First International Conference on METALS AND THE BRAIN: From Neurochemistry
to Neurodegeneration (University of Padova, Italy: 20-23 September 2000)
_____

RECOMMENDATIONS

Aluminum is an environmentally abundant element to which we are all exposed. The neurotoxicity of this metal has been known for more than a century. More recently, it has been implicated as an etiological factor in some pathologies (including encephalopathy, bone disease, anemia) related to dialysis treatment . In addition, it has been hypothesized to be a cofactor in the etiopathogenesis of some neurodegenerative diseases, including Alzheimer's disease (AD), although, despite many studies in several laboratories in different countries, direct evidence is still, so far controversial. Thus, examples of aluminum neurotoxicity are well recognized-in experimental animals and in individuals with renal failure (consequent upon aging, intoxication or renal disease) - and there are grounds to link neurodegenerative disorders to aluminum exposure. Furthermore, an increased concentration of Al in infant formulas and in solutions for home parenteral nutrition has been associated with neurological consequences and metabolic bone disease, characterized by low-bone formation rate, respectively.

For all these reasons and on the basis of our many years of scientific experience in this field, we propose the following recommendations as guidelines to avoid risks due to aluminum accumulation and potential intoxication. These recommendations are not rigid and will be updated when relevant new scientific data is available.

GENERAL RECOMMENDATIONS

1. It would be valuable to define as completely as possible which patient groups are at risk for iatrogenic aluminum loading, and under which conditions aluminum represents a health hazard. The more complete knowledge we have for the clinical, iatrogenic setting, the better basis we will have to judge whether different types of aluminum exposure are hazardous to the general population or to susceptible subgroups.
   
   
2. A provisional list of patients groups at risk of iatrogenic aluminum loading should include, at least, people with impaired renal function,
   infants, old people and patients on total home parenteral nutrition. Where such exposure occurs, serum aluminum concentrations should be less than 30 µg/l and possibly lower. However, further studies are necessary.
   
   
3. Urinary aluminum is also an indicator of aluminum absorption, the excreted Al/retained Al ratio depends on the integrity of the renal function.
   
   
4. Al may enter human body by mouth, intravenous infusions and by environment. Specific controls have to be adopted in order to reduce each risk of exposure.
   
   Oral exposure
   
   
5. Aluminum in drinking water should be less than 50 µg L-1. Silicon is relevant to aluminum toxicity and, therefore, the water silicon
   concentrations should be monitored in parallel.
   
   
6. The aluminum content should be declared in all food preparations and pharmacological products.
   
   
7. Citrate-containing compounds appear to increase the bioavailability of ingested aluminum. Therefore, particular care should be taken to avoid these compounds in combination with Al-containing drugs. With citric acid, the enhanced gastrointestinal absorption may by compensated for by a parallel increase in urinary Al excretion, where there is good renal function. However, it is strongly suspected from recent simulation studies that other dietary acids (e.g., succinic and tartaric acids) also increase Al-bioavailability but do not cause any compensatory increase in urinary excretion. Ascorbate and lactate also significantly enhance gastrointestinal absorption of Al, as was recently demonstrated in animal studies.
   
   
8. It is recommended that acidic food, e.g., acid cabbage, tomato, etc. should not be cooked or stored in aluminum ware. In this connection, it has been demonstrated that in the juice of acidic cabbage, cooked in aluminum, the
   metal ion content is up to 20 mg/ L.
   
   
9. Individual susceptibility to aluminum has been reported by the scientific literature. Thus, special efforts should be taken to prevent contamination of food and beverages etc. with aluminum either directly or during preparation, with special regard to infants, old people or individuals with suboptimal renal functionality.
   
   
10. Magnesium depletion is considered a high risk for aluminum accumulation especially during pregnancy and in the neonate with possible consequent problems for normal development and growth. Magnesium depletion is also
    common with aging.
    
    
11. Iron depletion is considered a high risk for aluminium accumulation, as iron and Al share common carriers.
    
    Parenteral exposure:
    
    
12. Aluminum in all intravenous (i.v.) fluids should be controlled monitored and labeled. There is a general consensus that the aluminum content of i.v. fluids used in children and adults with renal failure or undergoing dialysis, should be as low as possible and in any case no higher than 10 µg/L.
    
    
13. The use of parenteral nutrition fluids that are high in aluminum should be eliminated or significantly reduced.
    
    

CONTRIBUTORS (Provisional list)

* P. Zatta, CNR Center on Metalloproteins. University of Padova, Italy. Coordinator of the Project: Interdisciplinary Approach to The Study of Aluminum Toxicity. E.C.COST D8 "Metals in Medicine".

* C. Canavese, (On the behalf of the Italian Nephrological Society) Le Molinette Hospital, Torino, Italy.

* S. Costantini, Istituto Superiore di Sanit&Mac195;, Roma, Italy.

* M. Gallieni, Dept. of Nephrology, San Paolo Hospital, University of Milano, Italy.

* M. Andriani, +Chief Nephrologist, Dolo General Hospital, Venice, Italy (On the behalf of the SIN-Italian Nephrological Society).

* G. Berthon, CNRS FR1744, Università Paul Sabatier, Toulouse, France.

* D. Boggio - Bertinet, on the behalf of the Italian Society of Parenteral and Enteral Nutrition

* J. Domingo, Faculty of Medicine, Rovira I Virgili University, Reus, Spain.

* T. Flaten, Dept. of Chemistry, Norwegian University of Science and Technology, Trondheim, Norway.

* M. Golub, Dept. Internal medicine. University of California, Davis, USA.

* N. Goto, Laboratory of General Toxicology, Dept. Safety Research on Biologics, National Institute of Infectious Diseases, Tokyo, Japan.

* M. Kawahara, Metropolitan Institute for Neuroscience, Tokyo, Japan.

* T. Kiss, Dept. of Inorganic and Analytical Chemistry, University of Szeged, Hungary.

* W. Lukiw, LSU Neuroscience Center, New Orleans, LA, USA.

* W. Markesbery, University of Kentucky Alzheimer's Disease Research Center, Lexington, KY, USA.

* R. Milacic, Josef Stefan Institute, Ljubljana, Slovenia.

*
C. Ronco, Director of the Renal Research Laboratory, Beth Israel Med. Ctr, New York, NY, USA.

* H.H. Sandstead, University of Texas, Med. Branch, Galveston, TX, USA.

* A. Taylor, Center for Clinical Sciences and Measurement, School of Biological Sciences, University of Surrey, Guilford, U.K.

This document will be published in relevant scientific journals, and will be sent to all Health Ministers of the European Community as well as to other Public Health Authorities. (FDA, WHO etc.). For further information, please contact Prof. P. Zatta: [email protected]


Padova 20-23 September 2000

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ALZHEIMERS/ALUMINUM STUDIES YEAR HEAD INVESTIGATOR AFFILIATED INSTITUTION FINDINGS

1965 Klatzo NIH Injection of animal salts produced changes in the animal brains. J.Neuropathol Exp Neurol 24:187-199, 1965.
1970 Wisniewski Einstein Medical Center Changes in animal brains different from those in Alzheimer's Disease. J.Neuropathol Exp Neurol 29: 163-176, 1970.
1973 McLachlan University of Toronto Brains of Alzheimer's Disease victims have higher Aluminum content.
1976 Alfrey Denver V.A. Hospital Dialysis dementia attributed to Aluminum. NEngl J Med 294: 184-188, 1976.
1979 Ellis University of Sheffield Aluminum affects bones of dialysis patients
1980 Perl University of Vermont Aluminum in Alzheimer's Disease "tangles" in brain. Science 208: 297-299, 1980; Neurotoxicoloy 1: 133-137, 1980.
1981 Markesbery University of Kentucky Aluminum not elevated in Alzheimer's Disease brains. Ann Neurol 10: 511-516, 1981
1982 Perl University of Vermont ALS and Parkinson dementia on Guam associated with Aluminum. Science 217: 1053-1055, 1982.
1985 Greger University of Wisconsin Metallic Aluminum contributes very little to dietary intake
1986 Edwardson Newcastle General Hospital Aluminum in core of senile patient plaques 1986 Drezner Duke University Aluminum may not cause bone disease
1987 Perl Mt.Sinai Hospital Route of entry of Aluminum into body may be inhalation. Lancet1987: 1028
1988 Wisniewski N.Y. State Institute for Basic Research Aluminum not found in cores of senile patient plaques
1989 Martyn University of Southhampton Frequency of Alzheimer's Disease related to Aluminum in drinking water
1990 McLachlan University of Toronto Loss of cognitive function from exposure to McIntyre powder
1990 McLachlan University of Toronto Aluminum can be chemically extracted from brains of Alzheimer's Disease patients, clinical results being evaluated

B.Ghetti and O Bugiani. "Aluminum's Disease" and Alzheimer's Disease. Indiana Medical Center, Department of Pathology

Z. S. Khachaturian. Aluminum Toxicity Among Other Views on the Etiology of Alzheimer's Disease. Office of Alzheimer Disease Research, National Institute on Aging, National Institutes of Health, Bethesda, MD.

Jay W. Pettegrew. Aluminum and Alzheimer's Disease: An Evolving Understanding. Neurophysics Laboratory, University of Pittsburg, School of Medicine.

Richard S. Jope. Aluminum Toxicity: Transport and Sites of Action. Department of Pharmacology and euroscience Program, University of Alabama.

Allen C. Alfrey. Systemic Toxicity of Aluminum in Man. Renal Section, Denver Veterans Administration Hospital.

Daniel P Perl. The Aluminum Hypothesis of Alzheimer's Disease: A Personal View Based on Microprobe Analysis. Neuropathology Division, Mount Sinai Medical Center NY.

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G. M. Zemansky, Ph.D Aluminum in Drinking Water , an assessment document. Scientific/Technical Section, Illinois Pollution Control Board, Nov. 12, 1985.

S.G. Epstein, 1984, Aluminum in nature, in the body, and it's relationship to human health. In: Trace Substances in Environmental Health - XVIII. Proceeding of thew 18th Annual Conference on Enviromantal Health held at the University of Missouri, June 4-7, 1984, D.D. Hemphill, ed., University Of Missouri, Columbia, MO pp. 139-148.

USEPA, 1985, Proposed Phase I and II recommended maximum contaminant levels under the Safe Drinking Water Act. Office of Drinking Water USEPA, Washington, D.C., pp. 119 - 121a.

D.R. Crapper and U. DeBoni. 1980, Aluminum. In: Experimental and Clinical Neurotoxicology. P. S. Spencer and H.H. Schaumburg, eds., Williams and Wilkins, Baltimore, MD. pp. 326 - 335.

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Aluminum - Journal Articles

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Good, P; Perl, D; Bierer, L; et al. Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (LAMMA) study. Annals of Neurology. March 1992; vol. 31(3), pp. 286-292.

Graves, A; Rosner, D; Echeverria, D; et al. Occupational exposures to solvents and aluminum and estimated risk of Alzheimer's disease.
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Roberts, N; Clough, A; Bellia, J; et al. Increased absorption of aluminum from a normal dietary intake in dementia. Journal of Inorganic
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Yokel, R. The toxicology of aluminum in the brain: a review. Neurotoxicology. October 2000, vol. 21(5), pp. 813-828.

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For more information on Alzheimer's Disease (AD) see:

* Alzheimer's Disease Education and Referral (ADEAR)

http://www.alzheimers.org/index.html

* Alzheimer's Association