The cellular toxicity of aluminium.

Aluminium is a serious environmental toxicant and is inimical to biota. Omnipresent, it is linked with a number of disorders in man including Alzheimer's disease, Parkinson's dementia and osteomalacia. Evidence supporting aluminium as an aetiological agent in such disorders is not conclusive and suffers principally from a lack of consensus with respect to aluminium's toxic mode of action. Obligatory to the elucidation of toxic mechanisms is an understanding of the biological availability of aluminium. This describes the fate of and response to aluminium in any biological system and is thus an important influence of the toxicity of aluminium. A general theme in much aluminium toxicity is an accelerated cell death. Herein mechanisms are described to account for cell death from both acute and chronic aluminium challenges. Aluminium associations with both extracellular surfaces and intracellular ligands are implicated. The cellular response to aluminium is found to be biphasic having both stimulatory and inhibitory components. In either case the disruption of second messenger systems is observed and GTPase cycles are potential target sites. Specific ligands for aluminium at these sites are unknown though are likely to be proteins upon which oxygen-based functional groups are orientated to give exceptionally strong binding with the free aluminium ion.     

Influence of the glass packing on the contamination of pharmaceutical products by aluminium. Part II: Amino acids for parenteral nutrition

The presence of aluminium in amino acids parenteral nutrition solutions can be related to the affinity of the amino acids for aluminium present in glass containers used for storage. For this study solutions of 19 amino acids used in parenteral nutrition were stored individually in glass flasks and the aluminium measured at determined time intervals. Solutions of complexing agents for aluminium, as ethylene-diaminetetraacetic acid, nitrilotriacetic acid, citrate, oxalate and fluoride ions were also stored in the same flasks and the aluminium measured during the same time interval. The measurements were made by electrothermal atomic absorption spectrometry. The aluminium content of the glass containers was also measured. The results showed that the glasses have from 0.6% to 0.8% Al. Only solutions of cysteine, cystine, aspartic acid and glutamic acid became contaminated by aluminium. As the same occurred with the complexing agents, aluminum can be released from glass due to an affinity of the substances for aluminium. Comparing the action of complexing agents and amino acids for which the stability constants of aluminium complex are known, it is possible to relate the magnitude of the stability constant with the aluminium leached from glass, the higher the stability constant, the higher the aluminium released. The analysis of commercial formulations with and without cysteine, cystine, glutamic acid or aspartic acid stored in glass containers confirms that the presence of these amino acids combined with the age of the soLution are, at least partially, responsible for the aluminium contamination. The resuLts demonstrated that the contamination is an ongoing process due to the presence of aluminium in glass combined with the affinity of some amino acids for this element.     

Aluminum transfer as glutamate complex through blood-brain barrier

In vitro distribution of aluminium between plasma and erythrocytes has been studied in the presence of variable amounts of sodium L-glutamate. With a red blood cell suspension in isotonic sodium chloride, aluminium remains confined in erythrocytes even when the sodium L-glutamate concentration increases in the medium. Aluminium initially present in plasma penetrates red blood cells when sodium L-glutamate increases in whole blood, showing that this metal is able in vitro to cross the erythrocyte membrane as glutamate complex. In vivo experiments with male Wistar rats prove that aluminium is also able to pass the blood--brain barrier as glutamate complex and deposit in the brain cortex.     

Life cycle assessment of commercial furniture: a case study of Formway LIFE chair

Background, aims and scope  The environmental aspects of companies and their products are becoming more significant in delivering competitive advantage. Formway Furniture, a designer and manufacturer of office furniture products, is a New Zealand-based company that is committed to sustainable development. It manufactures two models of the light, intuitive, flexible and environmental (LIFE) office chair: one with an aluminium base and one with a glass-filled nylon (GFN) base. It was decided to undertake a life cycle assessment (LCA) study of these two models in order to: (1) determine environmental hotspots in the life cycle of the two chairs (goal 1); (2) compare the life cycle impacts of the two chairs (goal 2); and (3) compare alternative potential waste-management scenarios (goal 3). The study also included sensitivity analysis with respect to recycled content of aluminium in the product. Materials and methods  The LIFE chair models consist of a mix of metal and plastic components manufactured by selected Formway suppliers according to design criteria. Hence, the research methodology included determining the specific material composition of the two chair models and acquisition of manufacturing data from individual suppliers. These data were compiled and used in conjunction with pre-existing data, specifically from the ecoinvent database purchased in conjunction with the SimaPro7 LCA software, to develop the life cycle inventory of the two chair models. The life cycle stages included in the study extended from raw-material extraction through to waste management. Impact assessment was carried out using CML 2 baseline 2000, the methodology developed by Leiden University’s Institute for Environmental Sciences. Results  This paper presents results for global warming potential (GWP100). The study showed a significant impact contribution from the raw-material extraction/refinement stage for both chair models; aluminium extraction and refining made the greatest contribution to GWP100. The comparison of the two LIFE chair models showed that the model with the aluminium base had a higher GWP100 impact than the model with the GFN base. The waste-management scenario compared the GWP100 result when (1) both chair models were sent to landfill and (2) steel and aluminium components were recycled with the remainder of the chair sent to landfill. The results showed that the recycling scenario contributed to a reduced GWP100 result. Since production and processing of aluminium was found to be significant, a sensitivity analysis was carried out to determine the impact of using aluminium with different recycled contents (0%, 34% and 100%) in both waste-management scenarios; this showed that increased use of recycled aluminium was beneficial. The recycling at end-of-life scenarios was modelled using two different end-of-life allocation approaches, i.e. consequential and attributional, in order to illustrate the variation in results caused by choice of allocation approach. The results using the consequential approach showed that recycling at end-of-life was beneficial, while use of the attributional method led to a similar GWP100 as that seen for the landfill scenario. Discussion  The results show that the main hotspot in the life cycle is the raw-material extraction/refinement stage. This can be attributed to the extraction and processing of aluminium, a material that is energy intensive. The LIFE chair model with the aluminium base has a higher GWP100 as it contains more aluminium. Sensitivity analysis pertaining to the recycled content of aluminium showed that use of aluminium with high recycled content was beneficial; this is because production of recycled aluminium is less energy intensive than production of primary aluminium. The waste-management scenario showed that recycling at end-of-life resulted in a significantly lower GWP100 than landfilling at end-of-life. However, this result is dependent upon the modelling approach used for recycling. Conclusions  With respect to goal 1, the study found that the raw-material extraction/refinement stage of the life cycle was a significant factor for both LIFE chair models. This was largely due to the use of aluminium in the product. For goal 2, it was found that the LIFE chair model with the aluminium base had a higher GWP100 than the GFN model, again due to the material content of the two models. Results for goal 3 illustrated that recycling at end-of-life is beneficial when using a system expansion (consequential) approach to model recycling; if an attributional ‘cut-off’ approach is used to model recycling at end-of-life, there is virtually no difference in the results between landfilling and recycling. Sensitivity analysis pertaining to the recycled content of aluminium showed that use of higher recycled contents leads to a lower GWP100 impact. Recommendation and perspectives  Most of the GWP100 impact was contributed during the raw-material extraction/refinement stage of the life cycle; thus, the overall impact of both LIFE chair models may be reduced through engaging in material choice and supply chain environmental management with respect to environmental requirements. The study identified aluminium components as a major contributor to GWP100 for both LIFE chair models and also highlighted the sensitivity of the results to its recycled content. Thus, it is recommended that the use of aluminium in future product designs be limited unless it is possible to use aluminium with a high recycled content. With respect to waste management, it was found that a substantial reduction in the GWP100 impact would occur if the chairs are recycled rather than landfilled, assuming an expanding market for aluminium. Thus, recycling the two LIFE chair models at end-of-life is highly recommended.     

A systems biology approach to the blood-aluminium problem: the application and testing of a computational model

Transport and distribution of systemic aluminium are influenced by its interaction with blood. Current understanding is centred upon the role played by the iron transport protein transferrin which has been shown to bind up to 90% of serum total aluminium. We have coined what we have called the blood-aluminium problem which states that the proportion of serum aluminium which, at any one moment in time, is bound by transferrin is more heavily influenced by kinetic constraints than thermodynamic equilibria with the result that the role played by transferrin in the transport and distribution of aluminium is likely to have been over estimated. To begin to solve the blood-aluminium problem and therewith provide a numerical solution to the aforementioned kinetic constraints we have applied and tested a simple computational model of the time-dependency of a putative transferrin ligand (L) binding aluminium to form an Al-L complex with a probability of existence, K(E), between 0% (no complex) and 100% (complex will not dissociate). The model is based upon the principles of a lattice-gas automaton which when ran for K(E) in the range 0.1-98.0% demonstrated the emergence of complex behaviour which could be defined in the terms of a set of parameters (equilibrium value, E(V), equilibrium time, E(T), peak value, P(V), peak time, P(T), area under curve, AUC) the values of which varied in a predictable way with K(E). When K(E) was set to 98% the model predicted that ca. 90% of the total aluminium would be bound by transferrin within ca. 350 simulation timesteps. We have used a systems biology approach to develop a simple model of the time-dependency of the binding of aluminium by transferrin. To use this approach to begin to solve the blood-aluminium problem we shall need to increase the complexity of the model to better reflect the heterogeneity of a biological system such as the blood.     

Aluminium toxicity during regular haemodialysis.

In the west of Scotland the incidence of dialysis encephalopathy has been confined to three geographical areas where the concentration of aluminium in the water supply is greatly increased owing to the addition of aluminium sulphate. Eight patients with encephalopathy who dialysed at home in these areas had greatly increased serum aluminium concentrations, and a significant correlation was found between serum aluminium concentrations and the concentrations of aluminium in the water supply. This study provides further evidence that the dialysis encephalopathy syndrome is due to aluminium intoxication, the major source of aluminium being the water supply from which dialysis fluid prepared.     

Model calculations of casein micelle size distributions.

A previously proposed model for the formation and structure of casein micelles from subunits of variable composition is used to calculate theoretical micelle size distributions. Using the fractional content of k-casein as the only variable but with a value near that observed in a sample of milk serum, the model successfully reproduces experimentally determined distributions. Predicted size distributions are quite sensitive to the value of the variable and shift toward smaller average size as the assumed fractional content k-casein gets larger. Also, there is a discontinuity in the distributions which predicts that there will be essentially no micelles with radii smaller than 25-30 nm. These predictions are all in accord with experimental observations. The good agreement between theory and experimenet supports the micelle structure suggested by the model.     

Aluminium toxicity and iron homeostasis.

In an animal model of aluminum overload, (aluminium gluconate), the increases in tissue aluminium content were paralleled by elevations of tissue iron in the kidney, liver heart and spleen as well as in various brain regions, frontal, temporal and parietal cortex and hippocampus. Despite such increases in iron content there were no significant changes in the activities of a wide range of cytoprotective enzymes apart from an increase in superoxide dismutase in the frontal cortex of the aluminium loaded rats. Such increases in tissue iron content may be attributed to the stabilisation of IRP-2 by aluminium thereby promoting transferrin receptor synthesis while blocking ferritin synthesis. Using the radioactive tracer (26)Al less than 1% of the injected dose was recovered in isolated ferritin, supporting previous studies which also found little evidence for aluminium storage within ferritin. The increases in brain iron may well be contributory to neurodegeneration, although the pathogenesis by which iron exerts such an effect is unclear.     

Modelling More Sustainable Aluminium (4 pp)

Goal, Scope and Background This case study describes the development and utilization of a global, quantitative model of current and projected aluminium and life cycle inventory mass flows. The model and key results were developed to be shared with global aluminium industry technical experts, executives, and external stakeholders to better understand potential paths to more global sustainable aluminium. Methods The model is based on annual statistical data since 1950 provided by government agencies and regional aluminum associations and on the most recent life cycle inventory intensity data (year 2002) complied for the global industry by the International Aluminium Institute. Modeling of future aluminium and resource flows are based on literature and industry expert projections of future product shipment demand. The availability of recycle flows to meet these market demands are based on projected utilization, yield, and melt loss recovery rates, post-consumer recycling rates, and anticipated future product lifetimes. The model was developed with quantitative 'what-if' capability to determine the positive impact of enhanced recycling, lower resource intense production, and product usage scenarios. Results and Conclusion The model provides the first quantitative assessment of annual global aluminium and life cycle inventory flows. Results include a quantitative estimate by major market of global aluminium product inventory, system losses, recycle rates, and selected resource requirements and air emissions implications. - Recommendation and Perspective. Model results and scenarios have been reviewed and shared with global aluminium technical leaders, executives and key external stakeholders in support of the International Aluminum Institute's new voluntary global objective to better monitor and enhance aluminium recycling and sustainable development initiative.     

Acid-induced acute toxicity of aluminium to three species of filter feeding caddis larvae (Trichoptera, Arctopsychidae and Hydropsychidae)

1. Arctopsyche ladogensis , Hydropsyche angustipennis and Hydropsyche siltalai larvae were exposed to nominal aluminium concentrations of 0, 625, 1250, 2500 and 5000 μg Al l^–1 at pH 5.0 for 96 h. Larvae reared at pH 6.4 and without any aluminium treatment were used as controls. Morphological abnormalities in the anal papillae of the larvae were used as the response variable in estimating the median effective concentrations (EC₅₀) of aluminium.
2. No morphological abnormalities were observed in the control larvae. Only a few individuals of A. ladogensis had darkened anal papillae at pH 5.0 without additional aluminium treatment, whereas increasing aluminium concentrations significantly increased the number of individuals in all species displaying darkening and reduction of the papillae.
3. A. ladogensis appeared to be the most sensitive species to increasing aluminium concentrations, as reflected by the significantly lower mean EC₅₀ value for this species compared with those of H. siltalai and H. angustipennis . H. angustipennis larvae were the most tolerant to aluminium.
4. The results indicate that interspecific differences in sensitivity to aluminium may be a key factor influencing the guild structure of filter feeding caddis flies in acidified streams. The results also imply that toxic effects of aluminium on filter feeding caddis larvae occur due to the impairment of normal osmoregulation processes via damage to the ion-regulatory organs.     

Agarose as a suitable substrate for use in the study of Al dynamics in the rhizosphere

Because of experimental difficulties, few authors have studied the dynamics of aluminium in the rhizosphere. The aim of this paper is to present a suitable method for studying rhizosphere Al dynamics. It is based on the use of agarose as a substrate for plant growth. Agar and agarose gels are often used in rhizosphere studies, but most are poorly characterized and occasionally give rise to experimental artefacts, especially with low mobility elements like Al. The results reported here show that agarose is a relatively pure substrate, nearly devoid of phosphorus and other Al-complexing substances. Aqueous extracts of agarose also exhibit Al phytotoxicity equivalent to that of a nutrient solution. Since this substrate has the properties of a variable charge exchange complex, it can be considered as a physico-chemical model for organic matter. Finally, its Al adsorption capacity is high enough for the Al reserve in the substrate not to exert a limiting effect on plants and low enough to allow accurate measurement of Al depletion in the rhizophere.     

Acid-induced acute toxicity of aluminium to three species of filter feeding caddis larvae (Trichoptera, Arctopsychidae and Hydropsychidae)

1. Arctopsyche ladogensis , Hydropsyche angustipennis and Hydropsyche siltalai larvae were exposed to nominal aluminium concentrations of 0, 625, 1250, 2500 and 5000 μg Al l^–1 at pH 5.0 for 96 h. Larvae reared at pH 6.4 and without any aluminium treatment were used as controls. Morphological abnormalities in the anal papillae of the larvae were used as the response variable in estimating the median effective concentrations (EC₅₀) of aluminium.
2. No morphological abnormalities were observed in the control larvae. Only a few individuals of A. ladogensis had darkened anal papillae at pH 5.0 without additional aluminium treatment, whereas increasing aluminium concentrations significantly increased the number of individuals in all species displaying darkening and reduction of the papillae.
3. A. ladogensis appeared to be the most sensitive species to increasing aluminium concentrations, as reflected by the significantly lower mean EC₅₀ value for this species compared with those of H. siltalai and H. angustipennis . H. angustipennis larvae were the most tolerant to aluminium.
4. The results indicate that interspecific differences in sensitivity to aluminium may be a key factor influencing the guild structure of filter feeding caddis flies in acidified streams. The results also imply that toxic effects of aluminium on filter feeding caddis larvae occur due to the impairment of normal osmoregulation processes via damage to the ion-regulatory organs.     

Influence of the glass packing on the contamination of pharmaceutical products by aluminium. Part I: salts, glucose, heparin and albumin.

The presence of aluminium (Al) in pharmaceutical products used parenterally as sodium and potassium chlorides, glucose, heparin and albumin were investigated with respect to their storage in glass containers. As glasses can have aluminium in their composition, the aluminium may be released from the glass into the solution. The action of the substances above mentioned were investigated storing their solutions in glass and plastic containers, and measuring the aluminium in solution at determined time intervals. The aluminium present in the commercial pharmaceutical products, stored in both plastic and glass containers were also measured. All glass containers were analysed to determine their aluminium content. The aluminium determinations were done by atomic absorption spectrometry. The resuLts showed that aluminium is present in all analysed glasses in a percentage of 0.6 to 3%. Although all substances already have a residual aluminium contamination, the major contribution comes from the glass containers in which their solutions were stored. The contamination arising from glass depends too much on the nature of the substance. While the salts extracted about 400 microg Al/l in 60 days, glucose extracted 150 microg Al/l, and albumin and heparin about 500 microg Al/l in the same time interval. Commercial solutions of glucose contain about 10 microg Al/l when stored in polyethylene and from 350 to 1,000 microg Al/l when in glass ampules. Considering all commercial products, solutions stored in plastic containers contained no more than 20 microg Al/l whereas in glass the aluminium contamination reached 1,000 microg/l, and in all of them the aluminium increases with the age of the product.     

Aluminium accumulation and immunosuppressive effect in recipients of kidney transplants.

Aluminium that has accumulated in the body is thought to have a generalised cytotoxic effect. A prospective study of aluminium accumulation in bone-that is, subclinical aluminium toxicity--was carried out in 94 recipients of kidney allografts, who were followed up for three years. Subclinical aluminium toxicity was found in 66 patients. A significantly smaller proportion of patients with aluminium accumulation experienced a rejection episode: 30 (58%) nu 12 (86%) who received grafts from cadavers and 4 (29%) nu 10 (71%) who received grafts from living donors. On multivariate analysis only the source of the kidney and aluminium accumulation were found to influence the rejection rate. These findings suggest that aluminium accumulation has an immunosuppressive effect.     

Analysis of matched case-control data in presence of nonignorable missing exposure.

The present article deals with informative missing (IM) exposure data in matched case-control studies. When the missingness mechanism depends on the unobserved exposure values, modeling the missing data mechanism is inevitable. Therefore, a full likelihood-based approach for handling IM data has been proposed by positing a model for selection probability, and a parametric model for the partially missing exposure variable among the control population along with a disease risk model. We develop an EM algorithm to estimate the model parameters. Three special cases: (a) binary exposure variable, (b) normally distributed exposure variable, and (c) lognormally distributed exposure variable are discussed in detail. The method is illustrated by analyzing a real matched case-control data with missing exposure variable. The performance of the proposed method is evaluated through simulation studies, and the robustness of the proposed method for violation of different types of model assumptions has been considered.     

Aluminium bone disease in patients receiving plasma exchange with contaminated albumin.

Aluminium balance studies were carried out on eight patients with various immunological disorders who were receiving plasma exchange with albumin solutions known to be contaminated with aluminium. Four patients with impaired renal function (creatinine clearance less than 50 ml/min) retained between 60% and 74% of the aluminium infused during a single plasma exchange. Transiliac bone biopsy specimens from three patients in this group had a high content of aluminium and showed histological evidence of current or previous bone disease related to aluminium. Two of these patients suffered intermittent bone pain. The main route of excretion of injected aluminium was in urine, only a small proportion of the total input being removed in the "plasma bag" during plasma exchange. The extent of aluminium retention and bone deposition was not reflected by the plasma aluminium concentration before or after plasma exchange. Treatment of five patients with intravenous desferrioxamine increased the plasma aluminium concentration and urinary output of aluminium in those with evidence of aluminium retention. These studies show that patients with poor renal function receiving treatment with albumin contaminated with aluminium retain the metal and deposit it in bone, where it may eventually cause aluminium bone disease. Plasma exchange should be used with caution in patients with renal impairment.     

Water purification and the incidence of fractures in patients receiving home haemodialysis supervised by a single centre: evidence for "safe" upper limit of aluminium in water.

Between 1968 and 1980 fractures occurred in 56 of 284 patients treated by home haemodialysis in the Sheffield area for longer than one year. Patients sustained four times as many fractures while using dialysate prepared with water containing more than 1.0 mumol aluminium per 1 (2.7 micrograms/100 ml) than while using water containing a smaller concentration. When aluminium was removed from water by deionisation the incidence of fractures diminished during the next year and no patient developed dialysis encephalopathy. These findings show that 1.0 mumol/l is a safe maximum concentration of aluminium in water for use in home haemodialysis. It can be detected by the colorimetric aluminium analyses used by many water authorities. When financial resources are limited it is expedient to reserve aluminium analyses by electrothermal atomic absorption for plasma from patients receiving regular haemodialysis. Ingestion of aluminium hydroxide contributes significantly to the increased plasma aluminium concentration of these patients.     

Chronic exposure to aluminium impairs the glutamate-nitric oxide-cyclic GMP pathway in the rat in vivo.

Aluminium is neurotoxic and is considered a possible etiologic factor in Alzheimer's disease, dialysis syndrome and other neurological disorders. The molecular mechanism of aluminium-induced impairment of neurological functions remains unclear. We showed that aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons. The aim of this work was to assess by in vivo brain microdialysis whether chronic administration of aluminium in the drinking water (2.5% aluminium sulfate) also impairs the glutamate-nitric oxide-cGMP pathway in the cerebellum of rats in vivo. Chronic exposure to aluminium reduced NMDA-induced increase of extracellular cGMP by ca 50%. The increase in extracellular cGMP induced by the nitric oxide generating agent S-nitroso-N-acetylpenicillamine was higher (240%) in rats treated with aluminium than in controls. Immunoblotting experiments showed that aluminium reduced the cerebellar content of calmodulin and nitric oxide synthase by 34 and 15%, respectively. Basal activity of soluble guanylate cyclase was decreased by 66% in aluminium-treated rats, while the activity after stimulation with S-nitroso-N-acetylpenicillamine was similar to controls. Basal cGMP in the cerebellar extracellular space was decreased by 50% in aluminium-treated rats. These results indicate that chronic exposure to aluminium reduces the basal activity of guanylate cyclase and impairs the glutamate-nitric oxide-cGMP pathway in the animal in vivo.     

Cell nucleus intervention in aluminium concentration by the rat liver cells. Experimental study

Intravenous injections of Al gluconate enhances immediately the aluminium content of the Rat liver. The cell nuclei are mainly involved in Al accumulation which still remains 10 min. After injection. This experimental model of Al overload is of great potential interest to study Al-nucleic acid interactions.     

Implications of absence of measurement invariance for detecting sex limitation and genotype by environment interaction.

Using univariate sum scores in genetic studies of twin data is common practice. This practice precludes an investigation of the measurement model relating the individual items to an underlying factor. Absence of measurement invariance across a grouping variable such as gender or environmental exposure refers to group differences with respect to the measurement model. It is shown that a decomposition of a sum score into genetic and environmental variance components leads to path coefficients of the additive genetic factor that are biased differentially across groups if individual items are non-invariant. The arising group differences in path coefficients are identical to what is known as "scalar sex limitation" when gender is the grouping variable, or as "gene by environment interaction" when environmental exposure is the grouping variable. In both cases the interpretation would be in terms of a group-specific effect size of the genetic factor. This interpretation may be incorrect if individual items are non-invariant.