Guest guest Posted December 3, 2007 Report Share Posted December 3, 2007 This is a bit much for anyone to read, but let's just say that aluminum in vaccines is probably not a good idea as far as toxicity, brain and central nervous system cell death, motor, memory issues, oxidative stress, neurodegenerative disease and more. Aluminum is well studied as being a toxin. Here are 20 or so peer-reviewed citation summaries relating to aluminum. I have put together a draft of information to add to my anti-infection document. My best, - Stan Pubmed Search… aluminum[ti] AND (adverse OR toxic OR toxicity) 12-01-07 – By: 1: J Alzheimers Dis. 2006 Nov;10(2-3):179-201. Related Articles, Links Aluminum and Alzheimer's disease: a new look. Miu AC, Benga O. Program of Cognitive Neuroscience, Department of Psychology, Babe & #351;-Bolyai University, Cluj-Napoca, CJ, Romania. AndreiMiu@... Despite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimer's disease (AD) has subsisted in neuroscience. There are very few other examples of scientific hypotheses on the pathogenesis of a disease that have been revisited so many times, once a new method that would allow a test of Al's accumulations in the brain of AD patients or a comparison between Al-induced and AD neuropathological signs has become available. Although objects of methodological controversies for scientists and oversimplification for lay spectators, several lines of evidence have strongly supported the involvement of Al as a secondary aggravating factor or risk factor in the pathogenesis of AD. We review evidence on the similarities and dissimilarities between Al-induced neurofibrillary degeneration and paired helical filaments from AD, the accumulation of Al in neurofibrillary tangles and senile plaques from AD, the neuropathological dissociation between AD and dialysis associated encephalopathy, and the epidemiological relations between Al in drinking water and the prevalence of AD. We also critically analyze the prospects of Al-amyloid cascade studies and other evolving lines of evidence that might shed insights into the link between Al and AD. The message between the lines of the following article is that the involvement of Al in the pathogenesis of AD should not be discarded, especially in these times when the amyloid dogma of AD etiology shows its myopia. Publication Types: • Historical Article • Review PMID: 17119287 [PubMed - indexed for MEDLINE] 2: J Alzheimers Dis. 2006 Nov;10(2-3):223-53. Related Articles, Links Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. Yokel RA. College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536-0082, USA. ryokel@... The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter- mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and 's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP- dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations. Publication Types: • Research Support, N.I.H., Extramural • Research Support, Non-U.S. Gov't • Research Support, U.S. Gov't, Non-P.H.S. • Review PMID: 17119290 [PubMed - indexed for MEDLINE] 3: J Alzheimers Dis. 2006 Nov;10(2-3):135-44. Related Articles, Links Mechanisms of aluminum-induced neurodegeneration in animals: Implications for Alzheimer's disease. Savory J, Herman MM, Ghribi O. Department of Pathology, University of Virginia, Charlottesville, VA, USA. For four decades the controversial question concerning a possible role for aluminum neurotoxicity in contributing to the pathogenesis of Alzheimer's disease has been debated, and studies by different investigators have yielded contradictory results. The lack of sensitivity to aluminum neurotoxicity in transgenic mouse models of Alzheimer's disease has not allowed the system to be used to explore important aspects of this toxicity. Rabbits are particularly sensitive to aluminum neurotoxicity and they develop severe neurological changes that are dependent on dose, age and route of administration. The most prominent feature induced by aluminum in rabbit brain is a neurofibrillary degeneration that shares some similarity with the neurofibrillary tangles found in Alzheimer's disease patients. In the present review we discuss data from our laboratory and others, on the effects of aluminum on behaviour, neurologic function and morphology, using aluminum administered to rabbits via different routes. Finally, we will examine data on the possible cellular mechanisms underlying aluminum neurotoxicity, and potential neuroprotective strategies against aluminum toxicity. Publication Types: • Research Support, U.S. Gov't, Non-P.H.S. • Review PMID: 17119283 [PubMed - indexed for MEDLINE] 4: Brain Res Rev. 2006 Aug 30;52(1):193-200. Epub 2006 Mar 10. Related Articles, Links Some aspects of astroglial functions and aluminum implications for neurodegeneration. Aremu DA, Meshitsuka S. Division of Medical Environmentology, Department of Social Medicine, Graduate School of Medical Sciences, Tottori University, Yonago 683-8503, Japan. aremuda@... The present decade had witnessed an unprecedented attention focused on glial cells as a result of their unusual physiological roles that are being unraveled. It is now known that, rather than being a mere supporter of neurons, astroglia are actively involved in their modulation. The aluminum hypothesis seems to have been laid to rest, probably due to contradictory epidemiological reports on it as a causative factor of neurodegenerative diseases. Surprisingly, newer scientific evidences continue to appear and recent findings have implicated astrocytes as the principal target of its toxic action. In view of the likely detrimental effects of the interaction between these two infamous partners in neuroscience on neurons and nervous system, we have reviewed some aspects of glia- neuron interaction and discussed the implications of aluminum-impaired astrocytic functions on neurodegeneration. Because sporadic causes still account for the majority of the neurodegenerative diseases of which Alzheimer's disease is the most prominent, it has been suggested that neurotoxicologists should not relent in screening for the environmental agents, such as aluminum, and that considerable attention should be given to glial cells in view of the likely implications of environmental toxicants on their never- imagined newly reported roles in the central nervous system (CNS). Publication Types: • Review PMID: 16529821 [PubMed - indexed for MEDLINE] 5: J Alzheimers Dis. 2005 Nov;8(2):171-82; discussion 209-15. Related Articles, Links Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases. Kawahara M. Department of Analytical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka-city, Miyazaki, 882-8508, Japan. kawamasa@... Aluminum is environmentally abundant, but not an essential element. Aluminum has been associated with several neurodegenerative diseases, such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this association remains controversial, there is increasing evidence which suggests the implication of metal homeostasis in the pathogenesis of Alzheimer's disease. Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's amyloid-beta protein. Al causes the accumulation of tau protein and amyloid-beta protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as well as in vitro. Furthermore, a relationship between aluminum and the iron-homeostasis or calcium-homeostasis has been suggested. Based on these findings, the characteristics of aluminum neurotoxicity are reviewed, and the potential link between aluminum and neurodegenerative diseases is reconsidered. Publication Types: • Research Support, Non-U.S. Gov't • Review PMID: 16308486 [PubMed - indexed for MEDLINE] 6: Curr Opin Pharmacol. 2005 Dec;5(6):637-40. Epub 2005 Sep 28. Related Articles, Links Aluminum: new recognition of an old problem. Klein GL. Children's Hospital Room 3.270, University of Texas Medical Branch, 301 University Boulevard, Galveston TX 77555-0352, USA. gklein@... The aluminum problem is now over 25 years old, but has remained a neglected concern. Data indicate that aluminum contaminates much of the raw material used to manufacture solutions used for intravenous nutritional support of hospitalized and ambulatory patients, and that pharmaceutical manufacturers have only recently obtained the technology necessary to detect aluminum contamination of their products. As a result, aluminum bypassed normal barriers and entered the blood, accumulating in tissues such as bone, liver and the central nervous system with toxic consequences. Now that the FDA has finally issued a rule governing aluminum contamination in these solutions, manufacturers will need to develop methods to minimize such contamination; scientists should also realize that when data they obtain indicate a serious problem in the manufacturing sector they should be sure that the problem is properly addressed. Publication Types: • Review PMID: 16198633 [PubMed - indexed for MEDLINE] 7: Toxicol Ind Health. 2002 Aug;18(7):309-20. Related Articles, Links Aluminum as a toxicant. Becaria A, A, Bondy SC. Department of Community and Environmental Medicine, Center for Occupational and Environmental Health Sciences, Irvine, CA 92697-1820, USA. abecaria@... Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders. Publication Types: • Research Support, U.S. Gov't, P.H.S. • Review PMID: 15068131 [PubMed - indexed for MEDLINE] 8: Immunol Allergy Clin North Am. 2003 Nov;23(4):699-712. Related Articles, Links Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Gherardi RK, Authier FJ. Muscle and Nerve Group, Henri Mondor University Hospital, Créteil, France. lauret@univ- paris12.fr The authors conclude that the persistence of aluminum hydroxide at the site of intramuscular injection is a novel finding which has an exact significance that remains to be established fully. It seems mandatory to evaluate possible long-term adverse effects induced by this compound, because this issue has not been addressed (in the past, aluminum hydroxide was believed to be cleared quickly from the body). If safety concerns about the long-term effects of aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to rescue vaccine-based strategies should be proposed to ensure the enormous benefit for public health that these vaccines provide worldwide. Publication Types: • Review PMID: 14753387 [PubMed - indexed for MEDLINE] 9: Brain Res Bull. 2003 Nov 15;62(1):15-28. Related Articles, Links The role of metals in neurodegenerative processes: aluminum, manganese, and zinc. Zatta P, Lucchini R, van Rensburg SJ, A. CNR-Institute for Biomedical Technologies, Metalloproteins Unit, Department of Biology, University of Padova, 35121, Padova, Italy. zatta@... Until the last decade, little attention was given by the neuroscience community to the neurometabolism of metals. However, the neurobiology of heavy metals is now receiving growing interest, since it has been linked to major neurodegenerative diseases. In the present review some metals that could possibly be involved in neurodegeneration are discussed. Two of them, manganese and zinc, are essential metals while aluminum is non- essential. Aluminum has long been known as a neurotoxic agent. It is an etiopathogenic factor in diseases related to long-term dialysis treatment, and it has been controversially invoked as an aggravating factor or cofactor in Alzheimer's disease as well as in other neurodegenerative diseases. Manganese exposure can play an important role in causing Parkinsonian disturbances, possibly enhancing physiological aging of the brain in conjunction with genetic predisposition. An increased environmental burden of manganese may have deleterious effects on more sensitive subgroups of the population, with sub-threshold neurodegeneration in the basal ganglia, generating a pre- Parkinsonian condition. In the case of zinc, there has as yet been no evidence that it is involved in the etiology of neurodegenerative diseases in humans. Zinc is redox-inactive and, as a result of efficient homeostatic control, does not accumulate in excess. However, adverse symptoms in humans are observed on inhalation of zinc fumes, or accidental ingestion of unusually large amounts of zinc. Also, high concentrations of zinc have been found to kill bacteria, viruses, and cultured cells. Some of the possible mechanisms for cell death are reviewed. Publication Types: • Review PMID: 14596888 [PubMed - indexed for MEDLINE] 10: Nutr Rev. 2003 Sep;61(9):306-10. Related Articles, Links Parenteral nutrition-associated cholestasis in neonates: the role of aluminum. Arnold CJ, GG, Zello GA. College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7M 0Z9. Parenteral nutrition (PN) is an essential component in the care of premature and ill infants. The incidence of parenteral nutrition-associated cholestasis (PNAC) ranges from 7.4 to 84%. One substance in PN solutions that has been implicated in PNAC is aluminum. Aluminum loading in animals and humans causes hepatic accumulation and damage. The degree of aluminum contamination of PN solutions has decreased over time, but contamination still significantly exceeds levels that are safe for human neonates. Further study into the relationship between aluminum contamination in neonatal PN solutions and the development of PNAC is necessary. Publication Types: • Review PMID: 14552065 [PubMed - indexed for MEDLINE] Lithium as a protector of aluminum? 11: J Inorg Biochem. 2003 Sep 15;97(1):151-4. Related Articles, Links Intracellular mechanisms underlying aluminum-induced apoptosis in rabbit brain. Savory J, Herman MM, Ghribi O. Department of Pathology, University of Virginia, Charlottesville, VA, USA. jsr2@... Loss of neurons is a hallmark of neurodegenerative disorders and there is increasing evidence suggesting that apoptosis is a key mechanism by which neurons die in these diseases. Mitochondrial dysfunction has been implicated in this process of neuronal cell death, but there is a growing body of evidence suggesting also an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondria, or in concert with mitochondrial-initiated pathways. Investigations in our laboratory have focused on neuronal injury resulting from the administration of aluminum maltolate, via the intracisternal route, to New Zealand white rabbits. This treatment induces both mitochondrial and endoplasmic reticulum stress. Agents such as lithium or glial cell-line derived neurotrophic factor (GDNF) have the ability to prevent aluminum-induced neuronal death by interfering with the mitochondrial and/or the endoplasmic reticulum- mediated apoptosis cascade. Cytochrome c release from mitochondria and binding to Apaf-1 initiates the aluminum-induced apoptosis cascade; this is prevented by lithium treatment. GDNF also protects against aluminum-induced apoptosis but by upregulation of Bcl-X(L), thereby preventing the binding of cytochrome c to Apaf-1. This animal model system involving neurotoxicity induced by an aluminum compound provides new information on mechanisms of neurodegeneration and neuroprotection. Publication Types: • Research Support, Non-U.S. Gov't • Review PMID: 14507471 [PubMed - indexed for MEDLINE] 12: Vaccine. 2002 May 31;20 Suppl 3:S18-23. Related Articles, Links Erratum in: • Vaccine. 2002 Sep 10;20(27-28):3428. Aluminum salts in vaccines--US perspective. Baylor NW, Egan W, Richman P. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Vaccines Research and Review, Bethesda, MD, USA. baylor@... Aluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been commonly used as an adjuvant in many vaccines licensed by the US Food and Drug Administration. Chapter 21 of the US Code of Federal Regulations [610.15(a)] limits the amount of aluminum in biological products, including vaccines, to 0.85 mg/dose. The amount of aluminum in vaccines currently licensed in the US ranges from 0.85-0.125 mg/dose. Clinical studies have demonstrated that aluminum enhances the antigenicity of some vaccines such as diphtheria and tetanus toxoids. Moreover, aluminum-adsorbed diphtheria and tetanus toxoids are distinctly more effective than plain fluid toxoids for primary immunization of children. There is little difference between plain and adsorbed toxoids for booster immunization. Aluminum adjuvants have a demonstrated safety profile of over six decades; however, these adjuvants have been associated with severe local reactions such as erythema, subcutaneous nodules and contact hypersensitivity. Publication Types: • Review PMID: 12184360 [PubMed - indexed for MEDLINE] 14: Environ Res. 2002 Jun;89(2):101-15. Related Articles, Links Aluminum: impacts and disease. Nayak P. Department of Physiology, Sikkim Manipal Institute of Medical Sciences, 5th Mile, Tadong, Gangtok, 737102, Sikkim, India. 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. Publication Types: • Review PMID: 12123643 [PubMed - indexed for MEDLINE] 15: J Neurosci Res. 2001 Dec 1;66(5):1009-18. Related Articles, Links Aluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons. Szutowicz A. Chair of Clinical Biochemistry, Department of Laboratory Medicine, Medical University of Gda & #324;sk, Debinki 7, 80-211 Gda & #324;sk, Poland. aszut@... Several neurotoxic compounds, including Al, NO, and beta-amyloid may contribute to the impairment or loss of brain cholinergic neurons in the course of various neurodegenerative diseases. Genotype and phenotypic modifications of cholinergic neurons may determine their variable functional competency and susceptibility to reported neurotoxic insults. Hybrid, immortalized SN56 cholinergic cells from mouse septum may serve as a model for in vitro cholinotoxicity studies. Differentiation by various combinations of cAMP, retinoic acid, and nerve growth factor may provide cells of different morphologic maturity as well as activities of acetylcholine and acetyl-CoA metabolism. In general, differentiated cells appear to be more susceptible to neurotoxic signals than the non-differentiated ones, as evidenced by loss of sprouting and connectivity, decreases in choline acetyltransferase and pyruvate dehydrogenase activities, disturbances in acetyl-CoA compartmentation and metabolism, insufficient or excessive acetylcholine release, as well as increased expression of apoptosis markers. Each neurotoxin impaired both acetylcholine and acetyl-CoA metabolism of these cells. Activation of p75 or trkA receptors made either acetyl-CoA or cholinergic metabolism more susceptible to neurotoxic influences, respectively. Neurotoxins aggravated detrimental effects of each other, particularly in differentiated cells. Thus brain cholinergic neurons might display a differential susceptibility to Al and other neurotoxins depending on their genotype or phenotype-dependent variability of the cholinergic and acetyl-CoA metabolism. Copyright 2001 Wiley-Liss, Inc. Publication Types: • Research Support, Non-U.S. Gov't • Review PMID: 11746431 [PubMed - indexed for MEDLINE] 17: Neurotoxicology. 2000 Oct;21(5):813-28. Related Articles, Links The toxicology of aluminum in the brain: a review. Yokel RA. College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, USA. ryokel1@... Aluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al is a neurotoxicant in animals and humans. It has been implicated in the etiology of sporadic Alzheimer's disease (AD) and other neurodegenerative disorders, although this is highly controversial. This controversy has not been resolved by epidemiological studies, as only some found a small association between increased incidence of dementia and drinking water Al concentration. Studies of brain Al in AD have not produced consistent findings and have not resolved the controversy. Injections of Al to animals produce behavioral, neuropathological and neurochemical changes that partially model AD. Aluminum has the ability to produce neurotoxicity by many mechanisms. Excess, insoluble amyloid beta protein (A beta) contributes to AD. Aluminum promotes formation and accumulation of insoluble A beta and hyperphosphorylated tau. To some extent, Al mimics the deficit of cortical cholinergic neurotransmission seen in AD. Al increases Fe-induced oxidative injury. The toxicity of Al to plants, aquatic life and humans may share common mechanisms, including disruption of the inositol phosphate system and Ca regulation. Facilitation of Fe-induced oxidative injury and disruption of basic cell processes may mediate primary molecular mechanisms of Al-induced neurotoxicity. Avoidance of Al exposure, when practical, seems prudent. Publication Types: • Review PMID: 11130287 [PubMed - indexed for MEDLINE] 20: Ann N Y Acad Sci. 1997 Oct 15;825:152-66. Related Articles, Links Toxin-induced blood vessel inclusions caused by the chronic administration of aluminum and sodium fluoride and their implications for dementia. Isaacson RL, Varner JA, Jensen KF. Department of Psychology, Binghamton University, New York 13902-6000, USA. isaacson@... Publication Types: • Review PMID: 9369984 [PubMed - indexed for MEDLINE] 21: J Toxicol Environ Health. 1996 Aug 30;48(6):667-83. Related Articles, Links Prevention and treatment of aluminum toxicity including chelation therapy: status and research needs. Yokel RA, Ackrill P, Burgess E, Day JP, Domingo JL, Flaten TP, Savory J. College of Pharmacy, University of Kentucky Medical Center, Lexington 40536-0082, USA. ryokel1@... The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al- induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders. Publication Types: • Review PMID: 8772805 [PubMed - indexed for MEDLINE] Can't even figure out all the ways that aluminum damage the body systemically…. 22: J Toxicol Environ Health. 1996 Aug 30;48(6):649-65. Related Articles, Links Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney. Jeffery EH, Abreo K, Burgess E, Cannata J, Greger JL. Institute for Environmental Studies, University of Illinois, Urbana-Champaign 61801, USA. jeffery@... Although the full mechanisms are not yet elucidated, research into the mechanism of toxicity of aluminum (Al) on bone formation and remodeling and on hematopoietic tissue is ongoing. In contrast little information exists on the interactive effects of systemic Al and the kidney. In bone, both clinically and experimentally, high doses of Al inhibit remodeling, slowing both osteoblast and osteoclast activities and producing osteomalacia and adynamic bone disease. In contrast, while very low levels of Al are mitogenic in bones of experimental animals, the effect of low levels of Al in humans is unknown. Aluminum has been shown to have its mitogenic action at the osteoblast, but whether the effect on resorption is viz osteoblast-directed changes in osteoclast activity has not yet been determined. Parathyroid hormone (PTH) levels are disrupted by Al in humans and animals. Whether altered PTH levels play a major or even a minor role in Al-dependent osteotoxicity requires clarification. In hematopoietic tissue, Al causes a microcytic anemia, not reversible by iron. Friend leukemia cells treated with Al have been reported to accumulate excess iron, without incorporating it into ferritin or heme. It is not yet known which steps in iron metabolism are disrupted by Al, if they involve a single mechanism of action, or even if this disruption in iron metabolism accounts for the anemia seen in Al toxicosis. In kidney, research is needed to evaluate Al nephrotoxicity; there are almost no studies in this area. Furthermore, research is needed to evaluate mechanisms of renal Al excretion, presently shown by one study to occur at the distal tubule. Such studies might well throw light on whether Al plays a role in aggravating renal insufficiency, or whether the role of the kidney in Al toxicosis is limited to the causative effect of renal compromise on Al accumulation. In summary, while a number of mechanisms have been proposed for the toxic action of Al, no single mechanism emerges to explain these diverse effects of systemic Al. Recommendations for future research are presented and summarized in Table 1. Publication Types: • Review PMID: 8772804 [PubMed - indexed for MEDLINE] 23: J Toxicol Environ Health. 1996 Aug 30;48(6):585-97. Related Articles, Links What we know and what we need to know about developmental aluminum toxicity. Golub MS, Domingo JL. Department of Internal Medicine, University of California, 95616, USA. Information concerning developmental aluminum (Al) toxicity is available from clinical studies and from animal testing. An Al toxicity syndrome including encephalopathy, osteomalacia, and anemia has been reported in uremic children receiving dialysis. In addition, some components of the syndrome, particularly osteomalacia, have been reported in non-dialyzed uremic children receiving Al-based phosphate binders, nonuremic infants receiving parenteral nutrition with Al-containing fluids, and nonuremic infants given high doses of Al antacids. The number of children in clinical populations that are at risk of Al toxicity is not known and needs to be determined. Work in animal models (rats, mice, and rabbits) demonstrates that Al is distributed transplacentally and is present in milk. Oral Al administration during pregnancy produces a syndrome including growth retardation, delayed ossification, and malformations at doses that also lead to reduced maternal weight gain. The severity of the effects is highly dependent on the form of Al administered. In the postnatal period, reduced pup weight gain and effects on neuromotor development have been described as a result of developmental exposures. The significance of these findings for human health requires better understanding of the amount and bioavailability of Al in food, drinking water, and medications and from sources unique to infants and children such as breast milk, soil ingestion, and medications used specifically by pregnant women and children. We also need a better understanding of the unique biological actions of Al that may occur during developmental periods, and unique aspects of the developing organism that make it more or less susceptible to Al toxicity. Publication Types: • Review PMID: 8772800 [PubMed - indexed for MEDLINE] 24: J Toxicol Environ Health. 1996 Aug 30;48(6):569-84. Related Articles, Links Aluminum toxicokinetics. Exley C, Burgess E, Day JP, Jeffery EH, Melethil S, Yokel RA. Department of Chemistry, Keele University, Staffordshire, United Kingdom. cha38@... In this study of the toxicokinetics of aluminum we have examined some of the fundamental issues that currently define our understanding of the toxicology of aluminum in humans. There is a vast literature on this subject, and it was not our aim to review this literature but to use it to develop our understanding of the toxicokinetics of aluminum and to identify critical and unresolved issues related to its toxicity. In undertaking this task we have chosen to define the term toxicokinetics to encompass those factors that influence both the lability of aluminum in a body and the sites at which aluminum is known to accumulate, with or without consequent biological effect. We have approached our objective from the classical pharmacological approach of ADME: the absorption, distribution, metabolism, and excretion of aluminum. This approach was successful in identifying several key deficits in our understanding of aluminum toxicokinetics. For example, we need to determine the mechanisms by which aluminum crosses epithelia, such as those of the gastrointestinal tract and the central nervous system, and how these mechanisms influence both the subsequent transport and fate of the absorbed aluminum and the concomitant nature and severity of the biological response to the accumulation of aluminum. Our hope in highlighting these unresolved issues (summarized in Table 1) is that they will be addressed in future research. Publication Types: • Review PMID: 8772799 [PubMed - indexed for MEDLINE] 25: J Toxicol Environ Health. 1996 Aug 30;48(6):543-68. Related Articles, Links Speciation of aluminum in biological systems. WR, Berthon G, Day JP, Exley C, Flaten TP, Forbes WF, Kiss T, Orvig C, Zatta PF. Department of Chemistry, University of Missouri-St. Louis 63121, USA. As a " hard " , trivalent metal ion, Al3- binds strongly to oxygen-donor ligands such as citrate and phosphate. The aqueous coordination chemistry of Al is complicated by the tendency of many Al complexes to hydrolyze and form polynuclear species, many of which are sparingly soluble. Thus there is considerable variation among the Al stability constants reported for several important ligands. The complexity in the aqueous chemistry of Al has also affected Al toxicity studies, which have often utilized poorly characterized Al stock solutions. Serum fractionation studies show that most Al is protein bound, primarily to the serum iron transport protein transferrin. Albumin appears to play little, if any, role in serum transport. There is little agreement as to the speciation of the remaining low- molecular mass fraction of serum Al. The lability of the Al3+ion precludes the simple separation and identification of individual Al complexes. Computational methods are available for detailed computer calculations of the Al speciation in serum, but efforts in this area have been severely hampered by the uncertainties regarding the stability constants of the low molecular mass Al complexes with citrate, phosphate, and hydroxide. Specific recommendations for further research on Al speciation include: (1) Determine more accurate Al stability constants with critical low molecular mass ligands such as citrate and phosphate; (2) supplement traditional potentiometric studies on Al complexes with data from other techniques such as 27Al-NMR and accelerator mass spectrometry with 26Al; (3) develop new methods for generating reliable linear free energy relationships for Al complexation; (4) determine equilibrium and rate constants for Al binding to transferrin at 37 degrees C; (5) confirm the possible formation of low-molecular-mass Al-protein complexes following desferrioxamine therapy; (6) continue research efforts to incorporate kinetic considerations into the present equilibrium speciation calculations; (7) improve methods for preparing chemically well-defined stock solutions for toxicological studies; (8) incorporate more detailed speciation data into studies on Al toxicity and pharmacokinetics; and (9) incorporate more detailed speciation data into future epidemiological studies on the relationship between Al toxicity and various water quality parameters. 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Guest guest Posted December 3, 2007 Report Share Posted December 3, 2007 Thank you Stan. You rock the house.Stan Kurtz wrote: This is a bit much for anyone to read, but let's just say that aluminum in vaccines is probably not a good idea as far as toxicity, brain and central nervous system cell death, motor, memory issues, oxidative stress, neurodegenerative disease and more.Aluminum is well studied as being a toxin. Here are 20 or so peer-reviewed citation summaries relating to aluminum. I have put together a draft of information to add to my anti-infection document.My best,- StanPubmed Search…aluminum[ti] AND (adverse OR toxic OR toxicity)12-01-07 – By: 1: J Alzheimers Dis. 2006 Nov;10(2-3):179-201.Related Articles, LinksAluminum and Alzheimer's disease: a new look.Miu AC, Benga O.Program of Cognitive Neuroscience, Department of Psychology, Babe & #351;-Bolyai University, Cluj-Napoca, CJ, Romania. AndreiMiupsychology (DOT) roDespite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimer's disease (AD) has subsisted in neuroscience. There are very few other examples of scientific hypotheses on the pathogenesis of a disease that have been revisited so many times, once a new method that would allow a test of Al's accumulations in the brain of AD patients or a comparison between Al-induced and AD neuropathological signs has become available. Although objects of methodological controversies for scientists and oversimplification for lay spectators, several lines of evidence have strongly supported the involvement of Al as a secondary aggravating factor or risk factor in the pathogenesis of AD. We review evidence on the similarities and dissimilarities between Al-induced neurofibrillary degeneration and paired helical filaments from AD, the accumulation of Al in neurofibrillary tangles and senile plaques from AD, the neuropathological dissociation between AD and dialysis associated encephalopathy, and the epidemiological relations between Al in drinking water and the prevalence of AD. We also critically analyze the prospects of Al-amyloid cascade studies and other evolving lines of evidence that might shed insights into the link between Al and AD. The message between the lines of the following article is that the involvement of Al in the pathogenesis of AD should not be discarded, especially in these times when the amyloid dogma of AD etiology shows its myopia.Publication Types: • Historical Article• ReviewPMID: 17119287 [PubMed - indexed for MEDLINE]2: J Alzheimers Dis. 2006 Nov;10(2-3):223-53.Related Articles, LinksBlood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration.Yokel RA.College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536-0082, USA. ryokelemail (DOT) uky.eduThe etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and 's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.Publication Types: • Research Support, N.I.H., Extramural• Research Support, Non-U.S. Gov't• Research Support, U.S. Gov't, Non-P.H.S.• ReviewPMID: 17119290 [PubMed - indexed for MEDLINE]3: J Alzheimers Dis. 2006 Nov;10(2-3):135-44.Related Articles, LinksMechanisms of aluminum-induced neurodegeneration in animals: Implications for Alzheimer's disease.Savory J, Herman MM, Ghribi O.Department of Pathology, University of Virginia, Charlottesville, VA, USA.For four decades the controversial question concerning a possible role for aluminum neurotoxicity in contributing to the pathogenesis of Alzheimer's disease has been debated, and studies by different investigators have yielded contradictory results. The lack of sensitivity to aluminum neurotoxicity in transgenic mouse models of Alzheimer's disease has not allowed the system to be used to explore important aspects of this toxicity. Rabbits are particularly sensitive to aluminum neurotoxicity and they develop severe neurological changes that are dependent on dose, age and route of administration. The most prominent feature induced by aluminum in rabbit brain is a neurofibrillary degeneration that shares some similarity with the neurofibrillary tangles found in Alzheimer's disease patients. In the present review we discuss data from our laboratory and others, on the effects of aluminum on behaviour, neurologic function and morphology, using aluminum administered to rabbits via different routes. Finally, we will examine data on the possible cellular mechanisms underlying aluminum neurotoxicity, and potential neuroprotective strategies against aluminum toxicity.Publication Types: • Research Support, U.S. Gov't, Non-P.H.S.• ReviewPMID: 17119283 [PubMed - indexed for MEDLINE]4: Brain Res Rev. 2006 Aug 30;52(1):193-200. Epub 2006 Mar 10.Related Articles, LinksSome aspects of astroglial functions and aluminum implications for neurodegeneration.Aremu DA, Meshitsuka S.Division of Medical Environmentology, Department of Social Medicine, Graduate School of Medical Sciences, Tottori University, Yonago 683-8503, Japan. aremudagrape (DOT) med.tottori-u.ac.jpThe present decade had witnessed an unprecedented attention focused on glial cells as a result of their unusual physiological roles that are being unraveled. It is now known that, rather than being a mere supporter of neurons, astroglia are actively involved in their modulation. The aluminum hypothesis seems to have been laid to rest, probably due to contradictory epidemiological reports on it as a causative factor of neurodegenerative diseases. Surprisingly, newer scientific evidences continue to appear and recent findings have implicated astrocytes as the principal target of its toxic action. In view of the likely detrimental effects of the interaction between these two infamous partners in neuroscience on neurons and nervous system, we have reviewed some aspects of glia-neuron interaction and discussed the implications of aluminum-impaired astrocytic functions on neurodegeneration. Because sporadic causes still account for the majority of the neurodegenerative diseases of which Alzheimer's disease is the most prominent, it has been suggested that neurotoxicologists should not relent in screening for the environmental agents, such as aluminum, and that considerable attention should be given to glial cells in view of the likely implications of environmental toxicants on their never-imagined newly reported roles in the central nervous system (CNS).Publication Types: • ReviewPMID: 16529821 [PubMed - indexed for MEDLINE]5: J Alzheimers Dis. 2005 Nov;8(2):171-82; discussion 209-15.Related Articles, LinksEffects of aluminum on the nervous system and its possible link with neurodegenerative diseases.Kawahara M.Department of Analytical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka-city, Miyazaki, 882-8508, Japan. kawamasaphoenix (DOT) ac.jpAluminum is environmentally abundant, but not an essential element. Aluminum has been associated with several neurodegenerative diseases, such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this association remains controversial, there is increasing evidence which suggests the implication of metal homeostasis in the pathogenesis of Alzheimer's disease. Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's amyloid-beta protein. Al causes the accumulation of tau protein and amyloid-beta protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as well as in vitro. Furthermore, a relationship between aluminum and the iron-homeostasis or calcium-homeostasis has been suggested. Based on these findings, the characteristics of aluminum neurotoxicity are reviewed, and the potential link between aluminum and neurodegenerative diseases is reconsidered.Publication Types: • Research Support, Non-U.S. Gov't • ReviewPMID: 16308486 [PubMed - indexed for MEDLINE]6: Curr Opin Pharmacol. 2005 Dec;5(6):637-40. Epub 2005 Sep 28.Related Articles, LinksAluminum: new recognition of an old problem.Klein GL.Children's Hospital Room 3.270, University of Texas Medical Branch, 301 University Boulevard, Galveston TX 77555-0352, USA. gkleinutmb (DOT) eduThe aluminum problem is now over 25 years old, but has remained a neglected concern. Data indicate that aluminum contaminates much of the raw material used to manufacture solutions used for intravenous nutritional support of hospitalized and ambulatory patients, and that pharmaceutical manufacturers have only recently obtained the technology necessary to detect aluminum contamination of their products. As a result, aluminum bypassed normal barriers and entered the blood, accumulating in tissues such as bone, liver and the central nervous system with toxic consequences. Now that the FDA has finally issued a rule governing aluminum contamination in these solutions, manufacturers will need to develop methods to minimize such contamination; scientists should also realize that when data they obtain indicate a serious problem in the manufacturing sector they should be sure that the problem is properly addressed.Publication Types: • ReviewPMID: 16198633 [PubMed - indexed for MEDLINE]7: Toxicol Ind Health. 2002 Aug;18(7):309-20.Related Articles, LinksAluminum as a toxicant.Becaria A, A, Bondy SC.Department of Community and Environmental Medicine, Center for Occupational and Environmental Health Sciences, Irvine, CA 92697-1820, USA. abecariauci (DOT) eduAlthough aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.Publication Types: • Research Support, U.S. Gov't, P.H.S. • ReviewPMID: 15068131 [PubMed - indexed for MEDLINE]8: Immunol Allergy Clin North Am. 2003 Nov;23(4):699-712.Related Articles, LinksAluminum inclusion macrophagic myofasciitis: a recently identified condition.Gherardi RK, Authier FJ.Muscle and Nerve Group, Henri Mondor University Hospital, Créteil, France. lauretuniv-paris12 (DOT) frThe authors conclude that the persistence of aluminum hydroxide at the site of intramuscular injection is a novel finding which has an exact significance that remains to be established fully. It seems mandatory to evaluate possible long-term adverse effects induced by this compound, because this issue has not been addressed (in the past, aluminum hydroxide was believed to be cleared quickly from the body). If safety concerns about the long-term effects of aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to rescue vaccine-based strategies should be proposed to ensure the enormous benefit for public health that these vaccines provide worldwide.Publication Types: • ReviewPMID: 14753387 [PubMed - indexed for MEDLINE]9: Brain Res Bull. 2003 Nov 15;62(1):15-28.Related Articles, LinksThe role of metals in neurodegenerative processes: aluminum, manganese, and zinc.Zatta P, Lucchini R, van Rensburg SJ, A.CNR-Institute for Biomedical Technologies, Metalloproteins Unit, Department of Biology, University of Padova, 35121, Padova, Italy. zatta@....unipd.itUntil the last decade, little attention was given by the neuroscience community to the neurometabolism of metals. However, the neurobiology of heavy metals is now receiving growing interest, since it has been linked to major neurodegenerative diseases. In the present review some metals that could possibly be involved in neurodegeneration are discussed. Two of them, manganese and zinc, are essential metals while aluminum is non-essential. Aluminum has long been known as a neurotoxic agent. It is an etiopathogenic factor in diseases related to long-term dialysis treatment, and it has been controversially invoked as an aggravating factor or cofactor in Alzheimer's disease as well as in other neurodegenerative diseases. Manganese exposure can play an important role in causing Parkinsonian disturbances, possibly enhancing physiological aging of the brain in conjunction with genetic predisposition. An increased environmental burden of manganese may have deleterious effects on more sensitive subgroups of the population, with sub-threshold neurodegeneration in the basal ganglia, generating a pre-Parkinsonian condition. In the case of zinc, there has as yet been no evidence that it is involved in the etiology of neurodegenerative diseases in humans. Zinc is redox-inactive and, as a result of efficient homeostatic control, does not accumulate in excess. However, adverse symptoms in humans are observed on inhalation of zinc fumes, or accidental ingestion of unusually large amounts of zinc. Also, high concentrations of zinc have been found to kill bacteria, viruses, and cultured cells. Some of the possible mechanisms for cell death are reviewed.Publication Types: • ReviewPMID: 14596888 [PubMed - indexed for MEDLINE]10: Nutr Rev. 2003 Sep;61(9):306-10.Related Articles, LinksParenteral nutrition-associated cholestasis in neonates: the role of aluminum.Arnold CJ, GG, Zello GA.College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7M 0Z9.Parenteral nutrition (PN) is an essential component in the care of premature and ill infants. The incidence of parenteral nutrition-associated cholestasis (PNAC) ranges from 7.4 to 84%. One substance in PN solutions that has been implicated in PNAC is aluminum. Aluminum loading in animals and humans causes hepatic accumulation and damage. The degree of aluminum contamination of PN solutions has decreased over time, but contamination still significantly exceeds levels that are safe for human neonates. Further study into the relationship between aluminum contamination in neonatal PN solutions and the development of PNAC is necessary.Publication Types: • ReviewPMID: 14552065 [PubMed - indexed for MEDLINE]Lithium as a protector of aluminum?11: J Inorg Biochem. 2003 Sep 15;97(1):151-4.Related Articles, LinksIntracellular mechanisms underlying aluminum-induced apoptosis in rabbit brain.Savory J, Herman MM, Ghribi O.Department of Pathology, University of Virginia, Charlottesville, VA, USA. jsr2virginia (DOT) eduLoss of neurons is a hallmark of neurodegenerative disorders and there is increasing evidence suggesting that apoptosis is a key mechanism by which neurons die in these diseases. Mitochondrial dysfunction has been implicated in this process of neuronal cell death, but there is a growing body of evidence suggesting also an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondria, or in concert with mitochondrial-initiated pathways. Investigations in our laboratory have focused on neuronal injury resulting from the administration of aluminum maltolate, via the intracisternal route, to New Zealand white rabbits. This treatment induces both mitochondrial and endoplasmic reticulum stress. Agents such as lithium or glial cell-line derived neurotrophic factor (GDNF) have the ability to prevent aluminum-induced neuronal death by interfering with the mitochondrial and/or the endoplasmic reticulum-mediated apoptosis cascade. Cytochrome c release from mitochondria and binding to Apaf-1 initiates the aluminum-induced apoptosis cascade; this is prevented by lithium treatment. GDNF also protects against aluminum-induced apoptosis but by upregulation of Bcl-X(L), thereby preventing the binding of cytochrome c to Apaf-1. This animal model system involving neurotoxicity induced by an aluminum compound provides new information on mechanisms of neurodegeneration and neuroprotection.Publication Types: • Research Support, Non-U.S. Gov't • ReviewPMID: 14507471 [PubMed - indexed for MEDLINE]12: Vaccine. 2002 May 31;20 Suppl 3:S18-23.Related Articles, LinksErratum in:• Vaccine. 2002 Sep 10;20(27-28):3428. Aluminum salts in vaccines--US perspective.Baylor NW, Egan W, Richman P.Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Vaccines Research and Review, Bethesda, MD, USA. baylorcber (DOT) fda.govAluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been commonly used as an adjuvant in many vaccines licensed by the US Food and Drug Administration. Chapter 21 of the US Code of Federal Regulations [610.15(a)] limits the amount of aluminum in biological products, including vaccines, to 0.85 mg/dose. The amount of aluminum in vaccines currently licensed in the US ranges from 0.85-0.125 mg/dose. Clinical studies have demonstrated that aluminum enhances the antigenicity of some vaccines such as diphtheria and tetanus toxoids. Moreover, aluminum-adsorbed diphtheria and tetanus toxoids are distinctly more effective than plain fluid toxoids for primary immunization of children. There is little difference between plain and adsorbed toxoids for booster immunization. Aluminum adjuvants have a demonstrated safety profile of over six decades; however, these adjuvants have been associated with severe local reactions such as erythema, subcutaneous nodules and contact hypersensitivity.Publication Types: • ReviewPMID: 12184360 [PubMed - indexed for MEDLINE]14: Environ Res. 2002 Jun;89(2):101-15.Related Articles, LinksAluminum: impacts and disease.Nayak P.Department of Physiology, Sikkim Manipal Institute of Medical Sciences, 5th Mile, Tadong, Gangtok, 737102, Sikkim, India.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.Publication Types: • ReviewPMID: 12123643 [PubMed - indexed for MEDLINE]15: J Neurosci Res. 2001 Dec 1;66(5):1009-18.Related Articles, LinksAluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons.Szutowicz A.Chair of Clinical Biochemistry, Department of Laboratory Medicine, Medical University of Gda & #324;sk, Debinki 7, 80-211 Gda & #324;sk, Poland. aszut@....plSeveral neurotoxic compounds, including Al, NO, and beta-amyloid may contribute to the impairment or loss of brain cholinergic neurons in the course of various neurodegenerative diseases. Genotype and phenotypic modifications of cholinergic neurons may determine their variable functional competency and susceptibility to reported neurotoxic insults. Hybrid, immortalized SN56 cholinergic cells from mouse septum may serve as a model for in vitro cholinotoxicity studies. Differentiation by various combinations of cAMP, retinoic acid, and nerve growth factor may provide cells of different morphologic maturity as well as activities of acetylcholine and acetyl-CoA metabolism. In general, differentiated cells appear to be more susceptible to neurotoxic signals than the non-differentiated ones, as evidenced by loss of sprouting and connectivity, decreases in choline acetyltransferase and pyruvate dehydrogenase activities, disturbances in acetyl-CoA compartmentation and metabolism, insufficient or excessive acetylcholine release, as well as increased expression of apoptosis markers. Each neurotoxin impaired both acetylcholine and acetyl-CoA metabolism of these cells. Activation of p75 or trkA receptors made either acetyl-CoA or cholinergic metabolism more susceptible to neurotoxic influences, respectively. Neurotoxins aggravated detrimental effects of each other, particularly in differentiated cells. Thus brain cholinergic neurons might display a differential susceptibility to Al and other neurotoxins depending on their genotype or phenotype-dependent variability of the cholinergic and acetyl-CoA metabolism. Copyright 2001 Wiley-Liss, Inc.Publication Types: • Research Support, Non-U.S. Gov't • ReviewPMID: 11746431 [PubMed - indexed for MEDLINE]17: Neurotoxicology. 2000 Oct;21(5):813-28.Related Articles, LinksThe toxicology of aluminum in the brain: a review.Yokel RA.College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, USA. ryokel1pop (DOT) uky.eduAluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al is a neurotoxicant in animals and humans. It has been implicated in the etiology of sporadic Alzheimer's disease (AD) and other neurodegenerative disorders, although this is highly controversial. This controversy has not been resolved by epidemiological studies, as only some found a small association between increased incidence of dementia and drinking water Al concentration. Studies of brain Al in AD have not produced consistent findings and have not resolved the controversy. Injections of Al to animals produce behavioral, neuropathological and neurochemical changes that partially model AD. Aluminum has the ability to produce neurotoxicity by many mechanisms. Excess, insoluble amyloid beta protein (A beta) contributes to AD. Aluminum promotes formation and accumulation of insoluble A beta and hyperphosphorylated tau. To some extent, Al mimics the deficit of cortical cholinergic neurotransmission seen in AD. Al increases Fe-induced oxidative injury. The toxicity of Al to plants, aquatic life and humans may share common mechanisms, including disruption of the inositol phosphate system and Ca regulation. Facilitation of Fe-induced oxidative injury and disruption of basic cell processes may mediate primary molecular mechanisms of Al-induced neurotoxicity. Avoidance of Al exposure, when practical, seems prudent.Publication Types: • ReviewPMID: 11130287 [PubMed - indexed for MEDLINE]20: Ann N Y Acad Sci. 1997 Oct 15;825:152-66.Related Articles, LinksToxin-induced blood vessel inclusions caused by the chronic administration of aluminum and sodium fluoride and their implications for dementia.Isaacson RL, Varner JA, Jensen KF.Department of Psychology, Binghamton University, New York 13902-6000, USA. isaacsonbinghamton (DOT) eduPublication Types: • ReviewPMID: 9369984 [PubMed - indexed for MEDLINE]21: J Toxicol Environ Health. 1996 Aug 30;48(6):667-83.Related Articles, LinksPrevention and treatment of aluminum toxicity including chelation therapy: status and research needs.Yokel RA, Ackrill P, Burgess E, Day JP, Domingo JL, Flaten TP, Savory J.College of Pharmacy, University of Kentucky Medical Center, Lexington 40536-0082, USA. ryokel1pop (DOT) uky.eduThe prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.Publication Types: • ReviewPMID: 8772805 [PubMed - indexed for MEDLINE]Can't even figure out all the ways that aluminum damage the body systemically….22: J Toxicol Environ Health. 1996 Aug 30;48(6):649-65.Related Articles, LinksSystemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney.Jeffery EH, Abreo K, Burgess E, Cannata J, Greger JL.Institute for Environmental Studies, University of Illinois, Urbana-Champaign 61801, USA. jefferyux1 (DOT) cso.uiuc.eduAlthough the full mechanisms are not yet elucidated, research into the mechanism of toxicity of aluminum (Al) on bone formation and remodeling and on hematopoietic tissue is ongoing. In contrast little information exists on the interactive effects of systemic Al and the kidney. In bone, both clinically and experimentally, high doses of Al inhibit remodeling, slowing both osteoblast and osteoclast activities and producing osteomalacia and adynamic bone disease. In contrast, while very low levels of Al are mitogenic in bones of experimental animals, the effect of low levels of Al in humans is unknown. Aluminum has been shown to have its mitogenic action at the osteoblast, but whether the effect on resorption is viz osteoblast-directed changes in osteoclast activity has not yet been determined. Parathyroid hormone (PTH) levels are disrupted by Al in humans and animals. Whether altered PTH levels play a major or even a minor role in Al-dependent osteotoxicity requires clarification. In hematopoietic tissue, Al causes a microcytic anemia, not reversible by iron. Friend leukemia cells treated with Al have been reported to accumulate excess iron, without incorporating it into ferritin or heme. It is not yet known which steps in iron metabolism are disrupted by Al, if they involve a single mechanism of action, or even if this disruption in iron metabolism accounts for the anemia seen in Al toxicosis. In kidney, research is needed to evaluate Al nephrotoxicity; there are almost no studies in this area. Furthermore, research is needed to evaluate mechanisms of renal Al excretion, presently shown by one study to occur at the distal tubule. Such studies might well throw light on whether Al plays a role in aggravating renal insufficiency, or whether the role of the kidney in Al toxicosis is limited to the causative effect of renal compromise on Al accumulation. In summary, while a number of mechanisms have been proposed for the toxic action of Al, no single mechanism emerges to explain these diverse effects of systemic Al. Recommendations for future research are presented and summarized in Table 1.Publication Types: • ReviewPMID: 8772804 [PubMed - indexed for MEDLINE]23: J Toxicol Environ Health. 1996 Aug 30;48(6):585-97.Related Articles, LinksWhat we know and what we need to know about developmental aluminum toxicity.Golub MS, Domingo JL.Department of Internal Medicine, University of California, 95616, USA.Information concerning developmental aluminum (Al) toxicity is available from clinical studies and from animal testing. An Al toxicity syndrome including encephalopathy, osteomalacia, and anemia has been reported in uremic children receiving dialysis. In addition, some components of the syndrome, particularly osteomalacia, have been reported in non-dialyzed uremic children receiving Al-based phosphate binders, nonuremic infants receiving parenteral nutrition with Al-containing fluids, and nonuremic infants given high doses of Al antacids. The number of children in clinical populations that are at risk of Al toxicity is not known and needs to be determined. Work in animal models (rats, mice, and rabbits) demonstrates that Al is distributed transplacentally and is present in milk. Oral Al administration during pregnancy produces a syndrome including growth retardation, delayed ossification, and malformations at doses that also lead to reduced maternal weight gain. The severity of the effects is highly dependent on the form of Al administered. In the postnatal period, reduced pup weight gain and effects on neuromotor development have been described as a result of developmental exposures. The significance of these findings for human health requires better understanding of the amount and bioavailability of Al in food, drinking water, and medications and from sources unique to infants and children such as breast milk, soil ingestion, and medications used specifically by pregnant women and children. We also need a better understanding of the unique biological actions of Al that may occur during developmental periods, and unique aspects of the developing organism that make it more or less susceptible to Al toxicity.Publication Types: • ReviewPMID: 8772800 [PubMed - indexed for MEDLINE]24: J Toxicol Environ Health. 1996 Aug 30;48(6):569-84.Related Articles, LinksAluminum toxicokinetics.Exley C, Burgess E, Day JP, Jeffery EH, Melethil S, Yokel RA.Department of Chemistry, Keele University, Staffordshire, United Kingdom. cha38keele (DOT) ac.ukIn this study of the toxicokinetics of aluminum we have examined some of the fundamental issues that currently define our understanding of the toxicology of aluminum in humans. There is a vast literature on this subject, and it was not our aim to review this literature but to use it to develop our understanding of the toxicokinetics of aluminum and to identify critical and unresolved issues related to its toxicity. In undertaking this task we have chosen to define the term toxicokinetics to encompass those factors that influence both the lability of aluminum in a body and the sites at which aluminum is known to accumulate, with or without consequent biological effect. We have approached our objective from the classical pharmacological approach of ADME: the absorption, distribution, metabolism, and excretion of aluminum. This approach was successful in identifying several key deficits in our understanding of aluminum toxicokinetics. For example, we need to determine the mechanisms by which aluminum crosses epithelia, such as those of the gastrointestinal tract and the central nervous system, and how these mechanisms influence both the subsequent transport and fate of the absorbed aluminum and the concomitant nature and severity of the biological response to the accumulation of aluminum. Our hope in highlighting these unresolved issues (summarized in Table 1) is that they will be addressed in future research.Publication Types: • ReviewPMID: 8772799 [PubMed - indexed for MEDLINE]25: J Toxicol Environ Health. 1996 Aug 30;48(6):543-68.Related Articles, LinksSpeciation of aluminum in biological systems. WR, Berthon G, Day JP, Exley C, Flaten TP, Forbes WF, Kiss T, Orvig C, Zatta PF.Department of Chemistry, University of Missouri-St. Louis 63121, USA.As a "hard", trivalent metal ion, Al3- binds strongly to oxygen-donor ligands such as citrate and phosphate. The aqueous coordination chemistry of Al is complicated by the tendency of many Al complexes to hydrolyze and form polynuclear species, many of which are sparingly soluble. Thus there is considerable variation among the Al stability constants reported for several important ligands. The complexity in the aqueous chemistry of Al has also affected Al toxicity studies, which have often utilized poorly characterized Al stock solutions. Serum fractionation studies show that most Al is protein bound, primarily to the serum iron transport protein transferrin. Albumin appears to play little, if any, role in serum transport. There is little agreement as to the speciation of the remaining low-molecular mass fraction of serum Al. The lability of the Al3+ion precludes the simple separation and identification of individual Al complexes. Computational methods are available for detailed computer calculations of the Al speciation in serum, but efforts in this area have been severely hampered by the uncertainties regarding the stability constants of the low molecular mass Al complexes with citrate, phosphate, and hydroxide. Specific recommendations for further research on Al speciation include: (1) Determine more accurate Al stability constants with critical low molecular mass ligands such as citrate and phosphate; (2) supplement traditional potentiometric studies on Al complexes with data from other techniques such as 27Al-NMR and accelerator mass spectrometry with 26Al; (3) develop new methods for generating reliable linear free energy relationships for Al complexation; (4) determine equilibrium and rate constants for Al binding to transferrin at 37 degrees C; (5) confirm the possible formation of low-molecular-mass Al-protein complexes following desferrioxamine therapy; (6) continue research efforts to incorporate kinetic considerations into the present equilibrium speciation calculations; (7) improve methods for preparing chemically well-defined stock solutions for toxicological studies; (8) incorporate more detailed speciation data into studies on Al toxicity and pharmacokinetics; and (9) incorporate more detailed speciation data into future epidemiological studies on the relationship between Al toxicity and various water quality parameters.Publication Types: • ReviewPMID: 8772798 Be a better pen pal. 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Guest guest Posted December 3, 2007 Report Share Posted December 3, 2007 Stan would you mind if I posted your research to: www.copingwithepilepsy.com Robin Neudorfer Quote Link to comment Share on other sites More sharing options...
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