Aluminium exposure is associated with bone disease (an elevated bone content of aluminium and reduced bone formation on bone biopsy) and neurotoxicity (features of altered brain functions and/or typical spike and slow wave waveforms on electroencephalogram) in patients with elevated blood aluminium concentrations.

To critically analyse the literature to determine the dose-toxicity relationships between aluminium exposure and related bone disease and aluminium neurotoxicity.

A systematic review of the literature with collation and analysis of individual data of human cases of aluminium exposure was conducted between 1 January 1966 and 30 December 2020. Embase, MEDLINE (OVID MEDLINE), PubMed and TOXNET were searched with the following strategies: "Aluminium AND toxicity OR aluminium AND poisoning OR aluminium AND dialysis OR aluminium AND chronic renal failure OR aluminium AND intravenous" limited to "(human)". Inclusion criteria required individual data relating to aluminium exposure in humans. Papers in which features of aluminium toxicity and analytical confirmation of aluminium exposure could not be determined in individual patients were excluded.

Thirty-seven papers were identified, which included data on 179 individuals exposed to aluminium. The sources of aluminium exposure (median duration of exposure) were: dialysis fluid (48 months) in 110 cases; oral aluminium hydroxide (20 months) in 20 cases; plasma exchange (2 months) in 16 cases; infant formula feed (minimal duration of 2 weeks) in 14 cases; intravesical exposures (2 days) in 13 oncology patients and potable water exposure in six cases.

Of the 110 patients exposed to dialysis fluid, 99 were adults and 11 children, who were analysed separated. Of the adults, 50 with aluminium neurotoxicity had a median aluminium concentration of 467 µg/L (IQR 230 - 752), 28 with aluminium bone disease had a median aluminium concentration of 142 µg/L (IQR 46-309) and 21 with asymptomatic aluminium overload had a median aluminium concentration of 35 µg/L (IQR 26-51). Median aluminium concentrations were significantly greater in patients with aluminium neurotoxicity compared to those with aluminium bone disease (p < 0.0001) or asymptomatic aluminium overload (p < 0.0001).

Of the 20 cases, 11 were adults and nine were children. Of the 11 adults, eight with aluminium neurotoxicity had a median aluminium concentration of 682 µg/L (IQR 438-770) and three with aluminium bone disease had a median aluminium concentration of 100 µg/L (IQR 62-138) (p = 0.007). Of the nine children, five had aluminium neurotoxicity with a median aluminium concentration of 335 µg/L (IQR 229-601), one had aluminium bone disease and an aluminium concentration of 1030 µg/L and three had asymptomatic aluminium overload with a median aluminium concentration 98 µg/L (IQR 65-365).

Three patients with stage 5 chronic kidney disease developed aluminium bone disease during plasma exchange; their median blood or serum aluminium concentration was 73 µg/L (IQR 59-81). Asymptomatic aluminium overload was reported in six patients receiving outpatient plasma exchange who had a median creatinine clearance of 71 mL/min (IQR 40-106) and a median aluminium concentration of 49 µg/L (IQR 34-116), and in seven intensive care patients with acute kidney injury whose median aluminium concentration was 30 µg/L (IQR 17-35); (p = 0.02).

All 13 intravesical exposures developed aluminium neurotoxicity and had a median aluminium concentration of 157 µg/L (IQR 45-276).

All six patients developed aluminium bone disease and their median blood aluminium concentration was 17 µg/L (IQR 13-100).

Toxic aluminium exposure can result in neurotoxicity and bone disease, especially in patients with chronic kidney disease. Adults with stage 5 chronic kidney disease chronically exposed to aluminium developed aluminium neurotoxicity at higher concentrations than those with aluminium bone disease or with asymptomatic aluminium overload. Aluminium neurotoxicity was reported at lower concentrations following acute exposure to intravesical aluminium. Extrapolating the relevance of these concentrations to the general population is problematic in that the data were derived from oncology patients, however, the possibility that aluminium neurotoxicity may occur at concentrations lower that those reported historically in patients with stage 5 chronic kidney disease cannot be excluded.

A ditopic Schiff base ligand, H₂L has been synthesized and characterized by all spectroscopic techniques. It is highly selective and specific towards Al³⁺ in semi aqueous medium (DMF/H₂O mixture) by exhibiting a drastic increase in the fluorescence intensity. The emission studies, spectroscopic data, life time and quantum yield results have been used to understand its binding mode, explore its specificity and establish its efficacy. The intensity difference is remarkable in physiological pH range. Due to its reversible behavior this ditopic fluorescent chemosensor can be used multiple times to make it cost effective. Detection limit for this chemosensor was found to be 0.65 μM. Experiments with TLC plates show that it can be used as a practical and portable sensor for studying environmental samples in real life. The L-Al³⁺ complex generated in the solution acts as a sensor to sequentially detect pyrophosphate groups present in inorganic pyrophosphates, ATP and ADP among other anions by turning off the fluorescence. Inhibit logic gate and its corresponding truth table has been developed to aid in further exploiting its multidimensional applications.

Alcohol overuse may be related to increased aluminum (Al) exposure, the brain accumulation of which contributes to dementia. However, some reports indicate that silicon (Si) may have a protective role over Al-induced toxicity. Still, no study has ever explored the brain content of Al and Si in alcoholic use disorder (AUD).

To fill this gap, the present study employed inductively coupled plasma optical emission spectrometry to investigate levels of Al and Si in 10 brain regions and in the liver of AUD patients (n = 31) and control (n = 32) post-mortem.

Al content was detected only in AUD patients at mean ± SD total brain content of 1.59 ± 1.19 mg/kg, with the highest levels in the thalamus (4.05 ± 12.7 mg/kg, FTH), inferior longitudinal fasciculus (3.48 ± 9.67 mg/kg, ILF), insula (2.41 ± 4.10 mg/kg) and superior longitudinal fasciculus (1.08 ± 2.30 mg/kg). Si content displayed no difference between AUD and control, except for FTH. Positive inter-region correlations between the content of both elements were identified in the cingulate cortex, hippocampus, and ILF.

The findings of this study suggest that AUD patients may potentially be prone to Al-induced neurodegeneration in their brain-although this hypothesis requires further exploration.

Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.

Although iron is one of the most important metal ions for living organisms, it becomes toxic when in excess or misplaced. This review presents a glance at representative examples of hydroxypyridinone-based chelators, which have been recently developed as potential clinically useful drugs for metal overload diseases, mostly associated with excess of iron but also other hard metal-ions. It also includes a detailed discussion on the factors assisting chelator design strategy toward fulfillment of the most relevant biochemical properties of hydroxypyridinone chelators, highlighting structure-activity relationships and a variety of potential clinical applications, beyond chelatotherapy. This study appears as a response to the growing interest on metal chelation therapy and opens new perspectives of possible applications in future medicine.

In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl3) enhanced the neurotoxicity of the amyloid beta(25-35) fragment (Abeta(25-35)) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A2A adenosine receptors (A2AR), although it also inhibits A1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta(25-35)+AlCl3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta(25-35)+AlCl3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A1R and A2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl3 treatment exacerbated Abeta(25-35) toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta(25-35) only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta(25-35)+AlCl3-induced damage, suggesting that A1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A1R inhibition in the setting of combined Abeta(25-35)+AlCl3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum.

Aluminum potassium sulfate and tannic acid (ALTA) is an effective sclerosing agent for internal hemorrhoids. However, it is contraindicated for patients with chronic renal failure on dialysis, because the aluminum in ALTA can cause aluminum encephalopathy when it is not excreted effectively. We conducted this study to measure the serum aluminum concentrations and observe for symptoms relating to aluminum encephalopathy in dialysis patients after ALTA therapy.

Ten dialysis patients underwent ALTA therapy for hemorrhoids. We measured their serum aluminum concentrations and observed them for possible symptoms of aluminum encephalopathy.

The total injection volume of ALTA solution was 31 mL (24-37). The median serum aluminum concentration before ALTA therapy was 9 μg/L, which increased to 741, 377, and 103 μg/L, respectively, 1 h, 1 day, and 1 week after ALTA therapy. These levels decreased rapidly, to 33 μg/L by 1 month and 11 μg/L by 3 months after ALTA therapy. No patient suffered symptoms related to aluminum encephalopathy.

Although the aluminum concentrations increased temporarily after ALTA therapy, dialysis patients with levels below 150 μg/L by 1 week and thereafter are considered to be at low risk of the development of aluminum encephalopathy.

These proceedings will review the role of chelation in five metals-aluminum, cadmium, chromium, cobalt, and uranium-in order to illustrate various chelation concepts. The process of "chelation" can often be oversimplified, leading to incorrect assumptions and risking patient harm. For chelation to be effective, two critical assumptions must be fulfilled: the presumed "metal toxicity" must correlate with a given body or a particular compartment burden, and reducing this compartmental or the body burden (through chelation) attenuates toxicity. Fulfilling these assumptions requires an established dose-response relationship, a validated, reproducible means of toxicity assessment (clinical, biochemical, or radiographical), and an appropriate assessment mechanisms of body or compartment burden. While a metal might "technically" be capable of chelation (and readily demonstrable in urine or feces), this is an insufficient endpoint. Clinical relevance must be affirmed. Deferoxamine is an accepted chelator for appropriately documented aluminum toxicity. There is a very minimal treatment window in order to address chelation in cadmium toxicity. In acute toxicity, while no definitive chelation benefit is described, succimer (DMSA), diethylenetriaminepentaacetate (DTPA), and potentially ethylenediaminetetraacetic acid (EDTA) have been considered. In chronic toxicity, chelation is unsupported. There is little evidence to suggest that currently available chromium chelators are efficacious. Similarly, scant human evidence exists with which to provide recommendation for cobalt chelation. DTPA has been recommended for cobalt radionuclide chelation, although DMSA, EDTA, and N-acetylcysteine have also been suggested. DTPA is unsupported for uranium chelation. Sodium bicarbonate is currently recommended, although animal evidence is conflicting.

Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog.

Metal pollutants are a global health risk due to their ability to contribute to a variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is implicated in anemia, osteomalacia, hepatic disorder, and neurological disorder. In this review, we outline how this intracellular generator of reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished mitochondrial activity, anerobiosis, and the channeling of α-ketoacids towards anti-oxidant defense. The resulting metabolic reconfiguration leads to fat accumulation and a reduction in ATP synthesis, characteristics that are common to numerous medical disorders. Hence, the ability of Al toxicity to create an oxidative environment promotes dysfunctional metabolic processes in astrocytes and hepatocytes. These molecular events triggered by Al-induced ROS production are the potential mediators of brain and liver disorders.

Our objective is to illustrate the activity of the groups operating in Italy involved in identification and study of new chelating agents, mainly intended for treatment of human pathology correlated with metal overload. The objective of "chelation therapy" is removal of toxic metal ions from the human body or attenuation of their toxicity by transforming them into less toxic compounds or by dislocating them from the site at which they exert a toxic action. Because most of this research activity is related to chelating agents for iron and aluminium, diseases related to these two metal ions are briefly treated. Iron overload is the most common metal toxicity disease worldwide. The toxicity of aluminium in dialysis patients was a serious problem for haemodialysis units in the seventies and eighties of the last century. In particular, this review focuses on research performed by the group at Cagliari and Ferrara, and by that at Padova. The former is studying, above all, bisphosphonate and kojic acid derivatives, and the latter is investigating 3,4-hydroxypyridinecarboxylic acids with differently substituted pyridinic rings.

In pediatric oncology patients, hemorrhagic cystitis can be a life-threatening complication of bone marrow transplantation, chemotherapy, and radiation therapy. The treatment of this condition is often challenging and includes intravesical irrigation with aluminum, embolization, endoscopic laser coagulation, hydrostatic pressure, use of hyperbaric oxygen, instillation of formalin, prostaglandins, and oral sodium pentosan polysulfate. Although the efficacy of aluminum irrigation is well documented for the management of hemorrhagic cystitis in adults, there are limited reports describing its use in children. The potential multisystem toxic effects of aluminum are well described and the range and progression of aluminum toxicity can be devastating. We report a case of a 9-year-old girl suffering from acute lymphocytic leukemia with hemorrhagic cystitis. Although the symptoms resolved after intravesical aluminum treatment, she developed significant aluminum toxicity. We have reviewed the literature relating to aluminum toxicity in the pediatric age group and present our recommendations for the effective and safe use of aluminum in this cohort of patients.

Aluminum toxicity has been reported in renal failure patients exposed to aluminum-contaminated dialysate and oral phosphate binders. We report a case of significant aluminum toxicity in a non-hemodialysis patient.

A 43-year-old male IV drug user presented to the hospital with a seizure disorder of recent onset, progressive cognitive decline, ataxia, and dysarthria. The serum aluminum concentration was 180 micrograms/L (6.65 micromol/L). For 3 to 4 years prior, the patient had injected 'cooked' oral methadone. The methadone solution was heated in an aluminum pot to reduce the volume and then injected intravenously (IV). He was treated with IV deferoxamine over 9 months until he failed to return. Serum aluminum level after 9 months of treatment was 64.5 microgram/L (2.39 micromol/L). Neurological symptoms were partially improved.

Chronic IV injection of oral methadone solution heated in an aluminum-based cooking utensil may result in significant aluminum toxicity.

Haemorrhagic cystitis (HC) is a common and, in its severe form, potentially life-threatening complication of Haematopoietic stem cell transplantation (HSCT) in children. Recent data indicate an important role of BK virus reactivation during the time of maximal post-transplant immune suppression in the pathogenesis of late-onset HC. Treatment of HC is mainly symptomatic and often frustrating. To give clinicians guidance on prevention and treatment options and their backing by scientific evidence, we have systematically assessed the available literature and devised evidence-based guidelines. Our comprehensive review demonstrates that evidence for the most commonly used interventions (such as cidofovir, oestrogen, hyperbaric oxygen, bladder instillation with formalin, alum salts or prostaglandin) is very limited. Some of these interventions also carry significant risks. Higher level evidence exists only for 2-mercaptoethane sodium (MESNA) and hyperhydration as a preventative intervention, and for systemic recombinant Factor VII as a treatment to stop acute haemorrhage. Further high-quality studies are required to establish effective and safe prevention and treatment options for HC.

Long time ago aluminum (Al) was considered as a non-toxic element and its use had no restrictions. However, over the last two decades, scientific publications have indicated that Al is a toxic element. In line with this, aluminum accumulation in the organism is associated with a variety of human pathologies. Efficient therapeutics approach to treat Al intoxication are still not available, but there is a consensus that chelation therapy is the procedure to be used. However, the development of new chelating agents are highly desirable to improve the efficacy of the treatment of Al intoxication. The present study evaluates the chelating effect of two novel pyrimidines: 4-tricloromethyl-1-H-pyrimidin-2-one (THP) and (4-methyl-6-trifluoromethyl-6-pyrimidin-2-il)-hydrazine (MTPH) in a mice model of aluminum intoxication and compares their efficacy with those of desferrioxamine (DFO), a classical agent used for treat Al accumulation. The animals were exposed to aluminum by gavage (0.1 mmol aluminum/kg/day) 5 days/week for 4 weeks. At the end of this period, DFO was injected i.p. and the novel pyrimidines were given by gavage at 0.2 mmol/kg/day for five consecutive days. Aluminum concentration in tissues (brain, liver, kidney and blood) was determined by graphite furnace atomic absorption spectroscopy (GFAAS). The results showed that when administered by gavage, aluminum accumulated in the brain, kidney and liver of mice. MTPH was able to decrease aluminum levels in aluminum plus citrate animal groups, whereas THP was inefficient for this purpose. However, the novel pyrimidines used in this study were unable to surpass the aluminum chelating property of DFO. Thus, new studies must be performed utilizing other chelating agents which can decrease aluminum toxicity.

For the purpose of analyzing and imaging chemical components of cells and tissues at the electron microscopic level, 3 fundamental methods are available, chemical, physical and biological. Among the physical methods, two methods qualifying and quantifying the elements in the structural components are very often employed. The first method is radioautography which can demonstrate the localization of radiolabeled compounds which were incorporated into cells and tissues after the administration of radiolabeled compounds. The second method is X-ray microanalysis which can qualitatively analyze and quantify the total amounts of elements present in cells and tissues. We have developed the two methodologies in combination with intermediate high or high voltage transmission electron microscopy (200-400 kV) and applied them to various kinds of organic and inorganic compounds present in biological materials. As for the first method, radioautography, I had already contributed a chapter to PHC (37/2). To the contrary, this review deals with another method, X-ray microanalysis, using semi-thin sections and intermediate high voltage electron microscopy developed in our laboratory. X-ray microanalysis is a useful method to qualify and quantify basic elements in biological specimens. We first quantified the end-products of histochemical reactions such as Ag in radioautographs, Ce in phosphatase reaction and Au in colloidal gold immunostaining using semithin sections and quantified the reaction products observing by intermediate high voltage transmission electron microscopy at accelerating voltages from 100 to 400 kV. The P/B ratios of all the end products Ag, Ce and Au increased with the increase of the accelerating voltages from 100 to 400 kV. Then we analyzed various trace elements such as Zn, Ca, S and Cl which originally existed in cytoplasmic matrix or cell organelles of various cells, or such elements as Al which was absorbed into cells and tissues after oral administration, using both conventional chemical fixation and cryo-fixation followed by cryo-sectioning and freeze-drying, or freeze-substitution and dry-sectioning, or freeze-drying and dry-sectioning producing semithin sections similarly to radioautography. As the results, some trace elements which originally existed in cytoplasmic matrix or cell organelles of various cells in different organs such as Zn, Ca, S and Cl, were effectively detected. Zn was demonstrated in Paneth cell granules of mouse intestines and its P/B ratios showed a peak at 300 kV. Ca was found in human ligaments and rat mast cells with a maximum of P/B ratios at 350 kV. S and Cl were detected in mouse colonic goblet cells with maxima of P/B ratios at 300 kV. On the other hand, some elements which were absorbed by experimental administration into various cells and tissues in various organs, such as Al in lysosomes of hepatocytes and uriniferous tubule cells in mice was detected with a maximum of P/B ratios at 300 kV. From the results, it was shown that X-ray microanalysis using semi-thin sections observed by intermediate high voltage transmission electron microscopy at 300-400 kV was very useful resulting in high P/B ratios for quantifying some trace elements in biological specimens. These methodologies should be utilized in microanalysis of various compounds and elements in various cells and tissues in various organs.

Aluminum is the most widely distributed metal in the environment and is extensively used in modern daily life. Aluminum enters into the body from the environment and from diet and medication. However, there is no known physiological role for aluminum within the body and hence this metal may produce adverse physiological effects. The impact of aluminum on neural tissues is well reported but studies on extraneural tissues are not well summarized. In this review, the impacts of aluminum on humans and its impact on major physiological systems are summarized and discussed. The neuropathologies associated with high brain aluminum levels, including structural, biochemical, and neurobehavioral changes, have been summarized. In addition, the impact of aluminum on the musculoskeletal system, respiratory system, cardiovascular system, hepatobiliary system, endocrine system, urinary system, and reproductive system are discussed.