully be divided into two classes: basic phosphates and weak or nonbasic phos- phates (12). Basic phosphates with pKa ϭ 6–7 are monosubstituted with a 2 Ϫ charge and occur as HOPO 3 2Ϫ , as the terminal phosphate in nucleoside mono-, di-, and tri-phosphates, and in many other compounds. Weakly or nonbasic phosphates with the only pKa Ͻ 2 are di (or tri)-substituted, bear a 1 Ϫ charge, and appear as the internal phosphates in nucleoside di- and tri-phosphates and in DNA and RNA. Metal ions bind strongly to the basic phosphates but only weakly to the nonbasic phosphates. The disubstituted phosphates of the nucleo- tide polymers bear one negative charge per nucleotide residue, and the polymers behave as polyelectrolytes, binding most metal ions weakly and nonspecifically. Copyright © 2002 Marcel Dekker, Inc. Al 3ϩ binds strongly to basic phosphate groups. The strongest stability constants appear where chelation occurs: for ADP (log K 1 ϭ 7.82 and log K 2 ϭ 4.34) and for ATP (log K 1 ϭ 7.92 and log K 2 ϭ 4.55) (13). For comparison, the stability constant for Mg 2ϩ binding to ATP and other nucleoside triphosphates is log K 1 ϭ 4.3 (17), 4000 times weaker than for Al 3ϩ . Thus, 0.2 µMAl 3ϩ competes with 1mMMg 2ϩ for ATP. Within a cell, ATP competes effectively with solid A1PO 4 for Al 3ϩ , and the ATP complex promises to be the predominant binder for small- molecule Al 3ϩ . It has often been supposed that Al 3ϩ binds to DNA in the cell nucleus. However, Al 3ϩ binding to DNA is so weak that a quantitative study was limited to a high pH ϭ 5.5 owing to metal ion hydrolysis and precipitation. Therefore, DNA cannot compete with ATP and other ligands for Al 3ϩ . We deduce that Al 3ϩ binding to DNA is so weak under normal intracellular conditions that it fails by several orders of magnitude to compete with either metal ion hydrolysis or insolubility of even an amorphous Al(OH) 3 . These chemical conclusions are sup- ported by the lack of DNA or RNA phosphate-bound Al 3ϩ in human neuro- blastoma cells (18). Therefore, we conclude that the observation of Al binding with nuclear chromatin is due not to its coordination to DNA but to ligands containing basic phosphates. 2.4 What Ligands Might Bind Al 3؉ in the Cell, Especially in the Nuclear Chromatin Region? ATP and ADP are comparably strong Al 3ϩ binders (13). A crucial Al 3ϩ binding site in chromatin promises to be phosphorylated proteins, perhaps phosphorylated histones. Phosphorylation and dephosphorylation reactions normally accompany cellular processes. The phosphate groups of any phosphorylated protein provide the requisite basicity, and in conjunction with juxtaposed carboxylate or other phosphate groups become strong Al 3ϩ binding sites. Abnormally phosphorylated proteins have been found in brain tissue from Alzheimer’s disease patients (19). Al(III) induces covalent incorporation of phosphate into human microtubule- associated tau (tau) protein (20). Al 3ϩ aggregates highly phosphorylated brain cytoskeletal proteins (21) and induces conformational changes in phosphorylated neurofilament peptides that are irreversible to added citrate (22). More recent studies indicate that Al can induce conformational changes in tau peptides inde- pendent of phosphorylation, suggesting that there are binding sites that possess a high affinity for Al, and that phosphorylation, while decreasing the affinity of tau to microtubules, might have little effect on conformation (23). High Al(III) concentrations have been found associated with increased linker histones in the nuclear region of brain tissue obtained from patients with Alzheimer’s disease (24). Al(III) induces neurofibrillary tangles in the perikaryon of neurons (25). Copyright © 2002 Marcel Dekker, Inc. Ternary Al 3ϩ complexes have received little study, and Al(III) has been used as a tanning or cross-linking reagent. Al 3ϩ seems capable of cross-linking proteins, and proteins and nucleic acids. In fluids low in citrate, transferrin, and nucleotides, the catecholamines may well become important Al 3ϩ binders. While DOPA and epinephrine fail to bind Mg 2ϩ at pH 7.4, they bind Al 3ϩ at picomolar levels. In neutral solutions the main species is a 3:1 complex, with the catechol moiety chelating the Al 3ϩ and the ammonium group remaining protonated (26). The norepinephrine-Al 3ϩ complex inhibits enzymatic O-methylation but not N-methylation by catechol-O-methyl transferase (27). This result conforms to that expected if Al 3ϩ were to bind only to the catechol moiety of norepinephrine. When other metal ions are deficient, Al(III) decreases catecholamine levels in the rat brain (28). By binding to the catechol moiety of catecholamines, trace amounts of Al 3ϩ may disrupt neuro- chemical processes. Signal transduction pathways, particularly inositol phosphate and cAMP- mediated signaling, appear to be targets of Al both in vivo and in vitro. Al in drinking water decreases hippocampal inositol triphosphate levels, increases cAMP, and alters the distribution of protein kinase C (29,30). In vitro exposure to Al decreases agonist-stimulated inositol phosphate accumulation in rat brain slices (31,32). The potential mechanisms of inositol phosphate inhibition have been reviewed (33). Al can also interact with calcium and calcium-binding sites and probably disrupts calcium signaling and homeostasis, and can block calcium entry into the cell via voltage-sensitive channels (32). Several groups have shown that exposure to Al produces a decrease in choline acetyl transferase activity (34,35). There are regional reductions in glucose metabolism in Alzheimer’s dis- ease (36) and also following chronic Al chloride exposure to rats (31), which suggests that this effect may be important in human neurodegeneration. These mechanisms of Al neurotoxicity have been reviewed by Strong et al. (37). 3. HUMAN EXPOSURE 3.1 Aluminum Toxicity and Chronic Renal Failure There is considerable controversy regarding the toxicity of Al in individuals with normal renal function. However, there is no doubt about the importance of Al toxicity in patients with chronic renal failure, on treatment with hemodialysis. This topic, reviewed by us (38–40), has been the subject of intensive investigation since the original report by Alfrey and his colleagues (41), which proposed that dialysis encephalopathy, a feature of patients on long-term treatment with inter- mittent hemodialysis for chronic renal failure, resulted from Al intoxication. Ber- lyne et al. were the first to recognize that hyperaluminemia occurred in these Copyright © 2002 Marcel Dekker, Inc. patients, and that Al toxicity could be demonstrated in experimental animals (42,43). Aluminum in the dialysis solution is the major source of exposure to this metal ion in patients being treated long-term with either hemo- or peritoneal dialysis. The Al content is of course dependent on the water from which it is prepared, and it was this particular source of Al that caused major clinical prob- lems when city water treated with alum was used to produce dialysis solutions, resulting in severe Al toxicity in many dialysis patients. This phenomenon has been largely eliminated by the use of deionized water, but the problem occasion- ally reoccurs (44). Adding to the problem of Al contamination of dialysis solu- tions has been the extensive use of Al salts in the therapeutic management of the hyperphosphatemia that arises in chronic renal failure. Intestinal absorption of Al from this treatment adds to the hyperaluminemia, and consequently to the clinical complications associated with this condition in patients with impaired renal function. There is no doubt that hyperaluminemia in patients with chronic renal failure has constituted one of the major clinical problems in modern times associated with metal poisoning, and few, if any, other occurrences of iatrogenic poisoning have been more serious. Dialysis encephalopathy was in fact a fatal complication of hemodialysis treatment until Alfrey et al. elucidated the problem (41). Guidelines developed in the early 1980s for Al monitoring of both dialysis patients and water supplies (45), together with refinement of analytical methods (46), played a major role in controlling this iatrogenic poisoning. Although this aspect of Al toxicity is well understood, there are still ongoing investigations, particularly in the mechanisms of the metabolic bone disease associated with the treatment (47–50). Complications of bladder irrigation with alum in patients with compromised renal function have also been reported (51). 3.2 Exposure to Al in Parenteral Nutrition Products Most of the reported complications of contamination by Al of commercial intra- venous-feeding solutions are related to its involvement as a key factor in the pathogenesis of metabolic bone disease. There is also a highly significant report of impairment of cognitive function in infants exposed in this manner to Al. The major clinical problem of this type of Al contamination is its occurrence in pre- term infants. The U.S. Food and Drug Administration (FDA) has been investigat- ing this problem since 1986, which has led to recommendations that were best summarized in a position paper of the North American Society for Pediatric Gas- troenterology and Nutrition (52). This position statement supports the FDA’s proposal to add certain labeling requirements for large- and small-volume paren- terals used in total parenteral nutrition, to provide information on Al content, and to require validated analytical methods to be used for Al measurements. The FDA has taken this stance because of evidence linking the use of Al-containing Copyright © 2002 Marcel Dekker, Inc. materials being associated with morbidity and mortality among patients on total parenteral nutrition therapy, particularly premature infants and patients with im- paired renal function The first study of an increased body burden of Al being linked to total parenteral nutrition solutions as assessed by increased plasma, bone, and urine concentrations was that of Sedman et al. in 1985 (53). Bone disease in adult patients who were undergoing this treatment but without renal impairment was reported earlier (54,55). The source of the Al initially was casein hydrolysate, which was the protein source commonly in use at that time. Substitution of crys- talline amino acids for casein hydrolysate, together with other conventional prac- tices for reducing Al loading such as the use of low-Al dialysate solutions (pre- pared from deionized water) and the restriction of Al-containing phosphate binders, led to a resolution of bone pain in these patients (56). In the report of Sedman et al. (53) the Al souces were identified as being contaminated with calcium and phosphate salts, albumin, and heparin. The contamination of phos- phate salts is not surprising in view of the high affinity of Al for phosphate. Infant formulas were also identified as being potentially contaminated by Al (53). Koo et al. also contributed to this aspect of Al toxicity, showing that Al accumulated at the mineralization front in the bones of premature infants (57), and later that preterm infants were able to increase Al excretion in the urine with increased Al load, but that this response could not prevent bone Al deposition and hyperalumi- nemia (58). Koo et al. (59) also demonstrated that infant formulas can contain high concentrations of Al. The highest levels (up to 2346 µg/L) are found in highly processed and modified formulas, including soy formula, preterm infant formula, and formulas for specific metabolic disorders. Human milk has the low- est concentration of Al, being less than 50 µg/L. Bishop et al. in 1997 (60) showed that preterm infants who received total parenteral nutrition containing 45 µg/L of Al, which is the usual solution used for these patients, had a lower score on the Bayley Mental Development Index at age 18 months than did age- matched infants who were given total parenteral nutrition solutions having much lower Al concentrations. Thus, Al contamination of products used for preterm infants represents an important toxicity problem, which produces impairment of bone formation and neurological deficits. Preterm infants appear to be especially at risk. Intravenous administration circumvents the usual gastrointestinal barrier that keeps the major- ity of ingested Al out of the circulation. Once in the circulation Al becomes rapidly bound to transferrin (61) and cannot be readily excreted into the urine because of the relatively high molecular weight of this protein complex. The fact that renal function in preterm infants is developmentally impaired, taking up to 34 weeks to reach maturity, only adds to the problem. Total parenteral nutrition appears to be less of a problem in adult patients, but still exists and has been well documented (62–64). Metabolic bone disease Copyright © 2002 Marcel Dekker, Inc. can develop in these patients, as characterized by patchy osteomalacia and re- duced bone activity. There is also a reduction in serum levels of 1α,25-dihydroxy- vitamin D, with normal levels of 25-hydroxyvitamin D and 24,25-dihydroxy- vitamin D. Discontinuation of total parenteral nutrition containing Al-contami- nated solutions has resolved the metabolic bone disease within 6 weeks (64). Bone lesions have also been reported in adult patients with severe burn injury, and this complication has been related to Al toxicity resulting from con- tamination of human serum albumin and calcium gluconate (52,65). Contamina- tion of blood products such as factors VIII and IX with Al have also caused concern (66,67). 3.3 Al-Containing Fumes and Dust Several studies on occupational exposure to Al have been reported in which it has been observed that the mental status of exposed workers was impaired as compared to appropriate controls. This topic has been reviewed by McLachlan (68), Flaten et al. (69), and Sjogren et al. (70). Although there are a significant number of investigations reporting the possible hazards of occupational Al expo- sure, such reports are few in number when the vastness of the Al industry, thence the extent of worker exposure, is taken into consideration. There is certainly no clear evidence that this type of exposure leads to the development of Alzheimer’s disease, although there is some indication that excessive exposure can lead to cognitive impairment. The handling of Al-containing minerals also exposes the worker to silica; hence pulmonary disease is also a major concern in this type of occupation (70). Aluminum appears to be absorbed by all workers exposed to this metal in the course of their occupation, as demonstrated by increased urinary (71–76) and blood (74,75) Al levels. The urinary excretion of two workers who were exposed to welding fumes over several years was Ͼ10-fold higher than controls, and remained high for many years after cessation of exposure (75). Blood and bone Al levels were also increased, but not quite so dramatically as the urine level (75). A later study compared 38 welders exposed to Al fumes, but not manganese, to 39 unexposed controls (76). Assessment of these workers with a psychological examination showed that the workers exposed to Al achieved a significantly lower score in four of the tests than did the control group, and for two tests the effect was dose-related as assessed by urinary Al concentrations. An isolated case reported by these same workers described a man with aluminosis recognized in 1946 who developed a dementia with motor disturbances and elevated cerebrospi- nal fluid Al concentrations (77). This individual died in 1998 and his cerebrospi- nal fluid Al level was low, suggesting that the earlier measurement had been subjected to contamination. It was finally concluded that the patient had Alzhei- mer’s disease, and that it was not related to Al exposure (78). There have been Copyright © 2002 Marcel Dekker, Inc. other reports of Al exposure from working in the potroom of an Al plant. A significant number of the workers revealed mild to moderate impairment of mem- ory, as assessed by two separate memory tests (79). As in the other study dis- cussed above (76), Al was identified as the probable cause of the syndrome, since exposures to other agents by these same workers had caused no problems in other workers exposed to the same agents but not to Al. In a separate study the psychomotor and intellectual abilities were assessed in workers in an Al foundry in Yugoslavia (80). Eighty-seven exposed and 60 unexposed workers were evalu- ated. These tests revealed slower psychomotor reaction and dissociation of oc- ulomotor coordination in the exposed group. These workers also had memory impairment and emotional disturbances. Treatment with the Al chelator desferri- oxamine resulted in mobilization of Al as detected by elevated concentrations in blood and urine (81). Salib and Hillier used the risk of developing Alzheimer’s disease later in life as a monitor of occupational hazard for workers in the Al industry (82). Aluminum workers reported to have been directly exposed to Al dust and fumes did not appear to be more at risk for developing Alzheimer’s disease than were unexposed workers in the same factory. This same conclusion was the result of a more recent study of occupational exposures to solvents and Al (83). An interesting exposure to Al powder occurred between 1944 and 1979 in mines in northern Ontario, when McIntyre powder (which consists of finely ground Al and Al oxide) was used as a prophylactic agent against silicosis (84). Exposed miners performed worse than unexposed controls on cognitive state ex- aminations and this impairment increased with the duration of exposure. 3.4 Medications 3.4.1 Antacids Al-containing antacids are used extensively for the treatment of dyspepsia. Quan- tities of this medication are consumed in gram amounts, contrasting markedly with the milligram quantities of Al consumed daily in food and drinking water. In a study of epidemiological aspects of Alzheimer’s disease in 1984, Heyman et al. reported that the intake of Al-containing antacids was slightly higher in controls than in patients with Alzheimer’s disease (85). House demonstrated that office workers who were not occupationally exposed to Al had significant eleva- tions of their plasma Al concentrations if they were using antacids (86). In a surprising study, Graves et al. showed an association between antacid consump- tion and Alzheimer’s disease, but demonstrated that this association was less obvious if Al-containing antacid users were removed from the analysis (87). Fla- ten et al. have performed perhaps the largest study of patients with an apparent high intake of Al-containing antacids for gastroduodenal ulcer disease (88). The results of this study provide no significant evidence that a large intake of Al in the form of antacids causes an increased incidence of Alzheimer’s disease. The Copyright © 2002 Marcel Dekker, Inc. [...]... excreted into the urine (99) The form of the ingested Al is important, as stated in the first section of this review, which deals with speciation Slanina et al have shown in both humans and rats (100 ,101 ) that citrate enhances the gut absorption of Al In humans this amounts to a fourfold increase in plasma concentrations (101 ) In rats there are significant elevations in bone and in the brain in cerebral... apoptosis, and maintain Bcl-2 immunopositivity and negative Bax staining Our findings strongly support the key role that oxidative damage plays in the process of neurodegeneration and in the increased vulnerability to Alinduced injury in the aged animal These are novel observations that may have important implications for aiding in our understanding of the pathogenesis of neurodegeneration occurring in Alzheimer’s... small compared to the intake in some individuals derived from pharmaceutical products (94) The addition of Al during processing of foods increases its concentration appreciably Herbs and tea contain more Al, but do not represent major contributors to the daily intake, since the Al in tea leaves does not dissolve in the liquid consumed (93) Probably the average individual in the more industrialized affluent... represent geochemical differences in the drinking water supply Also, Wettstein et al (173) investigated only two drinking water sources, the water with high-Al levels having only about 100 µg/L of Al There is also the possibility that there was a disproportionate removal of individuals from the population because of dementia and its associated comorbidities The indication from the studies discussed above,... routine in daily living This tool was selected over others such as the Mini-Mental State Exam, and proved to be effective for conducting unbiased analysis and at the same time providing a permanent record for future review Forty-eight Alzheimer’s disease patients were studied in a randomized single-blind manner in which either desferrioxamine (125 mg i.m.) or oral placebos were administered and the. .. Most of the data linking Al exposure to Alzheimer’s disease have been derived from several epidemiological studies of Al in drinking water The most widely publicized investigation was that of Martyn et al (159) In a study of 88 county districts in the United Kingdom, these investigators found a 50% increase Copyright © 2002 Marcel Dekker, Inc in the risk of Alzheimer’s disease in districts where the mean... disorders, including the formation of neurofibrillary tangles and Aβ deposition It has been shown that cells in the rat brain possess a specific high-affinity receptor for transferrin that is independent of the metal being transported This system is postulated to be the route whereby the iron in the general circulation reaches the brain (207) Transferrin is predominantly considered an iron transporter protein,... that they both employed frozen sections stained with toluidine blue, and in both cases Al was detected Makjanic et al (149) had the advantage of using unstained tissue, and failed to detect Al within neurons in a region containing neurofibrillary tangles However, in view of the careful evaluation of contamination by Good et al (148), and the lack of detection of Al in the toluidine blue counterstain (D...power of this investigation to detect an Al effect was diluted by the fact that not all patients took Al-containing antacids, and that non-Alzheimer’s dementias were included Plasma Al concentrations have been evaluated in a reference population and the effects of Al-containing antacids have been investigated (89) Both acute and medium-term Al-containing antacid consumption results in increased plasma... susceptibility of the brain to Al toxicity, at least in rabbits Yokel at al related their Al-induced learning deficits to patients with Alzheimer’s disease when they demonstrated that 4-aminopyridine, which has been reported to improve learning in Alzheimer’s disease subjects, attenuates the Al-induced learning deficit in rabbits (128) 4.3 Phytotoxicity and Ecotoxicology of Al to Fish and Wildlife Aluminum phytotoxicity . from the Gastrointestinal Tract to the Brain Only a small amount of the total ingested Al is absorbed via the gastrointestinal tract, and the majority of that is excreted into the urine (99). The. as a tanning or cross-linking reagent. Al 3ϩ seems capable of cross-linking proteins, and proteins and nucleic acids. In fluids low in citrate, transferrin, and nucleotides, the catecholamines may well. neurofibrillary tangle- bearing neurons/mm 2 in a 1 0- m-thick section, and an Al concentration of 100 ppm within the neurofibrillary tangles. The expected increase in bulk Al concen- tration with these assumptions