Medical citations on aluminium
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Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?
Tomljenovic L, Shaw CA.
J Inorg Biochem. 2011 Nov;105(11):1489-99. Epub 2011 Aug 23.
pdf here
Autism spectrum disorders (ASD) are serious multisystem developmental disorders and an urgent global public health concern. Dysfunctional immunity and impaired brain function are core deficits in ASD. Aluminum (Al), the most commonly used vaccine adjuvant, is a demonstrated neurotoxin and a strong immune stimulator. Hence, adjuvant Al has the potential to induce neuroimmune disorders. When assessing adjuvant toxicity in children, two key points ought to be considered: (i) children should not be viewed as "small adults" as their unique physiology makes them much more vulnerable to toxic insults; and (ii) if exposure to Al from only few vaccines can lead to cognitive impairment and autoimmunity in adults, is it unreasonable to question whether the current pediatric schedules, often containing 18 Al adjuvanted vaccines, are safe for children? By applying Hill's criteria for establishing causality between exposure and outcome we investigated whether exposure to Al from vaccines could be contributing to the rise in ASD prevalence in the Western world. Our results show that: (i) children from countries with the highest ASD prevalence appear to have the highest exposure to Al from vaccines; (ii) the increase in exposure to Al adjuvants significantly correlates with the increase in ASD prevalence in the United States observed over the last two decades (Pearson r=0.92, p<0.0001); and (iii) a significant correlation exists between the amounts of Al administered to preschool children and the current prevalence of ASD in seven Western countries, particularly at 3-4 months of age (Pearson r=0.89-0.94, p=0.0018-0.0248). The application of the Hill's criteria to these data indicates that the correlation between Al in vaccines and ASD may be causal. Because children represent a fraction of the population most at risk for complications following exposure to Al, a more rigorous evaluation of Al adjuvant safety seems warranted.

[2008] Song Y, Xue Y, Liu X, Wang P, Liu L. Effects of acute exposure to aluminum on blood-brain barrier and the protection of zinc Our present studies suggest that aluminum increases the permeability of BBB by changing its ultrastructure and the expression of occludin and F-actin

[pdf 2006/7] ALUMINUM ADJUVANT LINKED TO GULF WAR SYNDROME INDUCES MOTOR NEURON DEATH IN MICE M.S. Petrik1,2, M.C. Wong1,2, R.C. Tabata1, R.F. Garry5 and C.A. Shaw1,3,4
ABSTRACT: Gulf War Syndrome (GWS) affects a high percentage of veterans of the 1991 conflict, but its origins remain unknown. One neurological complication of GWS is an increased incidence of amyotrophic lateral sclerosis (ALS). While many environmental factors have been linked to GWS, the role of the anthrax vaccine administered to deployed troops has come under increasing scrutiny. Among the vaccine’s potentially toxic components are the adjuvant aluminum hydroxide and squalene. To examine whether these materials might contribute to neurologic toxicity, we injected young male colony CD-1 mice with these adjuvants at doses equivalent to those given to service personnel.  Mice were subjected to a battery of motor and cognitive behavioral tests over a six month period. Following sacrifice, CNS tissue was examined using immunohistochemistry for evidence of neural death. Behavioral testing showed both motor and cognitive functions were impacted by the tested adjuvants to differing degrees. Apoptotic neurons were identified in lumbar spinal cord and motor cortex in the groups receiving the adjuvants.  Aluminum injected animals also showed a significant increase of astrocytes in the lumbar spinal cord. Our findings suggest a possible role for either or both compounds in some neurological features associated with GWS.

Bishop NJ, Morley R, Day JP, Lucas A. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. N Engl J Med. 1997 May 29;336(22):1557-61. Comment in: N Engl J Med. 1997 Oct 9;337(15):1090-1 PMID: 9324646 Medical Research Council (MRC) Dunn Nutrition Unit, Cambridge, United Kingdom.
BACKGROUND: Aluminum, a contaminant of commercial intravenous-feeding solutions, is potentially neurotoxic. We investigated the effect of perinatal exposure to intravenous aluminum on the neurologic development of infants born prematurely. METHODS: We randomly assigned 227 premature infants with gestational ages of less than 34 weeks and birth weights of less than 1850 g who required intravenous feeding before they could begin enteral feeding to receive either standard or specially constituted, aluminum-depleted intravenous-feeding solutions. The neurologic development of the 182 surviving infants who could be tested was assessed by using the Bayley Scales of Infant Development at 18 months of age. RESULTS: The 90 infants who received the standard feeding solutions had a mean (+/-SD) Bayley Mental Development Index of 95+/-22, as compared with 98+/-20 for the 92 infants who received the aluminum-depleted solutions (P=0.39). In a planned subgroup analysis of infants in whom the duration of intravenous feeding exceeded the median and who did not have neuromotor impairment, the mean values for the Bayley Mental Development Index for the 39 infants who received the standard solutions and the 41 infants who received the aluminum-depleted solutions were 92+/-20 and 102+/-17, respectively (P=0.02). The former were significantly more likely (39 percent, vs. 17 percent of the latter group; P=0.03) to have a Mental Development Index of less than 85, increasing their risk of subsequent educational problems. For all 157 infants without neuromotor impairment, increasing aluminum exposure was associated with a reduction in the Mental Development Index (P=0.03), with an adjusted loss of one point per day of intravenous feeding for infants receiving the standard solutions. CONCLUSIONS: In preterm infants, prolonged intravenous feeding with solutions containing aluminum is associated with impaired neurologic development.

Canales JJ, et al. Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology. J Inorg Biochem. 2001 Nov;87(1-2):63-9.
Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor in Alzheimer's disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggesting that Al accumulation in the brain can alter neuronal signal transduction pathways associated with glutamate receptors. In cerebellar neurons in culture, long term-exposure to Al added 'in vitro' impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO synthase and NO-induced activation of the cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also affected strongly the function of the glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to Al, we found reduced content of NO synthase and of guanylate cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also strongly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings suggest that the impairment of the Glu-NO-cGMP pathway in the brain may be responsible for some of the neurological alterations induced by Al.

Carpenter DO. Effects of metals on the nervous system of humans and animals. Int J Occup Med Environ Health. 2001;14(3):209-18. School of Public Health University at Albany Rensselaer, NY 12144, USA.
Several metals have toxic actions on nerve cells and neurobehavorial functioning. These toxic actions can be expressed either as developmental effects or as an increased risk of neurodegenerative diseases in old age. The major metals causing neurobehavioral effects after developmental exposure are lead and methylmercury. Lead exposure in young children results in a permanent loss of IQ of approximately 5 to 7 IQ points, and also results in a shortened attention span and expression of anti-social behaviors. There is a critical time period (<2 years of age) for development of these effects, after which the effects do not appear to be reversible even if blood lead levels are lowered with chelation. Methylmercury has also been found to have effects on cognition at low doses, and prenatal exposure at higher levels can disrupt brain development. Metals have also been implicated in neurodegenerative diseases, although it is unlikely that they are the sole cause for any of them. Elevated aluminum levels in blood, usually resulting from kidney dialysis at home with well water containing high aluminum, result in dementia that is similar to but probably different from that of Alzheimer's disease. However, there is some epidemiological evidence for elevated risk of Alzheimer's in areas where there is high concentration of aluminum in drinking water. Other metals, especially lead, mercury, manganese and copper, have been implicated in amvotrophic lateral sclerosis and Parkinson's disease.

Erasmus RT, Savory J, Wills MR, Herman MM. Aluminum neurotoxicity in experimental animals. Ther Drug Monit. 1993 Dec;15(6):588-92. Department of Pathology, University of Virginia Health Sciences Center, Charlottesville 22908.
Neurotoxic effects of aluminum (Al) were recognized > 100 years ago, but have only recently been studied in detail. By far, the most dramatic effect of Al is that of producing intraneuronal perikaryal neurofilamentous aggregates, which consist of phosphorylated neurofilaments. Several species have been used to demonstrate this effect, rabbit being most common; the effect also is seen in in vitro systems. Besides its role in producing neurofibrillary pathology, Al appears to modify the blood-brain barrier and exert cholinergic and noradrenergic effects. Possible mechanisms of Al neurotoxicity could be related to cell damage via free radical production, impairment of glucose metabolism, and effects on signal transduction.

Gupta RK, Relyveld EH. Adverse reactions after injection of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine are not due only to pertussis organisms or pertussis components in the vaccine. Vaccine. 1991 Oct;9(10):699-702. Review.PMID: 1759487; UI: 92101590
Aluminium compounds such as aluminium phosphate and aluminium hydroxide are the most commonly used adjuvants with vaccines for human use. Due to the increasing concern about the toxicity of aluminium, other adjuvants like calcium phosphate may be evaluated as an alternative to aluminium adjuvants. To minimize reactions after immunization with DPT vaccine due to impurities in the toxoids, the use of toxoided purified toxins is suggested.

Gherardi, R. K. et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle http://brain.oupjournals.org/cgi/content/abstract/124/9/1821  (WHALE: a/al2.html)
Macrophagic myofasciitis (MMF) is an emerging condition of unknown cause, detected in patients with diffuse arthromyalgias and fatigue, and characterized by muscle infiltration by granular periodic acid–Schiff's reagent-positive macrophages and lymphocytes. Intracytoplasmic inclusions have been observed in macrophages of some patients. To assess their significance, electron microscopy was performed in 40 consecutive cases and chemical analysis was done by microanalysis and atomic absorption spectrometry. Inclusions were constantly detected and corresponded to aluminium hydroxide, an immunostimulatory compound frequently used as a vaccine adjuvant. A lymphocytic component was constantly observed in MMF lesions. Serological tests were compatible with exposure to aluminium hydroxide-containing vaccines. History analysis revealed that 50 out of 50 patients had received vaccines against hepatitis B virus (86%), hepatitis A virus (19%) or tetanus toxoid (58%), 3–96 months (median 36 months) before biopsy. Diffuse myalgias were more frequent in patients with than without an MMF lesion at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent to the vaccination (median 11 months) in 94% of patients. MMF lesion was experimentally reproduced in rats. We conclude that the MMF lesion is secondary to intramuscular injection of aluminium hydroxide-containing vaccines, shows both long-term persistence of aluminium hydroxide and an ongoing local immune reaction, and is detected in patients with systemic symptoms which appeared subsequently to vaccination.

Nayak P, Chatterjee AK. Effects of aluminium exposure on brain glutamate and GABA systems: an experimental study in rats. Food Chem Toxicol. 2001 Dec;39(12):1285-9.
It has been postulated that the neurotoxic effects of aluminium could be mediated through glutamate, an excitatory amino acid. Hence the effects of aluminium administration (at a dose of 4.2mg/kg body weight daily as aluminium chloride, hexahydrate, intraperitoneally, for 4 weeks) on glutamate and gamma-amino butyrate (GABA), an inhibitory amino acid, and related enzyme activities in different regions of the brain were studied in albino rats. The glutamate level increased significantly in the cerebrum, thalamic area, midbrain-hippocampal region and cerebellum in response to in vivo aluminium exposure. The aluminium insult also caused significant increases in glutamate alpha-decarboxylase activity in all the brain regions. However, on aluminium insult, the GABA content was not significantly changed except in the thalamic area, where it was elevated. On the contrary, the GABA-T activities of all the regions were reduced significantly in all regions except the midbrain-hippocampal region. However, the succinic semi-aldehyde content of all brain regions increased, often significantly. The aluminium-induced modification of the enzyme activities may be either due to the direct impact of aluminium or due to aluminium-induced changes in the cellular environment. The aluminium-induced differential regional accumulation of glutamate or other alterations in enzymes of the glutamate-GABA system may be one of the causes of aluminium-induced neurotoxicity.

Skowron F, et al. Persistent nodules at sites of hepatitis B vaccination due to aluminium sensitization. Contact Dermatitis. 1998 Sep;39(3):135-6. No abstract available.PMID: 9771990; UI: 98442988

Redhead K, et al.     Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue. Pharmacol Toxicol. 1992 Apr;70(4):278-80. PMID: 1608913; UI: 92302160.

Aluminium is widely used as an adjuvant in human vaccines, and children can often receive up to 3.75 mg of parenteral aluminium during the first six months of life. We show that intraperitoneal injection of aluminium adsorbed vaccines into mice causes a transient rise in brain tissue aluminium levels peaking around the second and third day after injection. This rise is not seen in the saline control group of animals or with vaccine not containing aluminium. It is likely that aluminium is transported to the brain by the iron-binding protein transferrin and enters the brain via specific transferrin receptors.

Rob PM, Niederstadt C, Reusche E. Dementia in patients undergoing long-term dialysis: aetiology, differential diagnoses, epidemiology and management. CNS Drugs. 2001;15(9):691-9. Nephrologisches Zentrum am Klinikum Süd, Kalhlhorststrasse 31, D-23552 Lübeck, Germany. prof-rob@gmx.de
Dementia in patients undergoing long-term dialysis has not been clearly defined; however, four different entities have been described. Uraemic encephalopathy is a complication of uraemia and responds well to dialysis. Dialysis encephalopathy syndrome, the result of acute intoxication of aluminium caused by the use of an aluminium-containing dialysate, was a common occurrence prior to 1980. However, using modern techniques of water purification, such acute intoxication can now be avoided. Dialysis-associated encephalopathy/dementia (DAE) is always associated with elevated serum aluminium levels. Pathognomonic morphological changes in the brain have been described, but the mechanism for the entry of aluminium into the CNS is incompletely understood. The mechanisms involved in the pathogenesis of the neurotoxicity associated with aluminium are numerous. Although only a very small fraction of ingested aluminium is absorbed, the continuous oral aluminium intake from aluminium-based phosphate binders, and also of dietary or environmental origin, is responsible for aluminium overload in dialysis patients. Age-related dementia, especially vascular dementia, occurs in patients undergoing long-term dialysis as frequently as it does in the general population. The differential diagnoses of dialysis-associated dementias should include investigation for metabolic encephalopathies, heavy metal or trace element intoxications, and distinct structural neurological lesions such as subdural haematoma, normal pressure hydrocephalus, stroke and, particularly, hypertensive encephalopathy and multi-infarct dementia. To prevent DAE, dietary training programmes should aim to achieve the lowest phosphate intake and pharmacological tools should be used to keep serum phosphate levels below 2 mmol/L. To prevent vascular dementia, lifestyle modification should be undertaken, including optimal physical activity and fat intake, nicotine abstinence, and targeting optimal blood glucose, cholesterol and triglyceride levels, and blood pressure, to those outlined in current recommendations.

Szutowicz A. Aluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons. J Neurosci Res. 2001 Dec 1;66(5):1009-18.
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.

Yokel RA. The toxicology of aluminum in the brain: a review. Neurotoxicology. 2000 Oct;21(5):813-28. College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, USA. ryokel1@pop.uky.edu
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.

Zheng W. Neurotoxicology of the brain barrier system: new implications. J Toxicol Clin Toxicol. 2001;39(7):711-9.
The concept of a barrier system in the brain has existed for nearly a century. The barrier that separates the blood from the cerebral interstitial fluid is defined as the blood-brain barrier, while the one that discontinues the circulation between the blood and cerebrospinal fluid is named the blood-cerebrospinal fluid barrier. Evidence in the past decades suggests that brain barriers are subject to toxic insults from neurotoxic chemicals circulating in blood. The aging process and some disease states render barriers more vulnerable to insults arising inside and outside the barriers. The implication of brain barriers in certain neurodegenerative diseases is compelling, although the contribution of chemical-induced barrier dysfunction in the etiology of any of these disorders remains poorly understood. This review examines what is currently understood about brain barrier systems in central nervous system disorders by focusing on chemical-induced neurotoxicities including those associated with nitrobenzenes, N-methyl-D-aspartate, cyclosporin A, pyridostigmine bromide, aluminum, lead, manganese, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and 3-nitropropionic acid. Contemporary research questions arising from this growing understanding show enormous promises for brain researchers, toxicologists, and clinicians.

Medical citations (links) on vaccination originally compiled by Sebastiana Pienaar: http://www.geocities.com/alebencal/index.html

Neurotoxic effect of enteral aluminium
Aluminium phosphate but not calcium phosphate stimulates the specific IgE response in guinea pigs to tetanus toxoid.
Long-term effects of aluminium on the fetal mouse brain.
Effect of aluminium hydroxide administration on normal mice
Occupational asthma caused by aluminium welding.
Acute and long-term airway hyperreactivity in aluminium-salt
Aluminum as an adjuvant in vaccines and post-vaccine reactions
Aluminium-adjuvanted vaccines transiently increase aluminium levels
Aluminum in enteral nutrition formulas and parenteral solutions.
Aluminum content of vaccines used in Turkey.
The health effects of aluminium--a review.
Aluminium increases permeability of the blood-brain barrier
Central nervous system disease in patients with macrophagic myofasciitis.
Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle.
Characterization of aluminium-containing adjuvants.
Analysis of aluminum hydroxyphosphate vaccine adjuvants by (27)Al MAS NMR.
Public health. Aluminum is put on trial as a vaccine booster. No abstract