Aluminum hydroxide
Home

Curr Med Chem. 2011;18(17):2630-7.

Aluminum vaccine adjuvants: are they safe?

Source

Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, V5Z 1L8, Canada. lucijat77@gmail.com

Abstract

Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue.

PMID:
21568886
[PubMed - indexed for MEDLINE]
 

 

http://www.youtube.com/watch?v=zjpN8ZtNxbE

http://www.mothering.com/articles/growing_child/vaccines/aluminum-new-thimerosal.html


Is Aluminum the New Thimerosal?
By Robert W. Sears Issue 146, January/February 2008

Vaccines have become the most controversial parenting topic of the decade. When parents are considering whether or not to vaccinate their children, one of the things that must be considered is aluminum toxicity. Aluminum is added to a number of vaccines to help them work better. Normally, one wouldn't consider aluminum to be a problem. It's a naturally occurring element that is present everywhere in our environment—in food, water, air, and soil. It's also a main ingredient in over-the-counter antacids. And because the body doesn't absorb aluminum, it's harmless when swallowed.

I didn't think much about aluminum when, 13 years ago, I began researching vaccines. In fact, the early seminars on vaccine education that I offered to parents included a brief statement that aluminum was nothing to worry about. But as I read each product insert and saw the number of micrograms (mcg) of aluminum contained in several vaccines, I wondered, "Has anyone determined what a safe level of injected aluminum actually is?" I didn't have to wonder for long, because the answer is easy to find; go to www.fda.gov, search on "aluminum toxicity," and you'll find several documents about aluminum.

The first document I came across discusses the labeling of aluminum content in injected dextrose solutions (the sugar solutions added to intravenous fluids in hospitals): "Aluminum may reach toxic levels with prolonged parenteral administration [i.e., injected into the body] if kidney function is impaired. . . . Research indicates that patients with impaired kidney function, including premature neonates [i.e., babies], who received parenteral levels of aluminum at greater than 4 to 5 micrograms per kilogram of body weight per day, accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading [i.e., toxic buildup in certain body tissues] may occur at even lower rates of administration."1 For a tiny newborn, this toxic dose would be 10 to 20 mcg; for an adult, it would be about 350 mcg.

The second document discusses aluminum content in IV feeding solutions, or Total Parenteral Nutrition (TPN) solutions. The FDA requires these solutions to contain no more than 25 mcg of aluminum per liter of solution. A typical adult in the hospital would get around 1 liter of TPN each day, thus about 25 mcg of aluminum. The FDA document also states, "Aluminum content in parenteral drug products could result in a toxic accumulation of aluminum in individuals receiving TPN therapy. Research indicates that neonates and patient populations with impaired kidney function may be at high risk of exposure to unsafe amounts of aluminum. Studies show that aluminum may accumulate in the bone, urine, and plasma of infants receiving TPN. Many drug products used routinely in parenteral therapy may contain levels of aluminum sufficiently high to cause clinical manifestations [i.e., symptoms]. . . Aluminum toxicity is difficult to identify in infants because few reliable techniques are available to evaluate bone metabolism in premature infants. . . Although aluminum toxicity is not commonly detected clinically, it can be serious in selected patient populations, such as neonates, and may be more common than is recognized."2

Elsewhere, I found a relevant 2004 statement by the American Society for Parenteral and Enteral Nutrition (ASPEN), a group that monitors oral and injectable nutritional products for safety and side effects. It reiterated the cited FDA warnings to the letter, and recommended that doctors purchase IV products with the lowest aluminum content possible, "and should monitor changes in the pharmaceutical market that may affect aluminum concentrations."3

The source of the daily limit of 4 to 5 mcg of aluminum per kilogram of body weight quoted by the ASPEN statement seems to be a study that compared the neurologic development of about 100 premature babies who were fed a standard IV solution that contained aluminum, with the development of 100 premature babies who were fed the same solution with almost all aluminum filtered out. The study was prompted by a number of established facts: that injected aluminum can build up to toxic levels in the bloodstream, bones, and brain; that preemies have decreased kidney function and thus a higher risk of toxicity; that an autopsy performed on one preemie whose sudden death was otherwise unexplained revealed high aluminum concentrations in the brain; and that aluminum toxicity can cause progressive dementia. The infants who were given IV solutions containing aluminum showed impaired neurologic and mental development at 18 months, compared to the babies who were fed much lower amounts of aluminum. Those who got aluminum received an average of 500 mcg of the metal over a period of 10 days, or about 50 mcg per day. The other group received only about 10 mcg of aluminum daily—4 to 5 mcg per kilogram of body weight per day.4 This seems to be the source of this safety level.

However, none of these documents or studies mentions vaccines; they look only at IV solutions and injectable medications. Nor does the FDA require labels on vaccines warning about the dangers of aluminum toxicity, although such labels are required for all other injectable medications.

All of these studies and label warnings seem to apply mainly to premature babies and kidney patients. What about larger, full-term babies with healthy kidneys? Using the 5 mcg/kg/day criterion from the first document as a minimum amount we know a healthy baby could handle, a 12-pound, two-month-old baby could safely receive at least 30 mcg of aluminum per day. A 22-pound one-year-old could receive at least 50 mcg safely. Babies with healthy kidneys could probably handle much more than this, but we at least know that they can handle this much. However, these documents don't tell us what the maximum safe dose would be for a healthy baby or child, and I can't find such information anywhere. This is probably why the ASPEN group suggests, and the FDA requires, that all injectable solutions be limited to 25 mcg; we at least know that that level is safe.

Calculating Aluminum in Vaccines
Here are the current levels of aluminum per shot of the following vaccines, as listed on each vaccine's packaging:

* DTaP (for Diphtheria, Tetanus, and Pertussis): 170-625 mcg, depending on manufacturer
* Hepatitis A: 250 mcg
* Hepatitis B: 250 mcg
* HIB (for meningitis; PedVaxHib brand only): 225 mcg
* HPV: 225 mcg
* Pediarix (DTaP Hepatitis B Polio combination): 850 mcg
* Pentacel (DTaP HIB Polio combination): 1500 mcg
* Pneumococcus: 125 mcg

In other words, a newborn who gets a Hepatitis B injection on day one of life would receive 250 mcg of aluminum. This would be repeated at one month with the next Hep B shot. When, at two months, a baby gets its first big round of shots, the total dose of aluminum could vary from 295 mcg (if a non-aluminum HIB and the lowest-aluminum brand of DTaP are used) to a whopping 1225 mcg (if the Hep B vaccine is given along with the brands with the highest aluminum contents). If the Pentacel combo vaccine is given along with the Hep B and Pneumococcus vaccines, the total aluminum dose could be as high as 1875 mcg. These doses are repeated at four and six months. With most subsequent rounds of shots, a child would continue to get some aluminum throughout the first two years. But the FDA recommends that premature babies, and anyone with impaired kidney function, receive no more than 10 to 25 mcg of injected aluminum at any one time.

As a medical doctor, my first instinct was to worry that these aluminum levels far exceed what may be safe for babies. My second instinct was to assume that the issue had been properly researched, and that studies had been done on healthy infants to determine their ability to rapidly excrete aluminum. My third instinct was to search for these studies. So far, I have found none. It's likely the FDA thinks that the kidneys of healthy infants work well enough to excrete aluminum before it can circulate through the body, accumulate in the brain, and cause toxic effects. However, I can find no references in FDA documents that show that using aluminum in vaccines has been tested and found to be safe.

So I did what any pediatrician would do. I turned to the American Academy of Pediatrics (AAP), who in 1996 published a policy statement, "Aluminum Toxicity in Infants and Children," that made the following points:

* Aluminum can cause neurologic harm.
* A study from 30 years ago showed that human adults increase their urine excretion of aluminum when exposed to higher levels of the metal, which suggests that adults can clear out excess aluminum.
* Adults taking aluminum-containing antacids don't build up high levels of aluminum in their bodies.
* Reports of infants with healthy kidneys show elevated blood levels of aluminum from taking antacids.
* People with kidney disease who build up bloodstream levels of aluminum greater than 100 mcg per liter are at risk of toxicity.
* The toxic threshold of aluminum in the bloodstream may be lower than 100 mcg per liter.
* The buildup of aluminum in tissues has been seen even in patients with healthy kidneys who receive IV solutions containing aluminum over
extended periods.5

However, nowhere in this paper was there any mention of aluminum in vaccines.

To put this in perspective: Because the body of the average adult contains about 5 liters of blood, receiving more than 500 mcg of aluminum in the bloodstream all at once will be toxic if the kidneys aren't working well. (Toxicity has also been seen in patients with healthy kidneys.) Because a newborn's body contains about a liter (300 milliliters) of blood, more than 30 mcg of aluminum floating around in the bloodstream could be toxic if the baby's kidneys aren't working well. The body of a toddler or preschool-age child contains about 1 liter of blood, so more than 100 mcg in his system could be toxic—and, as we've seen, babies can receive more than 1000 mcg of injected aluminum all at one time. Fortunately, this amount doesn't all go into the blood at once, but is slowly diffused into the bloodstream over a period of time from the muscle or skin where it was injected.

But that is the main point of this article. No one has measured the levels of aluminum absorption by the bloodstream when it is injected into the skin and muscle of infants, or the levels of excretion from the body via urination. All of the FDA and AAP documents that I've read state that aluminum might be a problem, but that they haven't studied it yet, so we should limit the amount of aluminum included in injectable solutions. But,
again, no one is talking about the levels of aluminum in vaccines.

What I think may have happened is that because aluminum used to be found in only one vaccine—DTP, an older version of the current DTaP vaccine—no one
thought much about it. Then, in the 1980s, the PedVaxHib brand of HIB meningitis vaccine was released, which also included aluminum; but other brands of HIB vaccine did not, so again, no one thought much about it. In the 1990s, the Hepatitis B vaccine began to be widely used; in the 2000s, the Pneumococcus vaccine; and, more recently, the Hepatitis A vaccine. Administering one aluminum-containing vaccine at a time involves only a small amount of the metal; administering four such vaccines simultaneously is a different story. It seems this issue has simply escaped everyone's attention. Or has it?

Limited Studies limit thinking
Several years ago, some suspected cases of aluminum toxicity resulted in various neurologic and degenerative problems. The Cochrane Collaboration, a group that studies health-care issues around the world, wanted to look at a very large study group to see if there was a real correlation between neurologic problems and the aluminum in vaccines. They investigated all the reported side effects of one aluminum-containing vaccine, DTP (no longer used), and looked for any evidence that such vaccines caused more side effects than non-aluminum vaccines. Other than more redness, swelling, and pain at the injection site, they found no indication that an aluminum-containing vaccine caused any more problems, and concluded that no further research should be undertaken on this topic.6 That is a very bold statement. Most researchers will draw conclusions from the findings of their own research; it's unusual to say that no one else should do any more research into the matter.

This is especially surprising because of the limitations of the Cochrane Collaboration's study. They looked at the effects of only one standard aluminum-containing vaccine, rather than the effects of all four being administered at once. They didn't study aluminum metabolism itself. They didn't test aluminum levels in children after vaccination, nor did they explore whether or not the amount of aluminum in vaccines builds up in the brain or bone tissues. They looked only for evidence of external symptoms of aluminum toxicity, not internal effects. Nor did they do their own research; instead, they reviewed all available studies conducted by other investigators. Despite all this, the Cochrane Collaboration study essentially closed the book on investigating aluminum toxicity from vaccines, without really having opened it in the first place.

The most obvious way to study this matter would be to inject various amounts of aluminum into children and see what happens to them internally. We know from the FDA documents that aluminum toxicity does occur from other types of injectable treatments; that it accumulates in the brain and bones in toxic amounts; that this may occur more commonly than is recognized; and that aluminum toxicity is hard to detect by looking for external symptoms. The question remains: What happens when these amounts of aluminum are injected via vaccines? Vaccine manufacturers may have begun to wonder about the same thing; I found some interesting research in the product insert of the new HPV vaccine, Gardasil. In researching the safety of Gardasil, Merck & Co., Inc., the vaccine's developer and manufacturer, added a step to their testing procedure by injecting aluminum into a separate group of test subjects used as a safety control group. They then compared the side effects of the Gardasil vaccine with a saline placebo that contained neither Gardasil nor aluminum, as well as with the placebo containing no Gardasil but the same amount of aluminum as the vaccine. They found that the placebo containing aluminum was much more painful than the saline placebo, and about as painful as the full HPV shot. The aluminum placebo also caused much more redness, swelling, and itching than the saline
placebo, though not quite as much as the full HPV shot.

Unfortunately, Merck looked only at the effects of aluminum at the injection site. Nor did they state in the Gardasil product insert what role the aluminum placebo played in all the other standard side effects, such as fever and flu-like symptoms. Nor did they study the body's internal metabolism of aluminum. However, their research did show how irritating aluminum can be when injected into the muscles. It was a good first step. If aluminum can be toxic, why not just remove it from vaccines, as is being done with the preservative thimerosal, which contains the neurotoxin mercury? It's not that simple. Aluminum is an adjuvant; in other words, it helps vaccines work more effectively. When the metal is mixed with a vaccine, the body's immune system more easily recognizes the vaccine and creates antibodies against the disease. Thimerosal was easy to omit, because it has nothing to do with the efficacy of the vaccine itself. But the pharmaceutical companies would need good evidence that aluminum is harmful before they would invest in coming up with new, aluminum-free vaccines. (The Cochrane Collaboration report pointed out that removing aluminum from vaccines would then require extensive trials of the reformulated vaccines.7)

What, exactly, does a toxic level of aluminum do to the brain? While no one has studied healthy babies to see how much, if any, aluminum builds up in the brain from the amounts of aluminum used in vaccines, the study on IV feeding solutions in premature babies mentioned above revealed that aluminum impaired their neurologic and mental development.8 But that was in premature babies, not healthy, full-term infants. I found several animal studies involving aluminum and/or aluminum-containing vaccines that did show neurologic harm. Not only did aluminum build up in the brain and cause damage, but some of the damage looked similar to what is seen in the brains of Alzheimer's patients.9-1314 However, it's hard to draw conclusions about aluminum's effects on humans from studies of animals. What we need are more studies of human infants.

A Call for Better Research
There is good evidence that large amounts of aluminum are harmful to humans. Because no meaningful research has specifically been done on aluminum in vaccines, there is no existing evidence that the amount in vaccines is harmful to infants and children. However, no one has actually studied aluminum levels in healthy human infants after vaccination to make sure it is safe. Should we now stop and research this matter? Or should we just go on, continuing to hope that it is safe to use aluminum as an adjuvant in vaccines?

Vaccine policy makers and advocates may read this article, review my perspective, and initiate research studies to explore the risks of aluminum. I would hope that those researchers do not conduct a retrospective review of all the old vaccine safety studies and journal articles to look for the side effects of aluminum. As the FDA, AAP, and others have stated, aluminum toxicity can't be detected by external observation alone. It would be a waste of time, and a grave disservice to
the health of America's children, to have several such reports show up in the medical literature. The only way the issue of aluminum safety can be put to rest is to conduct real-time studies on thousands of infants and measure aluminum levels after vaccination.

In such a study, the researchers should look not only at blood levels. They should also find out whether or not aluminum accumulates in the body, where it accumulates, how the body eliminates it, and at what rate. Once I see such research, and have determined to my satisfaction that aluminum has been proven safe, I will post an update on www.thevaccinebook.com, and revise future editions of the book accordingly. If such research finds that aluminum may not be safe, then I would expect a new vaccine schedule to be adopted in which the administering of vaccines is spread out to minimize the amount of aluminum a child receives at any given time. I would also expect vaccine manufacturers to begin finding ways to reduce or remove aluminum from vaccines without compromising their effectiveness. We need to know the answers to many questions: Why does one brand of HIB vaccine require aluminum to make it work while another brand does not? Why does one brand of DTaP vaccine contain four times as much aluminum as another? Why does one brand of combination vaccine contain three times as much aluminum as the sum of its parts?

Learning from the Past
I worry that aluminum may end up being another thimerosal. I am relieved that, as of 2002, the mercury-containing preservative had been removed from most vaccines. But according to an article in the Los Angeles Times, Merck & Co., the makers of several vaccines, knew in 1991 that the cumulative amount of mercury in vaccines given to infants by six months of age was about 87 times the level then thought to be safe.14 The article includes a copy of an internal memo, written by one of Merck's research doctors and sent to the president of Merck's vaccine division, clearly stating the doctor's worry about mercury overload. What was done with that information back in 1991? We'll never know. What we do know is that vaccine manufacturers knew that we were overdosing babies, but that the mercury wasn't removed from vaccines until 10 years later. This was because few paid attention to the potential problems with mercury. When we did find out, we hoped it wasn't harmful, we did extensive research to try to show that it wasn't, and we slowly removed it from most vaccines.

The issue of mercury toxicity from vaccines is moot for infants receiving vaccines today, as long as doctors and parents choose a flu shot without mercury, know which brands of vaccines still contain barely detectable traces of mercury, and are aware that some plain Tetanus and Diphtheria-Tetanus vaccines still contain mercury (though these last vaccines are not parts of the routine vaccine schedule). [For a current list of vaccines and their thimerosal contents, go to www.vaccine safety.edu/thi-table.htm.—Ed.]

What isn't moot is the question of aluminum toxicity. As doctors, we can choose certain vaccine brands that contain less or no aluminum. We can be careful about giving only one aluminum-containing vaccine at a time. And we can talk about it instead of sweeping the issue under the rug. I pray that my fears about aluminum are unfounded, and that objective studies performed by completely independent groups with no ties to vaccine manufacturers or political organizations show that it is safe. If not, I would hope that manufacturers would start to reduce or eliminate the aluminum content of their vaccines as soon as possible. I know this won't be an easy task, but our children are worth it.

Excerpted from The Vaccine Book © 2007 by Robert Sears, MD. Reprinted by
permission of Little, Brown and Company. New York, NY. All rights reserved.
For more information, see www.thevaccinebook.com. For the notes to this
article, see www.mothering.com/
articles/growing_child/vaccines/aluminum-new-thimerosal-notes.html.

Michael Wagnitz: Aluminum in our vaccines: Is it safe?

Michael Wagnitz
February 9, 2009

With the vaccines available in the U.S. today, parents can avoid vaccines preserved with thimerosal (50% mercury) for their newborns and infants. This is not the case with aluminum, which has been linked to impaired neurological development in children. Aluminum has not replaced thimerosal as a vaccine preservative; it has always been used in vaccines. Its purpose is to generate an immune response, thus providing a person the ability to produce adequate levels of antibodies to the vaccine being administered. Unlike thimerosal, if aluminum is removed, the vaccine will not work.

In the recent past, most kids got exposed to both thimerosal and aluminum simultaneously with the hepatitis B, Hib, DTaP (diphtheria, tetanus and pertussis) and pneumococcal vaccines. Combining mercury with aluminum increases the likelihood that the mercury will damage human tissue. While aluminum is in the food we eat at much higher levels, it is not absorbed well through the gastrointestinal tract. When this protective gastrointestinal mechanism is bypassed, aluminum toxicity can cause serious problems.

There are currently eight childhood vaccines that contain aluminum ranging from 125 to 850 micrograms (mcg). These vaccines are administered 17 times in the first 18 months of life, an almost six-fold increase compared to the vaccine schedule of the 1980s. According to the American Society for Parenteral and Enteral Nutrition, based on IV feeding solutions, a child should not exceed a maximum daily dose of 5 mcg of aluminum per kilogram of weight per day. That means if a child weighs 11 pounds, the child should not exceed 25 mcg in a day. This level was determined to be the maximum safety limit based on a study published in the New England Journal of Medicine titled "Aluminum Neurotoxicity in Preterm Infants Receiving Intravenous Feeding Solutions."

The hepatitis B vaccine, administered at birth, contains 250 mcg.

In a 1996 policy statement, "Aluminum Toxicity in Infants and Children," the American Academy of Pediatrics states, "Aluminum can cause neurological harm. People with kidney disease who build up bloodstream levels of aluminum greater than 100 mcg per liter are at risk of toxicity. The toxic threshold of aluminum in the bloodstream may be lower than 100 mcg per liter."

So let's say an infant receives 1,250 micrograms at 2 months of age (three vaccines). Assuming a child's body contains a half liter of blood, this would put the blood level 25 times higher than the above mentioned levels.

Now people will argue whether an intramuscular injection (such as vaccines) would introduce aluminum into the bloodstream at the same level as an IV feeding solution. Unfortunately, the purpose of direct intramuscular injection is to provide rapid access to the bloodstream. This provides direct access to all target organs such as the brain.

The real eye-opener is a recently published paper where the authors investigated Gulf War syndrome based on the fact that soldiers were getting sick without deployment to the Persian Gulf region. They eventually focused on aluminum used in the anthrax vaccine. Injecting mice with aluminum at levels equal to what the soldiers received induced motor neuron death. The dose, per body weight, given to children easily exceeds what the soldiers received.

One must question whether exposing newborns to aluminum is worth the risk to protect them against a sexually transmitted disease (hepatitis B). If aluminum can cause injury to an adult, combat-ready soldier, what is it doing to newborns?

Michael Wagnitz of Madison is a chemist.

madison.com is operated by Capital Newspapers, publishers of the Wisconsin State Journal, The Capital Times, Agri-View and Apartment Showcase. All contents Copyright ©2009, Capital Newspapers. All rights reserved.

Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice.

Neuromolecular Medicine
February 2007, Volume 9, Issue 1

http://journals.humanapress.com/index.php?option=com_opbookdetails&task=articledetails&category=humanajournals&article_code=NMM:9:1:83

Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA.

Department of Ophthalmology and Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.

Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine's potentially toxic components are the adjuvants aluminum hydroxide and squalene.

To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive- behaviora l tests over a 6-mo period postinjections.

Following sacrifice, central nervous system tissues were examined using immunohistochemistr y for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk.

Apoptotic neurons were identified in aluminum- injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord.
The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.

Neuromolecular Med. 2007; 9(1); 83-100.

 

 

http://brain.oupjournals.org/cgi/content/full/124/9/1821 (Full text article)

Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminum hydroxide in muscle

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 aluminum 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 aluminum 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%), 396 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 aluminum hydroxide-containing vaccines, shows both long-term persistence of aluminum hydroxide and an ongoing local immune reaction, and is detected in patients with systemic symptoms which appeared subsequently to vaccination.
 

One of the more entertaining (scientifically entertaining) experiences I had in the year past was attendance at a workshop on aluminum-containing adjuvants in vaccines. The workshop was held in the felicitous environment of San Juan, Puerto Rico, last May, and was sponsored by the National Vaccine Program Office, a Health and Human Services-based office charged with coordination of the major federal players in the vaccine arena, namely, the National Institutes of Health, the Food and Drug Administration and the Centers for Disease Control and Prevention (CDC).

It was the second in a series of workshops that examined additives to vaccines. The first workshop, held the previous year, dealt with thimerosal, and exposed a great deal of scientific uncertainty extending in some areas to ignorance about the distribution and the behavior of the active compound, ethyl mercury. The same pervasive uncertainty, bordering in some instances on ignorance, characterized the aluminum-containing adjuvants workshop.

Mechanism of action uncertain
There are three basic aluminum salts used as vaccine adjuvants: aluminum hydroxide, aluminum phosphate and potassium-aluminum sulfate, or alum. Each has different chemical properties and isoelectric points, and they are not simply interchangeable when used in vaccine formulations. The mechanism of action of these adjuvants represents an area of scientific uncertainty, but they are believed to form a repository of antigen in tissue, to facilitate presentation of particulate antigen to immune cells, and perhaps, to activate complement and other immune enhancers.

The goal of adjuvant use in vaccines is to enhance immune contact, to increase the height of the antibody response, and to prolong the immune response - all this, of course, with total safety and freedom from adverse effects. The aluminum-containing adjuvants  have certainly succeeded as immune enhancers, and this is amply documented in the literature of the 1930s-1960s. The enhancement effect is most marked during the primary immunization series; there is little incremental benefit of aluminum adjuvants in booster doses. The adjuvants appear to facilitate a type 2 immunologic response and do not induce cytotoxic T cells and cell-mediated immune mechanisms. These adjuvants are, however, not totally free of adverse effects; sterile abscesses, erythema, swelling, subcutaneous nodules, granulomatous inflammation and contact hypersensitivity have been reported with variable frequency and severity.

U.S. licensed vaccines that contain aluminum salts include DTP, DTaP, some but not all Hib vaccines, and HepA and HepB, Lyme disease, anthrax and rabies vaccines. Among inactivated vaccines, only inactivated poliovirus and influenza vaccines do not contain aluminum salts used as adjuvants. This is true not only for U.S. licensed vaccines, but also is true around the entire world. The World Health Organization's Enhanced Program in Immunization (EPI) is highly reliant on vaccines containing aluminum adjuvants, and these vaccines have an established track record of safety extending over almost half a century.

Controversial data
By far the most controversial (scientifically  entertaining) part of the workshop was presented by a French investigator, Romain Gherardi, pathologist at the Henri Mondor University in Creteil. He had published an article in The Lancet two years previously (1998;352: 347-52) describing a clinica and pathologic entity he called macrophagic myofasciitis (MMF), an unusual "new inflammatory muscle disorder of unknown cause." Based on additional work done in the two years since that publication, he presented his data at the workshop and argued that the cause of this entity is actually the aluminum in vaccines given in France.

More than 100 patients have been identified to date, and the analysis he presented was confined to the first 50 patients. The entity itself has been identified in deltoid muscle biopsies of patients with a variety of complaints, including diffuse myalgia, arthralgia, and fatigue; some but not all of these patients met the CDC definition for chronic fatigue syndrome. Biopsies revealed extensive infiltration of macrophages around, but not inside muscle fibers, with a few CD8+ T cells. Typically, there was no tissue necrosis and little evidence of muscle damage. Many of the macrophages contained para-aminosalicylic acid (PAS)-positive crystalline structures, subsequently identified as aluminum. Laboratory evidence of inflammation was variable; most patients had a normal white blood cell count and creatine phosphokinase; about half had some serum autoantibodies present. In addition, levels of certain cytokines seemed to be increased, especially interleukin (IL)-1 receptor antagonist and IL-6.

The patients were mostly middle-age adults with males and females about equally represented. All had received aluminum-containing vaccines, mostly HepB  vaccine, in the biopsied deltoid muscle; a mean of 36 months had elapsed between vaccination and muscle biopsy. A high proportion of patients were health care workers, had a sports affiliation, or had traveled extensively. There was a seemingly higher than expected proportion of patients with concurrent autoimmune disease (34%). In fact, six of the 50 patients in an epidemiologic analysis had multiple sclerosis. Most patients responded to treatment with steroids and/or antibiotics.

Why only France? Dr. Gherardi related that there had been an extensive campaign there in the preceding five years to immunize adults with HepB vaccine. Also, the French typically do a deltoid biopsy whenever muscle biopsy is indicated; elsewhere, including the U.S., calf muscles such as the gastrocnemius are preferred.

Participants remained unconvinced Most workshop participants were frankly skeptical. Many were unconvinced that MMF really represented a new entity, and all doubted that the argument that it was caused by aluminum could be sustained. In particular, his argument was faulted for a lack of controls, for there were no data on unvaccinated patients, or on patients who had been vaccinated but were asymptomatic. For that reason, many participants suggested that this was simply an epiphenomenon, or represented an epidemic of recognition, which is now feeding in France on its own publicity. To quote that most overused concluding comment, "further investigation is warranted," and indeed many additional in vitro and in vivo studies are already underway to elucidate the etiology and significance of MMF.

All the scientific uncertainties notwithstanding, most participants left the workshop reassured about the safety of aluminum adjuvants. Yet, the most relevant question - "Do we really need them?"- was never really answered.

Lessons from Macrophagic Myofasciitis: Towards a Definition of a Vaccine Adjuvant-Related Syndrome [Chronic Fatigue Syndrome news]
ImmuneSupport.com


04-02-2003

Source: Rev Neurol (Paris) 2003 Feb;159(2):162-4
[original article published in French]

Gherardi RK.

Groupe Nerf-Muscle, Departement de Pathologie, Hopital Henri Mondor, Creteil.

Macrophagic myofasciitis is a condition first reported in 1998, and the cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called Chronic Fatigue Syndrome in about half of patients.

One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis. Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy.

Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant [auxiliary substance] used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile.

It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of Chronic Fatigue Syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic Chronic Fatigue Syndrome.

Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminum-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf War Syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome.

Indeed, both type and structure of symptoms are strikingly similar in Gulf War veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War Syndrome.

Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminum hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminum hydroxide are confirmed, it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.
 

http://books.nap.edu/books/0309044995/html/347.html#pagetop

Adverse Effects of Pertussis and Rubella Vaccines (1991)

Institute of Medicine (IOM)
  

The following text is provided to enhance readability. Many aspects of typography translate only awkwardly to HTML. Please use the page image as the authoritative form to ensure accuracy. Page 347E Possible Involvement of Aluminum Salts in Erythema Multiforme, Encephalopathy, or Other Adverse Events After Pertussis Immunization

DPT vaccine preparations regularly contain aluminum salts (aluminum hydroxide, aluminum potassium sulfate, or aluminum phosphate) that are intended to serve as adjuvants (British National Formulary, 1988; Physicians' Desk Reference, 1989). Orlans and Verbov (1982) suggested that DPT-associated rashes could be due to aluminum hydroxide. Other more significant local reactions including nodules at the site of injection, itching, eczema, and circumscribed hypertrichosis over nodules have been observed more frequently following administration of aluminum hydroxide-adsorbed DPT vaccine than after administration of unadsorbed DPT vaccine (Pembroke and Marten, 1979).Interest has developed recently in the potential health effects of aluminum, particularly in the setting of chronic renal failure, in which aluminum is not excreted from the body normally (Alfrey, 1984; Monteagudo et al., 1989). A severe, often fatal encephalopathy found in patients undergoing long-term dialysis was attributed to aluminum deposition in the brain (Alfrey et al., 1976). Reduction of aluminum in dialysate has largely eliminated this condition, but dialysis patients may still have subtle psychomotor defects that may be due to aluminum toxicity (Altmann et al., 1989). Animal studies have shown that aluminum can increase the rate of transmembrane diffusion across the blood—brain barrier (Banks and Kastin, 1989), which could possibly permit greater access of toxins to the brain. Patients receiving long-term injections of aluminum-containing allergenic   
 

Aluminum-Alzheimer's link Date: Sun, 20 Apr 2003 14:45:39 -0400
http://www.nlm.nih.gov/medlineplus/news/fullstory_12359.html
Aluminum in Drinking Water Tied to Alzheimer's

Reuters Health
By Jacqueline Stenson
Monday, April 14, 2003

SAN DIEGO (Reuters Health) - Adding support to a controversial theory linking aluminum with Alzheimer's disease, new research indicates the disease is more common in regions of northwest Italy where levels of aluminum in drinking water are highest.

And when the investigators studied the effects of one form of the metal on two types of human cells in the lab, they found it hastened cell death."We were absolutely surprised by these results," said study author Dr.Paolo Prolo, a researcher at the University of California at Los Angeles. "I did not expect any effect from aluminum." In findings released here Monday at the annual Experimental Biology meeting, Prolo and colleagues focused on monomeric -- single molecule --aluminum. This is the type that can be most easily absorbed by human cells, he said.

While there have been suggestions that aluminum cookware might pose a risk for Alzheimer's, the type of aluminum used in pots and pans consists of multiple molecules and does not appear to affect human cells, according to Prolo. "There is almost no evidence that the cookware is dangerous," he said. When the researchers tested water in regions of northwest Italy in 1998, they found that total aluminum levels -- including monomeric and other types of aluminum -- ranged from 5 to 1,220 micrograms per liter, while monomeric aluminum levels alone ranged from 5 to 300 micrograms per liter.

Environmental officials generally recommended that total aluminum levels be below 200 micrograms per liter, Prolo noted.After comparing this data to death rates from Alzheimer's in those regions, the researchers found that the disease was more common in areas with the highest levels of monomeric aluminum.

Back in the lab, Prolo and colleagues then tested the effects of monomeric aluminum on human immune-system cells and bone cancer cells. Ideally, human brain cells would be tested but these are not readily available because a biopsy of a patient's brain is necessary to acquire them, he said. "We found that a very low quantity of aluminum added to our cell cultures was modifying cellular processes" like normal cell death, Prolo told Reuters Health.

When the aluminum was paired with beta-amyloid, a protein found in the brains of Alzheimer's patients, the combination killed off even more cells. Because aluminum could kill both types of human cells, these findings raise the question of whether aluminum is potentially involved in other diseases, Prolo said.

But much more research is needed to understand how the metal does or does not affect people, he added.
Related News:
Related MEDLINEplus Pages:
http://www.healthwell.com/hnbreakthroughs/mar98/aluminum.cfm
 April 19, 2003 Can Aluminum Cause Alzheimer's Disease? by Melvyn R. Werbach, M.D.

Senile dementia is a progressive degenerative brain disease associated with old age. Its symptoms include short-term memory loss, slowness in thought and movement, confusion, disorientation, depression, difficulty communicating, and loss of physical function. Alzheimer's disease accounts for about half of all senile dementia cases. Although there are many theories about what causes Alzheimer's, the fact is, its origins remain poorly understood.

One theory proposed that the common occurrence of being exposed to aluminum could cause Alzheimer's dementia. Aluminum, the theory postulated, becomes concentrated in the characteristic lesions (senile plaques and neurofibrillary tangles) that develop in the brain during the course of the disease. At first, medical scientists thought this theory was absurd. Aluminum, they believed, accumulated merely as a result of a destructive process caused by some other factor.

In recent years, however, the aluminum hypothesis has been gaining respect. For example, studies have discovered a direct association between the level of aluminum in municipal drinking water and the risk of Alzheimer's dementia. One study found aluminum in drinking water was related to only this specific type of dementia;1 another found that the probability of the association being due to chance was only 1 in 24, with a 46 percent increased risk for people drinking water with the highest aluminum levels.2

The use of aluminum-containing antiperspirants--but not the use of antiperspirants and deodorants in general--has also been associated with a risk of Alzheimer's dementia, with a trend toward a higher risk corresponding with increasing frequency of use.3 This relationship does not extend to aluminum-containing antacids,4 which may simply be evidence that the aluminum in antacids is not absorbed--the process of absorption through the gut mucosa is quite different from absorption through the skin.

We also know that serum aluminum concentrations increase with age. Aluminum may accumulate slowly over our lifetimes or we may absorb it more easily as we age. Moreover, there is evidence that people with probable Alzheimer's disease have serum aluminum levels that are often significantly higher than those of people with other types of dementia, as well healthy people of similar ages.5

Further evidence that aluminum fosters the development of Alzheimer's dementia comes from a scientific (placebo-controlled) trial of desferrioxamine, a drug that removes aluminum from the body by binding with it. While regular administration of the drug failed to stop the disease from progressing, desferrioxamine did significantly reduce the rate of decline in the ability of a group of people with Alzheimer's dementia to care for themselves.6

Although the aluminum/Alzheimer's link remains unproven, I believe that waiting for definitive proof before taking a few easy and protective measures is foolhardy--and more scientists are starting to agree.7,8 Perhaps one person in 10 age 65 or older suffers from dementia; by age 80 that figure rises to one in five. This is too common an illness to ignore preventive measures until we can know for certain why it develops.

Ways To Avoid Aluminum Here are my suggestions for minimizing your exposure to aluminum.

* Drinking water should be low in aluminum. Some bottled-water companies provide an analysis of the aluminum content of their water. You might also find out from your public water company what the aluminum level is in the local drinking water.

* Aluminum-containing antiperspirants can easily be avoided, as can aluminum utensils and even, to play it safe, aluminum-containing antacids.

* Commercially processed foods such as cake and pancake mixes, frozen doughs and self-rising flour are sources of dietary aluminum, so their ingestion should be minimized. Watch for and avoid sodium aluminum phosphate, an ingredient in baking powder. Pickles and cheese should also be avoided.

* There is a close relationship between silicon and aluminum in Alzheimer brain lesions, as the two substances bind together to form aluminosilicates.9 High levels of silica in drinking water in the form of silicic acid do seem to protect against the adverse effects of aluminum ingestion, and silicic acid ingestion increases urinary aluminum excretion.10,11 Whether silica supplements protect against the development of dementia has yet to be determined.

* Besides minimizing aluminum exposure, taking the Recommended Dietary Allowance (RDA) of calcium, magnesium and zinc should help to protect against aluminum accumulation.12-14 Deficiencies of these important minerals are common among the elderly.15 Yet, unless there is laboratory evidence of a zinc deficiency, I would not recommend zinc supplementation to help prevent Alzheimer's disease, for two reasons. First, beta-amyloid protein, the major substance found in the brain lesions (usually in a liquid form), binds with zinc. At concentrations only slightly higher than those normally found in the brain, excess zinc may convert the protein to the solid form that is found in Alzheimer lesions.16 This suggests that, at least in theory, excess zinc could actually promote the development of the disease. Second, there is a lack of adequate research demonstrating the efficacy of zinc supplementation in preventing Alzheimer's, although in one study all six relatively young dementia victims had some memory improvement following supplementation with zinc aspartate.17

References
1. Martyn, C.N., et al. Lancet, 1: 59-62, 1989.
2. Neri, L.C., & Hewitt, D. Letter. Lancet, 338: 390, 1991.
3. Graves, A.B., et al. J Clin Epidemio,l 43(1): 35-44, 1990.
4. Ibid.
5. Zapatero, M.D. Biol Trace Elem Res, 47: 235-40, 1995.
6. McLachlan, D.R., et al. Lancet, 337: 1304-8, 1991.
7. Lukiw, W.J. Mineral and Metal Neurotoxicology. 113-26. CRC Press, 1997.
8. McLachlan, D.R., et al. Can Med Assoc J, 145(7): 793-804, 1991.
9. Candy, J.M., et al. Lancet, i: 354-57, 1986.
10. Jacqmin-Gadda, H., et al. Epidemiology 7(3): 281-85, 1996.
11. Bellia, J.P., et al. Ann Clin Lab Sci, 26: 227-33, 1996.
12. Foster, H.D. Health, Disease and the Environment. 311-16. Boca Raton,Fla.: CRC Press, 1992:
13. Durlach, J. Magnes Res, 3(3): 217-18, 1990.
14. Wenk, G.L., & Stemmer, K.L. Brain Res 288: 393-95, 1983.
15. Werbach, M.R. Foundations of Nutritional Medicine: Common nutritional deficiencies. Tarzana, Calif.: Third Line Press, 1997.
16. Bush, A.I., et al. Science, 265: 1464-67, 1994.
17. Constantinidis, J. Schweiz Arch Neurol Neurochir Psychiatr, 141(6):523-56, 1990.

Melvyn R. Werbach, M.D., is a faculty member at the UCLA School of Medicine and the author of Nutritional Influences on Illness (Third Line Press Inc.,1993).
http://www.bio.unipd.it/~zatta/alumin.htm

CNR NATIONAL RESEARCH COUNCIL OF ITALY INSTITUTE FOR BIOMEDICAL TECHNOLOGIES
Padova Unit "Metalloproteins" University of Padova Department of Biology Via G. Colombo 3, 35121 Padova, Italy

An International Aluminum Network was established in 1995 open to all scientists interested to a better understanding of the aluminum impact on biological systems from different point of views: Physiological, Pathological, Toxicological, Biochemical in humans as well as in vitro and in vivo experimentation.

This network is devoted to exchanging proposals and scientific data (relevant papers, experimental data etc.) as well as to inform on various activities around the world: workshops, round tables, symposia etc. where relevant issues on Chemistry or Biology related to the Physiopathology of aluminum could be discussed.

Besides, being the most abundant metal and the third most abundant element on the Earth's crust, aluminum has been implicated as an etiological factor in some pathologies related to long-term dialysis treatment of uremic patients and as a potential factor or cofactor in the Alzheimer's syndrome, as well as in the etiopathogenesis of other neurodegenerative diseases, Parkinsonism, Amyotrophic Lateral Sclerosis and other diseases.

Al(III) SPECIATION
Tamas Kiss
ALUMINUM DETERMINATION IN BIOLOGICAL SPECIMENS
Andrew Taylor
ALUMINUM WITH SILICIC ACID
Christopher Exley
TRANSFERRIN AS A METAL ION CARRIER

Peter Sadler and Hongyan Li

BINDING SPECIFICITY OF ANTI-ALUMINUM ANTIBODIES

R. Levy and B. Solomon

ALUMINIUM AND THE NEURONAL GLUTAMATE-NITRIC OXIDE-CYCLIC GMP PATHWAY

Vicente Felipo

ALUMINUM AND GENE EXPRESSION

Walter J. Lukiw

ALUMINUM AND NEUROFILAMENT ASSEMBLY

Thomas B. Shea

ALUMINUM INDUCED ALTERATIONS IN THE NEURONAL CYTOSKELETON

Nancy Muma

Al(III)AND FREE RADICALS

Patricia I. Oteiza

EFFECT OF IRON STATUS ON ALUMINIUM SPECIATION, ABSORPTION AND DISTRIBUTION

Christian Steinhausen

ALUMINUM AND HEPATOPOIETIC SYSTEM

Khalequz Zaman

INTERACTIONS OF ALUMINUM WITH NEURONAL PLASTICITY, SYNAPTIC TRASMISSION AND MEMBRANE PORES

Dietrich Busselberg and Bettina Platt

PROCESS OF ACCUMULATION OF ALUMINIUM IN HUMAN BRAIN

Satoshi Tokutake

ALUMINUM AND ALZHEIMER'S AMYLOID BETA-PROTEIN
Masahiro Kawahara ALUMINUM AND BLOOD-BRAIN BARRIER PERMEABILITY
William A. Banks NEUROFIBRILLARY PATHOLOGY AND ALUMINUM IN ALZHEIMER'S DISEASE

J. Q. Trojanowski
Ryong-Woon Shin
ALUMINUM AND THE PRECURSOR PROTEIN OF THE NON-A COMPONENT OF ALZHEIMER'S
DISEASE AMYLOID (NACP)

Seung R. Paik and Ju-hyun Lee

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

ALUMINUM AND HEALTH

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 Sanità, 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, Université 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: zatta@civ.bio.unipd.it


Padova 20-23 September 2000

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.

S.S. Krishnan, D.R. McLachlan, B. Krishnan, S.S.A. Fenton, and J.E. Harrison. Aluminum Toxicity to the Brain Toronto General Hospital and Departments of Physiology and Medicine, University of Toronto. Copyright 1988. Elsevier Science Publishers B.V. Reprint requests: S.S. Krishnan, Toronto General Hospital, Medical Physical Department, Room ccrw-g-803, 200  Elizabeth Street, Toronto, Ontario, Canada.

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.

Yoshimasu, F., M. Yasui, H. Yoshida, S. Yoshida, Y. Lebayashi, Y. Yase, D.C. Gajdusek, K.I.M. Chen. Aluminum in Alzheimer's disease in Japan and Parkinsonism dementia in Guam. XII World Congress of Neurology - 1985. (Abstr 15.07.02).

Aluminum - Journal Articles

Campbell, A; Bondy, S. Aluminum induced oxidative events and its relation to inflammation: a role for the metal in Alzheimer's disease. Cellular and Molecular Biology. (Noisy-le-grand) June 2000; vol. 46(4), pp.721-730.

Christen, Y. Oxidative stress and Alzheimer disease. American Journal of Clinical Nutrition. February 2000; vol. 71(2), pp. 621S-629S. 

Crapper-McLachlan, D; Dalton, A; Kruck, T; et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet. August 3, 1991; vol. 337(8753), pp. 1304-1308.

Flaten, T. Aluminum as a risk factor in Alzheimer's disease, with an emphasis on drinking water. Brain Research Bulletin. May 15, 2001; vol. 55(2), pp. 187-196.

Forbes, W; Hill, G. Is exposure to aluminum a risk factor for the development of Alzheimer disease?--Yes. Archives of Neurology. May 1998; vol. 55(5), pp. 740-741.

Gauthier, E; Fortier, I; Courchesne, F; et al. Aluminum forms in drinking water and risk of Alzheimer's disease. Environmental Research. November 2000; vol. 84(3), pp. 234-246.

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. Occupational and Environmental Medicine. September 1998; vol. 55(9), pp. 627-633.

Hachinski, V. Aluminum exposure and risk of Alzheimer disease. Archives of Neurology. May 1998; vol. 55(5), pp. 742.

Jansson, E. Aluminum exposure and Alzheimer disease. Journal of Alzheimer's Disease. December 2001; vol. 3(6), pp. 541-549.

Kiss, T. Interaction of aluminum with biomolecules -- any relevance to Alzheimer's disease? Archives of Gerontology and Geriatrics. July-August 1995; vol. 21(1), pp. 99-112.

Lovell, M; Ehmann, W; Markesbery W; et al. Standardization in biological analyses of aluminum: What are the needs? Journal of Toxicology and Environmental Health. August 30, 1996; 48(6), pp. 637-648.

Makjanic, J; McDonald, B; Li-Hsian C; et al. Absence of aluminum in neurofibrillary tangles in Alzheimer's disease. Neuroscience Letters. January 16, 1998; vol. 240(3), pp. 123-126.

Munoz, D. Causes of Alzheimer's disease. Canadian Medical Association Journal. January 2000; vol. 162(1), pp. 65-72.

Munoz, D. Is exposure to aluminum a risk factor for the development of Alzheimer disease? -- No. Archives of Neurology. May 1998; vol. 55(5), pp.737-739.

Newman, P. Alzheimer's disease revisited. Medical Hypotheses. May 2000; vol. 54(5), pp. 774-776. 

Rao, J; Katsetos, C; Herman, M; et al. Experimental aluminum encephalomyelopathy. Relationship to human neurodegenerative disease. Clinics in Laboratory Medicine. December 1998; vol. 18(4), pp. 687-698.

Roberts, N; Clough, A; Bellia, J; et al. Increased absorption of aluminum from a normal dietary intake in dementia. Journal of Inorganic Biochemistry. February 15, 1998; vol. 69(3), pp. 171-176.

Rogers, M; Simon, D. A preliminary study of dietary aluminum intake and risk of Alzheimer's disease. Age & Ageing. March 1999; vol. 28(2), pp. 205-209.

Rondeau, V; Commenges, D; Jacqmin-Gadda, H; et al. Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study. American Journal of Epidemiology. July 1, 2000; vol. 152(1), pp. 59-66.

Savory, J; Garruto, R. Aluminum, tau protein, and Alzheimer's disease: an important link? Nutrition. March 1998; vol. 14(3), pp. 313-314.

Savory, J; Exley, C; Forbes, W; et al. Can the controversy of the role of aluminum in Alzheimer's disease be resolved? What are the suggested approaches to this controversy and methodological issues to be considered? Journal of Toxicology and Environmental Health. August 30, 1996; vol.
48(6), pp. 615-636.

Smith, M; Perry, G. What are the facts and artifacts of the pathogenesis and etiology of Alzheimer disease? Journal of Chemical Neuroanatomy. December 1998; vol. 16(1), pp. 35-41.

Soni, M; White, S; Flamm W; et al. Safety evaluation of dietary aluminum. Regulatory Toxicology and Pharmacology. February 2001; vol. 33(1), pp. 66-79.

Study linking fluoride and Alzheimer's under scrutiny (Health Media Watch). Journal of the American Dental Association. Sept 1998; vol. 129(9), pp. 1216-1218.

Werbach, M. Healing foods: does aluminum exposure promote Alzheimer's? Nutrition Science News. January 1998; vol. 3(1), pp. 16.

Yokel, R. The toxicology of aluminum in the brain: a review. Neurotoxicology. October 2000, vol. 21(5), pp. 813-828.

Yokel, R; Ackrill, P; Burgess, E; et al. Prevention and treatment of aluminum toxicity including chelation therapy: status and researchneeds. Journal of Toxicology and Environmental Health. August 30, 1996; vol. 48(6), pp. 667-684.

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

 

http://www.realsalt.com/totalhealth.html

"Two of the most common anticaking agents used in the mass production of salt are sodium alumino-silicate and alumino-calcium silicate. These are both sources of aluminum, a toxic metal that has been implicated in the development of Alzheimer's disease and that certainly does not belong in a healthy diet. To make matters worse, the aluminum used in salt production leaves a bitter taste in salt, so manufacturers usually add sugar in the form of dextrose to hide the taste of aluminum. Refined sugar­as I explained in my previous book, Get the Sugar Out (Harmony Books, 1996)­severely disrupts the equilibrium of the body and is associated with the development of more than 60 diseases."
 

Oshiro S. [A new inducible transferrin-independent iron uptake system involved with aluminum accumulation in the brain of patients with Alzheimer's disease].
Tanpakushitsu Kakusan Koso. 1995 Aug;40(11):1738-43. Review. Japanese. PubMed PMID: 7676035.
 

 

 

Is Hidden True Cause Of Alzheimer's Your Toothpaste?
From Paul Kuhlman
5-3-3

Hello Jeff...

I am a truck driver, and have hauled just about everything over the past 13 years. I read your site's article postulating that naturally occurring aluminum found in water might be the key to Alzheimer's disease. I'll go one better than that.

I once picked up a 44,000 pound load of aluminum dioxide powder in the aptly-named town of Bauxite, Arkansas. Noting that the destination for the load was not a processing plant or a mill, I enquired as to why this load was destined for the Colgate-Palmolive Company. The shipping agent said that the quality of bauxite (Aluminum dioxide) found in Arkansas was too low grade for manufacturing purposes, but was fine for toothpaste.

"Toothpaste?" I enquired. He then went on to explain that common white toothpaste is made largely from Aluminum Dioxide, which is a mildly abrasive, brilliantly white powder. They'll simply add a sudsing agent to make the bubbles, a flavoring agent to make it palatable, perhaps a food coloring agent, some water, and presto - toothpaste.  Go read the ingredients on your tube of toothpaste. It'll list one or two 'active ingredients'...notice the combined total amounts of 'active ingredients' is usually less than 1%. What about the other 99%?

* Were you aware that every day of your life, you are filling your mouth with a gob of nearly pure aluminum dioxide?

* Can you imagine the possible health effects?

* Do you see how this is the number one entry point for aluminum to enter the body?

* Can you guess why the inactive ingredients aren't listed?

* Imagine the outcry from all the millions of health conscious Americans who suddenly discovered that they are being poisoned!

*Yes, that's why they aren't listed.

So, if you and your vast readership are concerned about getting too much aluminum in their diets, you can all relax about naturally occurring aluminum in the water, or cooking with pots and pans. These are trivial sources of aluminum compared with the several pounds of aluminum directly swallowed or absorbed through the tissues while brushing our teeth.

On the bright side, we can all still have a beautiful smile in our old age, if only we can remember how to smile.

From KT Feller
5-4-3
 

 

Toxicity, Aluminum

Last Updated: November 26, 2002

 

 

Synonyms and related keywords: hyperaluminosis, aluminum-related illness, aluminum concentration, aluminum intoxication, peritoneal dialysis, impaired renal function, renal insufficiency, aluminum clearance, aluminum-related disease, osteomalacia, osteoid mineralization, dialysis encephalopathy, aluminum deposition, uremic pruritus, microcytic anemia, anisocytosis, poikilocytosis, chromophilic cells, basophilic stippling, deferoxamine therapy

 

Author: Barbara Barnett, MD, Associate Program Director, Assistant Professor, Departments of Internal Medicine and Emergency Medicine, Albert Einstein College of Medicine

Coauthor(s): Michael R Edwards, MD, Staff Physician, Department of Emergency Medicine, Long Island Jewish Medical Center, Jacobi Medical Center

 

 

Barbara Barnett, MD, is a member of the following medical societies:
American Academy of Emergency Medicine, American Medical Association, and
Society for Academic Emergency Medicine

 

 

Editor(s): Lisa Kirkland, MD, Senior Associate Consultant, Department of Internal Medicine, Division of Area Internal Medicine, Mayo Clinic, Rochester; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Harold L Manning, MD, Associate Professor, Departments of Medicine, Anesthesiology, and Physio, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University; and Michael R Pinsky, MD, Research Fellowship Program Director, Professor, Department of Critical Care Medicine, University of Pittsburgh School of Medicine

 

 

 

 

Background: Aluminum is a trivalent cation found in its ionic form in most kinds of animal and plant tissues and in natural waters everywhere. It is the third most prevalent element and the most abundant metal in the earth’s crust. Dietary aluminum is ubiquitous, but in such small quantities that it is not a significant source of concern in persons with normal elimination capacity. Urban water supplies may contain a greater concentration because water is usually treated with the element before becoming part of the supply. Subsequent purification processes that remove organic compounds take away many of the same compounds that bind the element in its free state, further increasing aluminum concentration.

All metals can cause disease through excess, deficiency, or imbalance. Malabsorption through diarrheal states can result in essential metal and trace element deficiencies. Toxic effects are dependent upon the amount of metal ingested, entry rate, tissue distribution, concentration achieved, and excretion rate. Mechanisms of toxicity include inhibition of enzyme activity and protein synthesis, alterations in nucleic acid function, and changes in cell membrane permeability.

No known physiologic need exists for aluminum; however, because of its atomic size and electric charge (0.051 nm and 3+, respectively), it is sometimes a competitive inhibitor of several essential elements of similar characteristics, such as magnesium (0.066 nm, 2+), calcium (0.099 nm, 2+), and iron (0.064 nm, 3+). Approximately 95% of an aluminum load becomes bound to transferrin and albumin intravascularly and is then eliminated renally.

Aluminum is absorbed from the GI tract in the form of oral phosphate-binding agents (aluminum hydroxide) and parenterally via dialysate or total parenteral nutrition (TPN) contamination. It is also absorbed during peritoneal dialysis. Lactate, citrate, and ascorbate all facilitate GI absorption. If a significant load exceeds the body's excretory capacity, the excess is deposited in various tissues, including bone, brain, liver, heart, spleen, and muscle. This accumulation causes morbidity and mortality through various mechanisms.

Pathophysiology: Aluminum toxicity is usually found in patients with impaired renal function. Acute intoxication is extremely rare; however, in persons in whom aluminum clearance is impaired, it can be a significant source of pathology. Aluminum toxicity was originally described in the mid-to-late 1970s in a series of patients in Newcastle, England, through an associated osteomalacic dialysis osteodystrophy that appeared to reverse itself upon changing of the dialysate water to deionized water (ie, aluminum-depleted water). Previously, the only known dialysis-associated bone disease was osteitis fibrosa cystica, which was the result of abnormalities in vitamin D production that resulted in a secondary hyperparathyroidism, increased bone turnover, and subsequent peritrabecular fibrosis. In aluminum-related disease, the predominant features are defective mineralization and osteomalacia that result from excessive deposits at the site of osteoid mineralization.

Since the role of aluminum in disease has been identified, more attention has been paid to the element, leading to its recognition in several other processes. For example, among patients with osteomalacia, there has been a closely associated dialysis encephalopathy, which is thought to be caused by aluminum deposition in the brain. Aluminum causes an oxidative stress within brain tissue, leading to the formation of Alzheimerlike neurofibrillary tangles.

Aluminum also has a direct effect on hematopoiesis. Excess aluminum has been shown to induce anemia. Daily injections of aluminum into rabbits produced severe anemia within 2-3 weeks. The findings were very similar to those found in patients suffering from lead poisoning. Aluminum may cause anemia through decreased heme synthesis, decreased globulin synthesis, and increased hemolysis. Aluminum may also have a direct effect on iron metabolism. Patients with anemia from aluminum toxicity often have increased reticulocyte counts.

Other organic manifestations of aluminum intoxication have been proposed, but the mechanism by which it exerts its effect is complex and multifactorial.

Frequency:

bullet

In the US: The actual incidence of toxicity is unknown. The greatest incidence is observed in patients with any degree of renal insufficiency. A higher incidence is observed in populations who have aluminum-contaminated dialysate or who are taking daily oral phosphate-binding agents. Patients who require long-term TPN are at increased risk as well. Recent case reports have implicated the use of oral aluminum-containing antacids during pregnancy as a possible cause for abnormal fetal neurologic development.

bullet

Internationally: No evidence indicates a preponderance of aluminum toxicity in any one geographic region or country.

Mortality/Morbidity: The mortality rate may be as high as 100% in patients in whom the condition goes unrecognized. Today, however, recognition by nephrologists is the norm, and increased awareness by all practitioners has led to earlier detection and overall avoidance of the syndrome. Morbidity and mortality have been diminished significantly. Prior to this, bone pain, multiple fractures, proximal myopathy, and the sequelae of dementia have been the main sources of morbidity.

Race: Aluminum toxicity has no predilection for any race.

Sex: Aluminum toxicity has no predilection for either sex.

Age: Aluminum toxicity is observed in all age groups.

History: The signs and symptoms of aluminum toxicity are usually nonspecific.

bullet

In patients on long-term hemodialysis, osteomalacia is associated with the accumulation of aluminum in bone. Most evidence to support skeletal toxicity is from animal studies.

bullet

Studies have also shown that hemodialysis patients exposed to dialysate containing high aluminum concentrations are at increased risk of osteomalacia.

bullet

Some of the clinical symptoms of the disease entity reflect the chief complaint. An ED physician will rarely consider aluminum toxicity as a possible diagnosis in a dialysis patient who presents with an acute mental status change; however, these patients are the specific group most closely associated with the syndrome.

bullet

Typical presentations may include proximal muscle weakness, bone pain, multiple nonhealing fractures, acute or subacute alteration in mental status, and premature osteoporosis.

bullet

These patients almost always have some degree of renal disease. Most patients are on hemodialysis or peritoneal dialysis.

bullet

When obtaining the history, ask specifically about the supplemental use of oral aluminum hydroxide, particularly if the patient does not undergo dialysis.

bullet

In children, special awareness must be made in those who require parenteral nutrition so as not to give excessive amounts of aluminum in the TPN.

Physical: Unfortunately, physical findings are often noticeably lacking in patients with aluminum toxicity, and findings usually mimic other disease processes.

bullet

Patients can present with multiple fractures (particularly of the ribs and pelvis), proximal muscle weakness, mutism, seizures, and dementia.

bullet

Some studies have shown a direct correlation between aluminum levels and intensity of uremic pruritus.

bullet

In children, however, bony deformity is more commonly due to the increased rate of growth and remodeling.

bullet

Children may also express varying degrees of growth retardation.

bullet

The areas of deformity in children usually involve the epiphyseal plates (ie, femur, wrist).

bullet

In adults, thoracic cage abnormalities, lumbar scoliosis, and kyphosis can be present.

Causes:

bullet

Toxic effects are dependent upon the amount of metal ingested, entry rate, tissue distribution, concentration achieved, and excretion rate.

bullet

Mechanisms of toxicity include inhibition of enzyme activity and protein synthesis, alterations in nucleic acid function, and changes in cell membrane permeability.

bullet

Aluminum toxicity is usually found in patients with renal impairment. Acute intoxication is extremely rare; however, in persons in whom aluminum clearance is impaired, it can be a source of significant toxicity.

Brain Abscess

Cryptococcosis
Cysticercosis
Delirium
Delirium Tremens
Depression
Eastern Equine Encephalitis
Encephalopathy, Dialysis
Encephalopathy, Hepatic
Encephalopathy, Hypertensive
Encephalopathy, Uremic
Ependymoma
Glioblastoma Multiforme
Head Trauma
Hemolytic-Uremic Syndrome
Hepatorenal Syndrome
Hyperosmolar Coma
Hyperparathyroidism
Hyperphosphatemia
Hypocalcemia
Hypoglycemia
Hypothermia
Hypothyroidism

Other Problems to be Considered:

A broad differential exists for each potential problem, depending upon the presenting complaint (eg, musculoskeletal trauma, altered mental status, anemia).

Lab Studies:

bullet

Generally, findings from an aluminum level blood test are unreliable, as most of the body's stores are bound in tissue and are not reflected in the serum value. A deferoxamine infusion test can be performed but may take more than 48 hours to yield a result (see Medical Care). Deferoxamine liberates aluminum from tissues by chelating it and leads to an increased serum level compared to one taken prior to infusion. The combination of a baseline immunoreactive parathyroid hormone level of less than 200 mEq/mL and a change in serum aluminum value of 200 ng/mL after deferoxamine is 90% specific and has a positive predictive value of 85% for aluminum toxicity.

bullet

Aluminum excess has a direct effect on hematopoiesis and has been shown to induce anemia. Findings on peripheral smears in patients with aluminum toxicity include microcytic anemia (hypochromic, normochromic), anisocytosis, poikilocytosis, chromophilic cells, and basophilic stippling. Note that these are the same findings observed in patients with lead poisoning. Aluminum can also be found in bone marrow macrophages.

Imaging Studies:

bullet

In radiographs, Looser zones (ie, lines of radiolucency parallel to the plane of growth in long bones) may be observed in severe cases, although they are more common with other causes of adult osteomalacia. Pathological fractures may also be observed. Bone scintigraphy shows a characteristic pattern in aluminum toxicity.

Other Tests:

bullet

Bone biopsy from the iliac crest is frequently performed to determine the etiology of bone disease in dialysis patients because renal osteodystrophy can be multifactorial (eg, osteomalacia, uremic bone disease, hyperparathyroidism, aluminum deposition). Histochemical staining for aluminum and determination of osteoid volume, bone turnover rate, and osteoblast/clast cell count are some of the methods used for subtyping the bone disease.

Procedures:

bullet

Very few procedures are involved in the diagnosis of aluminum-related illness. Bone marrow biopsy is performed to distinguish between aluminum osteodystrophy and other causes of osteomalacia.

Histologic Findings: Histologic findings in aluminum-related osteomalacia reflect the decrease in mineralization of newly formed bone matrix.

bullet

An increase in the surface covered by osteoid occurs, as does an increase in the osteoid seams.

bullet

Osteoid volume and thickness also increase.

bullet

In histologic sections stained with eosin, the areas of greater mineralization tend to appear violet or blue, whereas the osteoid seams appear pink.

Medical Care: Treatment of aluminum toxicity includes elimination of aluminum from the diet, TPN, dialysate, medications, and an attempt at the elimination and chelation of the element from the body's stores.

bullet

Avoidance of aluminum is easily achieved once the need to do so is recognized.

bullet

Elimination is accomplished through the administration of deferoxamine through any of several routes.

bullet

Deferoxamine, the metal-free ligand of the iron-chelate isolated from the bacterium Streptomyces pilosus, is used for acute and chronic iron toxicity and aluminum toxicity.

bullet

It has a high affinity for ferric iron and does not affect iron in hemoglobin or cytochromes.

Surgical Care: No surgical care is applicable to this disorder. Hemodialysis is performed in conjunction with deferoxamine as therapy for whole body chelation

Consultations:

bullet

Usually, a nephrologist is already a part of the patient's medical team. If not, one should be consulted early in the course.

bullet

A hematologist and a neurologist may be able to assist with the patient's care.

Diet: Since dietary aluminum is ubiquitous, there are no specific dietary guidelines for its avoidance. Special diets should be maintained for specific associated disease entities (eg, diabetes, renal failure).

Activity: Activity modification may not be necessary unless the patient is at risk for frequent falls. If this is the case, a home attendant or family member should assist the patient with daily living activities.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Metal chelators -- Bind free metal and do not chelate other trace metals of nutritional importance. Metals are excreted in the urine and bile.

Drug Name

Deferoxamine mesylate (Desferal mesylate) -- Metal-free ligand of the iron chelate isolated from the bacterium S pilosus. Used for acute and chronic iron toxicity as well as aluminum toxicity and has a high affinity for ferric iron. Does not affect iron in cytochromes or hemoglobin. PO/IM administration not established. Several case reports and cohorts using varying doses indicate effectiveness when administered IV.

Adult Dose

6 g/wk average at 14.5 mg/kg/h IV 3 times/wk during first 2 h of dialysis or 85 mg/kg/wk at 14.5 mg/kg/h IV

CAPD: 500-750 mg added to each 2-L bag of dialysate for approximately 2 mo; varying amount of exchanges using deferoxamine (eg, only hs, once/d) would prolong therapy; alternatively, administer prolonged SC infusion over 8-16 h via pump

Pediatric Dose

Not established; consult nephrologist

Contraindications

Documented hypersensitivity, profound hypotension, anuria, and severe renal disease without ability to dialyze

Interactions

Vitamin C >500 mg/d can cause cardiac dysfunction; concomitant administration with prochlorperazine can cause transient loss of consciousness; gallium-67 scanning results can be affected

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Tachycardia, hypotension, and shock may occur in patients receiving long-term therapy and could add to the cardiovascular collapse due to iron toxicity; adverse GI effects of the drug include abdominal discomfort, nausea, vomiting, and diarrhea, which may add to the symptoms of acute iron toxicity; flushing and fever are reported

Deterrence/Prevention:

bullet

Avoid all aluminum-containing antacids, dialysate, and TPN solutions.

Complications:

bullet

See Clinical.

Prognosis:

bullet

Depending upon the degree of dementia and overall medical frailty of the patient, most improve in with deferoxamine therapy. Some patients, however, succumb to their underlying disease processes before any noticeable improvement in mental status or anemia occurs. Whether aluminum toxicity itself is fatal is unknown. Typically, patients' underlying diseases and medical frailty lead to early morbidity and mortality.

Patient Education:

bullet

Educate pregnant and breastfeeding females, and any patient with compromised renal function, about the use of aluminum-containing antacids and the potential dangers of their use and overuse. A safe alternative includes calcium carbonate, such as found in Tums.

bullet

Educate patients to refrain from driving or operating hazardous machinery if they develop dizziness or impaired vision or hearing during treatment.

Medical/Legal Pitfalls:

bullet

Failure to educate a pregnant female, particularly in her first trimester, about potential damage to the fetus

bullet

Misdiagnosing abuse in a child or elderly patient with a pathologic rib fracture when the injury is actually secondary to renal/aluminum osteodystrophy

bullet

Prescribing an aluminum-containing antacid to a patient with impaired renal function

bullet

Failure to advise patients to refrain from driving or operating hazardous machinery if dizziness, impaired vision or hearing, or other nervous system dysfunction develops

bullet

Candy JM, McArthur FK, Oakley AE: Aluminium accumulation in relation to senile plaque and neurofibrillary tangle formation in the brains of patients with renal failure. J Neurol Sci 1992 Feb; 107(2): 210-8[Medline].

bullet

Chang TM, Barre P: Effect of desferrioxamine on removal of aluminum and iron by coated charcoal haemoperfusion and haemodialysis. Lancet 1983 Nov 5; 2(8358): 1051-3[Medline].

bullet

Drueke TB, Lacour B, Touam M: Effect of aluminum on hematopoiesis. Kidney Int Suppl 1986 Feb; 18: S45-8[Medline].

bullet

Friga V, Linos A, Linos DA: Is aluminum toxicity responsible for uremic pruritus in chronic hemodialysis patients? Nephron 1997; 75(1): 48-53[Medline].

bullet

Gilbert-Barness E, Barness LA, Wolff J: Aluminum toxicity. Arch Pediatr Adolesc Med 1998 May; 152(5): 511-2[Medline].

bullet

Hem JD: Geochemistry and aqueous chemistry of aluminum. Kidney Int Suppl 1986 Feb; 18: S3-7[Medline].

bullet

Key, L, Bell, N: Osteomalacia and disorders of vitamin D metabolism. In: Internal Medicine. 4th ed. 1994: 1526-1527.

bullet

Malluche HH, Smith AJ, Abreo K: The use of deferoxamine in the management of aluminium accumulation in bone in patients with renal failure. N Engl J Med 1984 Jul 19; 311(3): 140-4[Medline].

bullet

McCarthy JT, Milliner DS, Johnson WJ: Clinical experience with desferrioxamine in dialysis patients with aluminium toxicity. Q J Med 1990 Mar; 74(275): 257-76[Medline].

bullet

Trapp GA: Interactions of aluminum with cofactors, enzymes, and other proteins. Kidney Int Suppl 1986 Feb; 18: S12-6[Medline].

bullet

Ward MK, Feest TG, Ellis HA: Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminium. Lancet 1978 Apr 22; 1(8069): 841-5[Medline].

 Advent of the Adjuvant: QS-21 Makes Vaccines Look Good
June 2002
by Bruce Goldman

The vaccine market is going to explode.

And when it does, it will be in large part due to the addition of a set of essential but unsung immunological tools called adjuvants. These immune enhancers will be vital components in making new vaccine types viable, making old ones more efficacious, and making those that are expensive to manufacture or in scarce supply go further.

A new generation of vaccines is being brought into being by giants like GlaxoSmithKline, Merck and Wyeth, says Garo Armen, PhD, CEO of New York City-based biotech Antigenics Inc. All three pharmaceutical houses are moving vaccines for a large number of indications containing Antigenics' powerful new adjuvant, QS-21, toward or through clinical trials. "With a successful assault on such major diseases as AIDS, most hepatitis forms, and herpes, the market for prophylactic vaccines could easily double by the end of this decade," Armen says. "And the total size of the vaccine market theoretically could be as large as the entire pharmaceutical market is today, because most diseases can theoretically be treated with therapeutic vaccines, which harness the immune system to cure - rather than prevent - illnesses."

Vaccinology has expanded beyond its traditional mainstays - attenuated or killed microorganisms - to the likes of recombinant proteins and glycoproteins, synthetic peptides, and conjugate vaccines, in which relatively nonimmunogenic, carbohydrate-based antigens are tethered to strongly immunogenic carrier proteins. But paradoxically, the new, pared down vaccines may become less intrinsically immunogenic, even as they become safer and more precisely targeted. This is because although they contain antigens that tell the immune system's warriors and weaponry exactly what to attack, they may lack other components that kick the immune system's logistical support machinery into higher gear.

Enter the adjuvant: a substance that, although not necessarily eliciting an immune response itself, improves the immune response to a co-administered antigen. Adjuvants can work in many ways: raising antibody titers, enhancing mucosal immune responses, or making better cell responses. Considering that a vaccine may spend close to 20 years in development, research and development (R&D) expenses dwarf other aspects of its cost structure. So an adjuvant doesn't add much to the cost of a vaccine - but it can add immensely to its potency. Indeed, experimental vaccines often just won't work without one.

Clinical immunologist and public health specialist Bob Edelman, MD, a professor of medicine and pediatrics at the University of Maryland, says an ideal adjuvant would open up new worlds of prevention and treatment: "It might make for an effective vaccine against malaria or HIV. We could stop with those two." But his list also includes autoimmune diseases and a variety of cancers.

A superior adjuvant might also extend the benefits of existing vaccines to poor responders such as older or immunocompromised people. An adjuvant that rendered lower doses more effective, moreover, would allow for cheaper vaccines in cases in which the antigen is expensive to produce (a recombinant protein, for example). It could also stretch supplies in a hurry during an epidemic or after a bioterrorist incident. Dose sparing, as this property is called, is of increasing importance in the development of conjugate vaccines, in which difficult chemistry limits antigen dose size, especially when several antigens must be packed into a single shot.

Adjuvant activity has been found in numerous natural products through serendipity and trial and error. One of the very first papers on the subject was written in 1925 by a French researcher who learned he could enhance immunogenicity by injecting crude products such as tapioca or bread crumbs, and chemical substances such as lecithin or saponins (soap-like substances isolated from plants).

That early discovery presaged one of the most promising new adjuvants in the burgeoning arsenal of vaccinology. In 1986, biochemist Charlotte Kensil, PhD, now vice president for research operations and strategy at Antigenics, came to work for what was then Cambridge Biosciences, taking on the analysis of a complex saponin extract from the bark of Quillaja saponaria (a South American tree) with which the company hoped to adjuvant its vaccine for feline leukemia virus (FeLV). The extract was very effective, but toxic. Looking to purify out the toxicity using high-performance liquid chromatography (HPLC), Kensil identified 23 separate peaks, or components, and set about characterizing them. Several proved irrelevant, others toxic. The 21st HPLC peak, however, yielded a saponin that was both active and nontoxic.

This substance - actually a mixture of two compounds that co-exist in a relatively constant ratio and are virtually identical in both structure and activity - was christened QS-21 (Kensil is one of the two inventors on the patent); by 1990, it was in a successfully licensed FeLV vaccine in the United States and Europe. In a restructuring move about seven years ago, Cambridge Bioscience spun off Aquila Biopharmaceuticals, which retained the rights to QS-21. Long on intellectual property but short on cash, Aquila Biopharmaceuticals was in turn bought by Antigenics at the end of 2000.

Adjuvants on Trial
These days, the US Food and Drug Administration (FDA), rather than grant blanket approval for an adjuvant itself, reviews each vaccine-adjuvant combination as a separate package. The exception is alum, the only currently approved adjuvant per se. Alum - a generic term for salts of aluminum, chiefly aluminum hydroxide and aluminum phosphate - was first employed in 1926 and was effectively grandfathered in when the FDA first assumed new drug approval authority in 1938.

But Is Alum Worth Its Salt?

Oldest doesn't always mean best, says cancer vaccine specialist Phil Livingston, MD, attending physician at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University's medical school. In fact, he says, "as adjuvants go, alum's the weakest."

On the other hand, "Billions of doses of alum have been administered - not millions, billions - and it has a track record of being generally safe," says the University of Maryland's Edelman. "As a result of this long experience, we've grown to have a warm, fuzzy feeling about it, and it's become the benchmark adjuvant against which all others are now tested."

Alum is known to work chiefly though a depot effect. Small antigens, injected into the bloodstream, can quickly become degraded in the liver or filtered by the kidneys. Alum, by precipitating soluble antigens, forces them to linger longer in the area near the injection site, where antigen-presenting cells - mainly macrophages and dendritic cells - can ingest and process them, thus ensuring a greater immunologic response. An immunostimulatory adjuvant such as QS-21 does much more than simply prevent degradation or discharge. It may facilitate uptake of the antigen - the actual vaccine itself - into antigen-presenting cells. (Saponins such as QS-21, for example, are detergents; they may therefore render cell membranes temporarily more permeable.) Or it may induce a cytokine response in local tissues. Cytokines are molecular messengers that act systemically and at close range to fine-tune the immune response's course. Under their influence, the system strikes a balance between two poles called Th1 and Th2, named for the two classes of T-helper cells. To put it somewhat simplistically, Th1 primes a cell-mediated immune response that includes the activation of killer T cells (essential for, say, combating a chronic viral infection like HIV), whereas Th2 primes an antibody response mediated by B cells, which may be adequate for fending off certain blood borne infectious organisms. Different cytokines - and different adjuvants - tend to tilt the immune system toward characteristic points on the Th1-Th2 continuum.

Edelman cautions: "You're going to find article after article saying that 'this adjuvant causes a Th1 response in this animal, or a Th1 response in that animal.' What they fail to go on to say is: 'It hasn't been put into man yet.' The use of adjuvants is an empirical science, and you can learn only so much from preclinical studies. I've grown very skeptical because I've been burned so many times. It really comes down to clinical trials. If you want your vaccine to work in a human, you'd better get it into a human, quickly. Otherwise you're going to spend a lot of time with animal studies and never be able to predict what it will do in people."

In animals and humans, alum tends to skew things towards Th2, says infectious disease vaccinologist Tom Evans, MD, professor of medicine at the University of California, Davis. Evans has also worked with MF59, a squalene/water emulsion manufactured by Chiron that is in a licensed influenza vaccine in Italy. "MF59 gives you better responses than alum, but it's very Th2-skewed," Evans says.

At the other end of the continuum sits an adjuvant class called CpG, which is still confined to early-phase clinical trials of vaccines for cancer, HIV and hepatitis B. (The term CpG denotes a category of bacterial cytosine- and guanine-rich oligonucleotide motifs found in bacterial, but not human, DNA.) A few companies are developing competing adjuvants consisting of different CpG sequence variations. "In animal studies, at least," says Antigenics' Charlotte Kensil, "CpG produces almost entirely Th1 cytokines."

Right in the middle is QS-21, which, according to results of extensive testing in both animal and human studies, not only elicits both Th1- and Th2-type cytokines but also unleashes the antibodies and T cells those cytokines are supposed to bring about. For example, in a clinical trial of a melanoma vaccine reported in the July 1, 1995, issue of Cancer Research, researchers comparing QS-21 with monophosphoryl lipid A (MPL), which is in a licensed melanoma vaccine in Canada, reported that QS-21 elicited much higher titer and longer lasting antibody responses, in addition to recruitment of T cells.

Antigenics' leading platform technology - personalized vaccines prepared from patients' tumors - derives from the discovery by its chief scientific officer, Pramod Srivastava, PhD, that a species of molecules known as heat shock proteins, or HSPs, can be extracted from a tumor to activate a powerful Th1-type response targeted to unique antigens that characterize that tumor. Antigenics' vaccines for kidney cancer and melanoma have progressed to Phase III trials.

QS-21's virtually unsurpassed ability to induce a vigorous antibody response, which parallels HSPs' penchant for stimulating the cell side, made the Aquila Biopharmaceuticals acquisition a logical complement to Antigenics' HSP-driven business strategy. "When it comes to activating the antibody arm of the immune system, QS-21 is the most powerful adjuvant out there that can be used in people, and my studies at Sloan-Kettering showed a T-cell response, too," says cancer specialist Jon Lewis, MD, PhD, who left Sloan-Kettering a few years ago to become chief medical officer of Antigenics and chairman of the company's medical board.

Stanford University's Ron Levy, MD, has conducted early-phase clinical trials of a QS-21-containing vaccine employing personalized antigens from lymphoma patients. In lymphoma, one B cell begins dividing out of control, resulting in a huge number of cells all secreting large volumes of a single antibody (the composition and structure of which differ from one patient to the next) into the blood. Levy says patients' immune systems responded to the vaccine with strong T-cell proliferation and high antibody titers specific to their personalized antigens.

"QS-21 has been extensively tested in about 3,500 patients in over 50 Phase I and II studies," says Lewis of Antigenics. "Of all adjuvants, this has by far the greatest record. It's been shown to be extremely safe and extremely potent. And now it's down to crunch time" - in other words, late-phase clinical trials.

And that's happening right now, in several indications ranging from malaria to melanoma.

Milestones in Malaria
Plasmodium falciparum, which causes more than 2 million malaria deaths annually, is a complex, multistage parasite that makes its home, by turns, in mosquitoes, human blood, and human livers - each time presenting different surface antigens. P. falciparum has frustrated the efforts of many medical researchers who have been working for years to develop a vaccine against it. But GlaxoSmithKline (GSK) has reported a string of successes using QS-21 in combination with two other adjuvants and an antigen GSK calls RTS,S: a recombinant protein from an early stage of the parasite, fused to hepatitis B surface antigen, in association with a second molecule of the identical hepatitis antigen. Besides QS-21, the adjuvant mixture contains MPL, licensed from Seattle-based Corixa, and an oil/water emulsion proprietary to GSK.

"We took the vaccine into a challenge trial in the United States in the late 1990s," says Moncef Slaoui, PhD, who, as senior vice president for business and new product development, heads the clinical R&D organization at GSK's vaccine subsidiary. In that trial, conducted in collaboration with the Walter Reed Army Research Institute and published in the January 9, 1997, issue of the New England Journal of Medicine, volunteers were given RTS,S along with one of three different adjuvant formulations, and then exposed to P. falciparum-carrying mosquitoes. All six immunized controls contracted malaria. So did seven of the eight who received alum plus MPL, and five of the seven given the oil/water emulsion.

But of those receiving the third adjuvant formulation - oil/water emulsion, MPL and QS-21, with the same antigen - five out of seven subjects resisted infection, Slaoui says. "So we brought this one into clinical trials in Africa. And we completed an efficacy trial in adults that confirmed what we'd observed in the mosquito challenge trial." In this study, published in the December 2001 issue of The Lancet, about 250 Gambian men aged 18-45 years got three doses of either RTS,S or rabies vaccine (as a control) during the malaria season. They were then monitored for 15 weeks to see if they would succumb to natural infection. Not only did the subjects show strong antibody and T-cell responses, but the vaccine's actual efficacy in preventing infection during the first nine weeks of follow-up was an attention-grabbing 71 percent.

Antigenics' Jon Lewis minces no words: "RTS,S plus that QS-21-containing adjuvant formulation is the most significant malaria vaccine ever tested."

In the final six weeks of follow-up, the vaccine's efficacy plummeted. Then again, Slaoui notes, here the term "efficacy" means a total absence of infection. "The endpoint in our trials is very stringent: detection of parasites in the blood of vaccinated subjects or controls," he says. "As soon as any parasite presence is detected, the subject is treated. But what we don't know is whether the level of immunity that remains is still good enough to combat disease. In real life, deaths are usually accompanied by a high level of parasitemia. So I do not exclude that immunity against death or very severe disease might still be sustained well beyond three months."

With side effects shown not to have been an issue for adults, GSK has been moving down the age bracket first to adolescents, and then to very young children. Trials addressing two different age groups between one and seven years of age are now reasonably far along. "There will be a long follow-up period for safety, but the active part of immunizing the children is mostly completed," says Slaoui. "Our objective is to assess whether the immune response and the efficacy induced by this vaccine in children is as good and/or as short-lived as was shown in adults. And if it is also short-lived, we would like to improve on the design to make it effective for at least six months or a year, or longer.

"We're very satisfied with our access to QS-21," Slaoui continues. "We're using the three-adjuvant formulation in other vaccines, primarily ones that are very complex to develop and that require very strong immune responses." Vaccines for hepatitis B and non-small cell lung cancer are already in Phase II studies; a vaccine using a glycoprotein called gp120 (the dominant coat protein in HIV) entered the clinic in January. Still other candidates are in preclinical development.

A 600-Fold Stretch
Interestingly, Ron Levy's lymphoma vaccine experiments at Stanford compared both QS-21 as a stand-alone adjuvant with GSK's three-adjuvant cocktail and found QS-21 alone to be just as good as the mix in eliciting an immune response, and no more reactogenic. "There was no significant difference in side effects," Levy says. In neither case was pain upon injection much of a problem.

So, what if gp120 were to be tested with QS-21 alone, instead of in an adjuvant mix?

UC Davis' Evans is principal investigator of GSK's 80-subject, ongoing Phase I trial of its HIV vaccine: gp120 plus its QS-21-containing, three-adjuvant combination. Before coming to UC Davis, Evans was at the University of Rochester, where he was principal investigator for a 37-subject, National Institutes of Health (NIH)-funded Phase II study of a version of QS-21 plus gp120 produced by VaxGen, a San Francisco-based biotech.

"While gp120 is an obvious target for a preventive immune response, it's not very immunogenic," says Evans. "It doesn't elicit much antibody, and the antibodies it does elicit don't tend to be the ones we're looking for."

Then there's the cost. Capacity constraints are already a problem with bacterially produced recombinant proteins. But glycoproteins such as gp120 can't be made in bacteria. They have to be produced in mammalian cells, and the yield is always low. "If VaxGen's gp120 is successful, there will be a huge production problem," Evans says. "There's no way they can make enough even for the domestic market, let alone developing countries."

A previous trial had shown no useful QS-21 effect on the immune response at good-sized doses - 100 to 600 micrograms - of VaxGen's gp120. In contrast, the trial that Evans ran was designed to look at not whether QS-21 boosted a maximum dose of gp120, but whether QS-21 could reduce the necessary dose of gp120 and, therefore, permit decreased manufacturing costs.

Evans and his colleagues found that when the dose of gp120 was dropped to 30 or 3 micrograms, addition of QS-21 not only elicited antibody titers equivalent to those generated by high doses of the antigen, but aroused T cells, too. "QS-21 was a phenomenal adjuvant," Evans says.

But unlike Levy's lymphoma patients, these subjects complained of significant early pain at the injection site. A study co-authored by Antigenics' Kensil and several others and published in Vaccine last year indicated that adding either polysorbate 80 or cyclodextrin to QS-21 significantly reduced injection pain. (Polysorbate also stabilizes QS-21, giving it a longer shelf life, Kensil says.)

"We did a 60-subject follow-on study in which we added polysorbate 80," says Evans. "But this time we took the dose of gp120 from 3 micrograms all the way down to 0.5 micrograms. And we learned that 0.5 micrograms of gp120 given with QS-21 elicited at least as good or better antibody and T-cell responses than 300 micrograms given with alum - a 600-fold dose reduction. And our neutralizing antibody responses - the ones that really count - were at least as good as we got lower, and trending towards being better: the lower the dose, the better it looked. The data are irrefutable. This is the most impressive dose-sparing effect that's been seen to date."

Polysorbate 80 diminished the injection pain, Evans says, but not enough for VaxGen, which decided to conduct its ongoing, 5,000-person Phase III efficacy trial in North America and Europe with a formulation containing alum but not QS-21.

However, Evans wants to do his own follow-on Phase II study of gp120 with lower doses or other formulations of QS-21 than were used in previous studies to strike a balance between decreased reactogenicity and robust immunogenicity. "QS-21's the best adjuvant I've ever evaluated. Unless you use something like it, these antigens can't be manufactured on a large enough scale to allow you to deliver them worldwide," he says. "But if, all of a sudden, you can cut the dose you need to give by 100-fold, which QS-21 does, you now have effectively increased your manufacturing capability by 100-fold."

Learning to Growl at Sugar
A vaccine that's dynamite for one population may be a dud for another. This is certainly the case with vaccines composed of complex carbohydrates. Take, for example, the only currently approved vaccine for prevention of pneumococcal disease in adults. Pneumococcus, short for Streptococcus pneumoniae, is surrounded by a polysaccharide capsule. The vaccine works by generating antibodies that bind to the invading microorganism's capsule, allowing the bacteria to be effectively eliminated.

"Young adults respond quite vigorously to polysaccharides," says infectious disease specialist John Treanor, MD, of the University of Rochester School of Medicine. "But efficacy seems to decrease as you get older."

Tissue-localized infections such as bacterial pneumonia are bad enough. But in addition, says Treanor, "the risk of invasive pneumococcal diseases such meningitis and bacteremia also goes up quite dramatically once you start getting beyond age 50. Rates among otherwise healthy people over 65 are about 10 or 20 times higher - in fact, maybe more like 100 times higher - than among adults in general. And antibiotics are not that effective, particularly because a lot of the mortality occurs within the first 48 hours, before you have a chance to do anything with antibiotics. So the elderly are the real target for an improved pneumococcal vaccine."

The vaccine consists of purified capsular polysaccharides from 23 different bacterial strains, adsorbed to alum. "There are on the order of 90 or so distinct serotypes, or antigenic structures, of the pneumococcal capsule," says Treanor, "and they're fairly distinctive from one another, so in general, an antibody that recognized one would not recognize a different one. You need to include an example of the polysaccharide of each strain of epidemiological importance. Fortunately, 85 percent of all of invasive pneumococcal disease in adults is accounted for by the 23 serotypes contained in the vaccine."

The immune systems of kids under two years of age don't respond to naked polysaccharides. A similar type of conjugate vaccine against Haemophilus influenzae (another polysaccharide-coated microbe) had generated very robust antibody and T-cell responses in kids, so Wyeth (formerly known as American Home Products) developed a vaccine made of pneumococcal polysaccharides conjugated to immunogenic carrier proteins. "But instead of trying to conjugate just one polysaccharide to a carrier, as with H. influenzae," says Treanor, "with pneumococcus you've got to conjugate as many serotypes as you can. There's a limit to the amount of polysaccharide you can get on a carrier. So you're constrained as to the number of serotypes you can include in your vaccine."

In February 2000, the FDA approved Wyeth's pared down, seven-serotype conjugate vaccine adjuvanted with alum. That vaccine, called Prevnar, proved extremely effective among children. "We'd actually been hoping Prevnar could rev up some arm of immune responsiveness that doesn't occur with the elderly," says Treanor, referring to his role as principal investigator for a Phase I trial among healthy adults 65 years of age or older, conducted at the University of Rochester over the course of about a year. "But when we tried it, it didn't work. There was essentially no difference between Prevnar and polysaccharide vaccine alone. Prevnar was no better - and in some cases, worse.

"Then we added QS-21 to it. QS-21 seemed attractive because the amount of polysaccharide used in those conjugate vaccines is considerably less than the amount that's given with standard polysaccharide, and QS-21 seems to have a good dose-sparing effect and had had quite a big effect with several protein antigens-in particular, with gp120," says Treanor, who worked closely with Evans while the latter was still at Rochester.

Of the 30 enrollees in Treanor's trial, 10 were inoculated with the standard polysaccharide vaccine, 10 received Prevnar alone, and 10 were given Prevnar along with QS-21 and polysorbate 80 - a combination Antigenics calls Quilimmune-P.

"Quilimmune-P was significantly better," says Treanor. Only one person out of the 10 getting the polysaccharide vaccine, versus five out of the nine who were injected with Quilimmune-P, had antibody responses to at least six of the seven serotypes contained in the conjugate vaccine - a result that attained statistical significance even with this small number of subjects. There was no significant difference in side effect profile in these three treatment arms. Treanor presented the data in May 2002 at a Baltimore meeting of the National Foundation for Infectious Diseases Vaccine Symposium.

"Having proved the principle that adjuvanting the vaccine would be useful, the next logical step is to try to expand the coverage by putting in more serotypes," says Jon Lewis of Antigenics. "Prevnar doesn't have enough serotypes in it to be ideal for older people because the range of serotypes responsible for invasive disease is broader in adults than it is in children." But in a conjugate vaccine, more different antigens means smaller doses of each of them. The constraints of chemistry call for careful calibrations of QS-21's dose-sparing capabilities on a serotype-by-serotype basis, a task likely to require partnering with a large pharmaceutical company.

Throwing the Book at Cancer
Dose sparing is not an issue with cancer patients, says Phil Livingston of Sloan-Kettering. "For cancer, you always go for the maximum antigen dose," he says.

A group led by Livingston has been conducting Phase I and II clinical trials of QS-21 in conjugate vaccines for melanoma, and breast, ovarian, prostate and non-small cell lung cancers. In these vaccines, carrier proteins are linked to up to five or six different antigens - some of them peptides and others gangliosides (complex lipopolysaccharides found in normal tissue such as nerve, spleen and thymus) - that tend to be overexpressed on tumor cells. "It's hard enough to raise a high-titer antibody response to a polysaccharide antigen in any indication," Livingston says. "But on top of that, all those overexpressed carbohydrate antigens on cancer cell surfaces are self-antigens - they're also present to some extent on normal cells - so the immune system has been trained to ignore them. That's why conjugate vaccines are so important in the cancer world."

(Vaccines targeting overexpressed self antigens differ from Antigenics' heat shock proteins in that the latter, rather than having to overcome immunotolerance, confer immunogenicity to mutant antigens that are unique to the tumor.)

"Really potent adjuvants are clearly necessary, too," continues Livingston. "You just don't get a detectable response without the adjuvant." In a study reported in Vaccine in 2000, he and his colleagues compared 19 new adjuvants, included in a conjugate cancer vaccine, for their ability to induce two subclasses of immunoglobins - IgM and IgG - and to trigger production of both Th1 and Th2 cytokines. "QS-21 was right at the top," Livingston says.

A couple of years ago, Livingston licensed a melanoma vaccine he'd designed - an overexpressed ganglioside called GM2 conjugated to a carrier protein and mixed with QS-21 - to Progenics Pharmaceuticals. The Tarrytown, NY, company has brought the formulation along to a Phase III trial in the United States. But preliminary results of that trial, in which the vaccine went head to head with interferon-alpha, have been lackluster. "QS-21's not the problem," says Livingston. "It did what it was supposed to do. The patients are making antibodies. The ones who have the highest titer have the best prognosis."

Progenics has started a European trial of the QS-21-adjuvanted, single-ganglioside conjugate with somewhat earlier-disease patients. But Livingston says, "I just don't think a single antigen is enough. While every melanoma seems to express GM2, only a subset of them - about a quarter or a fifth of melanoma cell lines - have enough so that you can get killing of the cell, even with the best antibodies."

Livingston's hopes lie with a multi-antigen, ganglioside conjugate vaccine. "We really need to use multiple antigens so that we can kill everybody's melanoma cell lines in vitro. There are 10 times more GD3 [another of Livingston's experimental gangliosides] than GM2 molecules on the surface of melanoma cells." GD3 is only weakly immunogenic, but recently Livingston's lab found ways to induce a good antibody response against GD3 using QS-21.

"We'd like all of our partners to go in that direction," says Armen, Antigenics' CEO. "GlaxoSmithKline's malaria trials also are just using a single RTS,S antigen. But their melanoma trial is using a multi-antigen approach."

Risk and Reward
"Cancer patients will gladly take the risk of strong reactions because their alternative is, simply, death or worsening disease," says the University of Maryland's Bob Edelman. But when a disease resides in the central nervous system (CNS), the line between efficacy and immune overstimulation is extremely fine.

After QS-21 came out as the winner in Elan Corporation's animal tests of a host of adjuvants, the Ireland-based pharmaceutical firm anointed QS-21 as the only adjuvant for the company's clinical trials of AN-1792, the first ever immunotherapeutic treatment for a neurological disorder. AN-1792's relevant antigen is the peptide A-beta, which has been strongly implicated in formation of plaques that accumulate in the brains of Alzheimer's disease patients. The idea is that training the immune system to attack A-beta may result in a lower burden of Alzheimer's-associated plaque - and, it is hoped, slow, arrest or even reverse the course of the disease.

An 80-patient Phase I trial completed about a year ago showed an excellent safety profile, and Elan's randomized Phase II trial was fully enrolled at about 375 patients within six hours of its announcement - the fastest recruitment in clinical trial history. But after all patients had received at least two shots, more than a dozen of them developed symptoms of CNS inflammation, some quite severe. Fortunately, most patients' symptoms resolved with the cessation of dosing.

Although press reports suggest that the AN-1792 trial has been abandoned, that's not the case. Patients are still being carefully monitored not only for inflammatory symptoms, but also for signs of efficacy. Should any beneficial effect of the vaccine be found among Phase II patients (and there have been a few such reports, albeit guarded and purely anecdotal), a series of issues will have to be addressed.

First, correlation of benefit to inflammation will have to be sought on a patient-by-patient basis. If such a correlation does exist, the question becomes: Can the inflammatory CNS reaction be separated from the targeted immune response? It's possible that a rejiggering of the vaccine formulation or dosing schedule can eliminate the connection. "An overwhelming number of factors control immune response in humans," says Edelman. "It depends on the type and dose of antigen, the dose of the adjuvant, the number of injections, and amount of time between them." Certainly, given the total absence of any adverse reaction in Phase I, it's a safe bet that trial records will be carefully combed for any signs of difference in the design and execution of Elan's Phase II versus its Phase I trials.

But to the extent inflammation appears to be a necessary concomitant to T-cell and B-cell activation, vaccine developers and regulators alike will have to answer another, more Hobbesian question: "Is the risk-to-reward ratio favorable?" The cytokine interleukin 2 (IL-2), to name a precedent, received FDA approval for the treatment of renal cell carcinoma, another severe disease. This is despite the fact that only 12 percent to 15 percent of patients' tumors responded to IL-2 and IL-2 directly kills about 3 percent of the patients. The FDA approved it simply because no other effective agent was available. And to date, there's no available drug that can arrest or reverse the course of Alzheimer's disease.

Sudden Demand for Short Supplies
A globalized society confers many benefits on its participants, but it does not come without its risks. Among those risks is the potential for the rapid spread of natural epidemics-and, more recently, of diseases deliberately sowed by bioterrorists. Recognizing these realities, the federal government has been turning its funding attention to ways of meeting the sudden need for increased supplies of vaccines for diseases thought to have been brought under control, as well as for those that recur with every passing season - influenza, for instance.

The current influenza vaccine is less than optimally effective in elderly and, even in younger individuals, may fail to provide full protection. Nor, according to Phil Wyde, PhD, of Baylor University's school of medicine, does alum pass muster as a helpful adjuvant for the influenza vaccine. But in animal studies of that vaccine conducted by Wyde, QS-21 has shown the kind of dose-sparing potential reminiscent of Tom Evans' HIV trials in which, at ultra-low doses of gp120, QS-21 achieved an immune response so strong that, to get the same reaction with alum, would have required an antigen dose 600 times as large. As was the case with the human gp120 trials, in Wyde's mouse studies this effect was apparent only at low doses of antigen.

"Every year for the last several years there's been an influenza vaccine shortage," says Jon Lewis. "According to the National Institutes of Health, there's now also a pneumonia vaccine shortage. We've shown that when we add QS-21 to the pneumonia vaccine, we get an immune response from older patients, and that's tough to do."

In mouse studies, QS-21 has induced a solid immune response to tetanus toxoid, the active antigen of tetanus vaccines, also in short supply now. And in a study conducted by U.S. Army researchers at Walter Reed and reported in 1998 in Vaccine, QS-21 plus an antigen from bacteria responsible for anthrax fully protected Rhesus monkeys against aerosol blasts containing almost 100 times the amount that would be expected to kill half of them. What's more, the vaccine wiped out all traces of bacteria in the monkeys' blood - a performance besting that of alum, MPL, and even the currently licensed human anthrax vaccine.

"QS-21 holds a huge potential, in both a quantitative and qualitative sense, for increasing our prophylactic and therapeutic vaccine stores," says Garo Armen, Antigenics' CEO. "I think we've just started to scratch the surface of this potential."

Bruce Goldman is a freelance scientific writer who lives in San Francisco.
 

Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome

Journal: Rev Neurol (Paris) 2003 Feb;159(2):162-4

Author: Gherardi RK.

Affiliation: Groupe Nerf-Muscle, Departement de Pathologie, Hopital Henri Mondor, Creteil.

Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients.

One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis.

Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures,  and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile. It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome.

Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome.

Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant.

If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worlwide.

NLM Citation: PMID: 12660567 [Article in French]
 

http://www.wwns.com/sanders/gh/aluminum.htm
We have moved to http://www.prismiclight.com

ALUMINUM
Aluminum in the Human Diet
Aluminum: Contamination of Human Neurophysiology and Behavior
KEYWORDS: Aluminum in cookware, antacids, adjuvants in vaccines,toothpaste tubes,drink cans, cooking foil, baking powder,food containers,foods, pharmaceuticals,etc.

INTRODUCTION
The majority of the human population in the industrialized nations ingest a minimum of 30 to 50 milligrams of aluminum metal per day. An examination of labels on consumer products will reveal that many of them contain the metal. Most foods contain aluminum products. Beverage cans, aluminum foil in contact with food, aluminum pots and pans and aluminum in drugs (including most antacids) insure that the cumulative load of aluminum in the human body eventually reaches critical level.

Aluminum in consumer drugs is a big problem. Aspirin is commonly buffered with aluminum hydroxide, aluminum glycinate and other aluminum compounds. Vaginal douches contain potassium aluminum sulfate, ammonium aluminum sulfate, and alum. Antacids contain aluminum hydroxide, magaldrate, dihydroxyaluminum, and aluminum oxide. Antidiarrheal drugs contain aluminum magnesium silicate and kaolin, an aluminum salt. Cake mixes, self-rising flour, processed cheese, baking powder, food starch modifiers, pickling salts and anti-caking agents provide additional aluminum in the form of sodium aluminum, sodium aluminum sulfate, aluminum ammounium sulfate, and sodium aluminum silicate. Aluminum contaminates drinking water, milk and other products.

The Problem of Aluminum Cookware
One wonders why aluminum cookware, as opposed to stainless steel, was introduced in the United States in the first place. Along with aluminum foil, cookware made of aluminum is a significant source of excess aluminum in the diet. Boiling water in aluminum containers, especially water containing acidic substances, causes aluminum to leach into the water and food. Water containing fluorides encourages the leaching process from aluminum cookware.

Water containing 1ppm fluoride[The usual level of fluoride in public water supplies.], boiled for ten minutes in an aluminum pot, will increase the concentration of aluminum to 200 ppm. Prolonged boiling can increase the concentration to 600 ppm.[Tennakone et al., "Aluminum leaching from cooking utensils" Nature, Vol 325, January 15-21, 1987.] Add acidic food (tomato sauce, for example) and it even goes higher. In addition, as we see in the chapter in fluorides, the presence of aluminum increases the negative effects of fluorides (which is why fluoride toothpaste comes in aluminum tubes). Since the scientific data has been around for some time on all these issues, it cannot be anything but intentional. Aluminum cookware has been around since the late 1920's.

The Effect of Aluminum on the Human Brain
In order to prove that all of this is intentional, we have to prove that it was known early enough that aluminum causes a problem. One would assume that indications of negative effect would preclude introduction of aluminum cookware. Not in the United States. German experiments done in 1897 , where aluminum was analyzed for pathological reaction in animals, showed that aluminum is a selective neurotoxin and a nerve cell poison of specific affinity for the brain.[ Doellken, P. "Ueber die wirkung des aluminum mit sonder beruecksichtigung der durch das aluminum verursachten lasionen im zentralnervensystem" Naunyn-Schmiedebergs Arch Exper Path Pharmakol 40:58-120, 1897.] Exposure of the central nervous system to aluminum salts produces a progressive encephalopathy.[ Munoz-Garcia et al, "An immunocytochemical comparison of cytoskeletal proteins in aluminum-induced and Alzheimer-type neurofibrillary tangles." Acta Neuropathology Vol 70, 1986, p.243-248. Now we see that aluminum deposition produces encephalopathy, vaccines produce encephalopathy, fluorides and mercury amalgams produce encephalopathy, and they knew about all of it early on. Someone or some group in high position, more than 70 years ago, intentionally planned to use the United States as a testing ground for all of this, ultimately resulting in a sociopathic society pleading for totalitarian control. They knew about the effect of mercury and vaccines in 1926. It's in the medical literature. All of this is not an accident. Are you going to stand by and not take responsibility for your health and the health of those you love? The government isn't, because it's a conflict of interest.]

Earlier we mentioned the fact that a great number of cases of degenerative brain diseases in Guam drew the curiousity of researchers. Ten percent of the total population of native Guamanians die of brain disease. Fifteen percent of the natives in the Mariana Islands die of neurodegenerative disease. Why? Part of the answer is that there are high levels of aluminum in the drinking water. There are also high levels of aluminum in the food.[Perl, D., et al., "The association of aluminum, Alzheimer's disease, and neurofibrillary tangles" Journal of Neural Transmutation, Vol 24, 1987, pp.205-211; Dalton et al, "Aluminium and calcium in soil and food from Guam, Palau and Jamaica: implications for ALD and Parkinsonism-dementia syndromes of Guam", Brain, Vol 112, 1989, p. 45-53.]

Aluminum Interaction With Brain Chemicals
Aluminum is a potent inhibitor of the uptake of choline and dopamine.[ Banks, W., et al., "Aluminum increases permeability of blood-brain barrier to labelled DSIP and beta-endorphin: possible implications for senile and dialysis dementias" Lancet Vol 26, Hov 1983, p.1227 ; Guest, J., et al., "The effects of aluminum on sodium-potassium-activated adenosine triphosphatase activity and choline uptake in rat brain synaptosomes" Biochemical Pharmacology, Vol 29, 1980, p.141; Davison, A., et al., "Differences in the inhibitory effect of aluminum 3+ on the uptake of dopamine by synaptosomes from forebrain and from striatum of the rat", Biochemical Pharmacology, Vol 30, 1981, p.3123-3125.] Both are vital chemicals released during nerve inpulse transmission, as well as nerve impulse conduction to muscles and various glands. As a result, the presence of aluminum ions in the brain has an adverse impact on thought and reasoning processes, as well as short-term memory. Furthermore, there is significant evidence that aluminum ions alter enzymes involved with acetylcholine metabolism,[ Wong, P.C., et al., "The effects of aluminum on the methylation of phospolipids in the rat brain synaptosomal membrane", Biochemical Pharmacology, Vol 30, 1981, p.1704; Simpson, J., et al, "Cholinergic enzymes in neurofibrillary degeneration produced by aluminum", Brain Research, Vol 197, 1980, p. 269-274. affecting interplay between thought processes and motor coordination, resulting in ataxia and other serious problems so obvious in those with Alzheimer syndrome and other "senile" degenerative conditions.
 

 

A BEHAVIORAL AND HISTOLOGICAL STUDY OF THE EFFECTS OF LONG-TERM
EXPOSURE OF ADULT RATS TO ALUMINUM.

Miu AC, Andreescu CE, Vasiu R, Olteanu AI.

Neuroscience Research Group, Department of Psychology, Babes-Bolyai University, Cluj-Napoca, Romania.

Aluminum (Al) has been etiologically and epidemiologically related to several neurologic conditions, including Alzheimer's disease (AD). The effects of Al long-term exposure were investigated to describe the associated behavioral and brain modifications. Adult rats were intraperitoneally injected three times a week for 6 months with ecological doses of Al gluconate (0.85 mg/kg). The Al overload was confirmed by the significantly increased level of Al in serum. We assessed fear conditioning, spatial memory and emotional reactivity by shuttle-box task, Morris water maze, and open-field, respectively. The performance of the experimental animals at the shuttle-box task was significantly lower (p <.01) compared to that of control. The experimental animals had impaired spatial memory, with lower and more fluctuant performance at Morris water maze. The noxious-driven behavior of the experimental animals was also altered, with significantly lower activity scores (p <.05), and high emotionality scores (p <.01) at the open-field. We recovered and processed the brain for aluminum and amyloid deposits. The brains of experimental animals, studied by optical microscopy, displayed a massive cellular depletion in the hippocampal formation, particularly, the CAl field, and also in the temporal and parietal cortex. We observed numerous ghost-like neurons with cytoplasmic and nuclear vacuolations, and with Al deposits. The hippocampus contained extracellular accumulations of Al and amyloid surrounded by nuclei of degenerating cells, which we interpreted as neuritic plaques. The cerebrovasculature was distorted, with a significant thickening of the wall of capillaries, associated with amyloid deposits. These behavioral and neuropathological modifications associated with long-term exposure to Al are reminiscent of those observed in AD.
 

 

Vaccines Containing Aluminum Appear Safe
Tue February 3, 2004 02:36 PM ET

NEW YORK (Reuters Health) - While mercury compounds used to preserve some childhood vaccines has been a worry for many parents, aluminum compounds added to vaccines have also raised concern. Now, however, the results of a review of studies looking at this question suggest that the aluminum salts found in DTP (diphtheria-tetanus-pertussis) vaccines cause no serious or lasting adverse effects.

Although aluminum salts have been used for decades to boost vaccine effectiveness, there have been reports linking them to various problems, including a progressive disorder involving muscle wasting and fatigue, according to a report in The Lancet Infectious Diseases medical journal. Determining the safety of aluminum is important because replacing the compound would be a huge undertaking requiring numerous safety trials before new vaccines become available, the researchers note.

To investigate the safety of aluminum-containing DTP vaccines, Dr. Tom Jefferson, from Cochrane Vaccines Field in Rome, and colleagues reviewed eight studies that recorded patient outcomes following vaccination and the amount of aluminum in the vaccine. Immunization with an aluminum-containing vaccine was tied to an increased risk of redness at the injection site in young children, and with prolonged local pain in older children. However, there was no evidence in either age group linking such vaccines to serious or lasting adverse effects.

"Despite a lack of good-quality evidence we do not recommend that any further research on this topic is undertaken," the authors conclude.

SOURCE: Lancet Infectious Diseases, February 2004.

 

[Aluminum as an adjuvant in vaccines and post-vaccine reactions]

[Article in Polish]

Fiejka M, Aleksandrowicz J.

Zakladu Badania Surowic, Warszawie.

Aluminium compounds have been widely used as adjuvants in prophylactic and therapeutic vaccines. Adjuvants are able to stimulate the immune system in a nonspecific manner, i.e. high antibody level can be obtained with minimal dose of the antigen and with reduced number of inoculations. Adjuvants use has been mostly empirically determined by such factors as efficacy and safety. The mechanism of action of the aluminium adjuvants is not completely understood and is very complex. The basic factors of the mode of action: 1) the complex of antigen and aluminium gel is more immunogenic in structure than free antigen, 2) effect "depot"--The antigen stimulus last longer, 3) the production of local granulomas. Vaccines adsorbed onto aluminium salts are a more frequent cause of local post-vaccinal reactions than plain vaccines. 5-10% those vaccinated can develop a nodule lasting several weeks at the injection site. In some rare cases the nodules may become inflammatory and even turn into an aseptic abscess. The nodules persisting more than 6 weeks may indicate development of aluminium hypersensitivity. Finally aluminium adjuvant immunogens induce the production of IgE antibodies.

Publication Types:
bullet

Review

bullet

Review, Tutorial

PMID: 8235346 [PubMed - indexed for MEDLINE]

Ugeskr Laeger. 1992 Jun 29;154(27):1900-1.  

[Aluminum allergy caused by DTP vaccine]

[Article in Danish]

Nielsen AO, Kaaber K, Veien NK.

Hudklinikken, Herning.

All children referred to two private dermatological practices from 1 Jan. 1985 to 31 Dec. 1990 who had pruritus and subcutaneous infiltrates in the areas of immunization with Di-Te-Pol vaccine were patch tested with a Finn Chamber or with 2% aqueous aluminium chloride. Di-Te-Pol vaccine contains aluminium hydroxide. Contact allergy to aluminium was demonstrated in 32 children (20 girls and 12 boys). Of the three patch test methods used, testing with 2% AlCl3 occluded with a Finn Chamber proved to be the most sensitive. Immunization of children who have been shown to be allergic to aluminium should be carried out with vaccines which do not contain aluminium.

PMID: 1509548 [PubMed - indexed for MEDLINE]

Aluminum Hydroxide-Adjuvant-Anthrax (BioThrax), DTaP (Certiva, Infanrix, Acel-Imune), DT (Massachusetts), Td

(Massachusetts), Hib (PedvaxHib), Hib-Hepatitis B (Comvax), Hepatitis A (Havrix, Vaqta), Hepatitis B (Engerix-B,

Recombivax-HB), Lyme disease (LymeRix) http://www.cdc.gov/nip/publications
/pink/Appendices/A/Excipient.pdf

Synonyms: hydrated alumina, aluminum hydroxide

Stability: Stable. Incompatible with strong bases.

Toxicology: May act as a skin, respiratory or eye irritant.

Toxicity data: IPR (intraperitoneal) RAT LDLO (lowest published lethal dose) 150 mg kg-1

Risk phrases: R36 (Irritating to eyes) R37 (Irritating to respiratory system) R38 (Irritating to skin)

Transport information: Non-hazardous for air, sea and road transport.

Personal protection: Safety glasses.

Safety phrases: S26 (In case of contact with eyes, rinse immediately with plenty of water and seek medical advice)

S36 (Wear suitable protective clothing) http://physchem.ox.ac.uk/MSDS/AL/
aluminium_hydroxide.html

 

http://www.amershamhealth.com/
medcyclopaedia/Volume%20III%201/osteomalacia.asp

Aluminum poisoning: a toxic state due to excess amounts of aluminium from any of a number of causes. Patients with chronic renal disease may develop aluminium toxicity with a resulting low-turnover osteomalacia, termed dialysis osteomalacia or aluminium osteomalacia. Children may develop rickets. Significant morbidity and even death may ensue.

In uraemic patients, aluminium toxicity initially occurred as a complication of excess amounts of aluminium in the dialysate. The main source of toxicity now is aluminium from oral phosphate binders, such as aluminium hydroxide, which lower serum phosphate levels by binding with phosphate in the intestine. The mechanism for the production of bone disease is unknown. However, accumulation of aluminum at the site of calcification (the bone – osteoid junction) appears to inhibit mineralization through blocking of skeletal uptake of calcium.

Early symptoms and signs of aluminium toxicity include bone pain, muscle weakness, dementia, microcytic anaemia and hypercalcaemia. Later complications may include pathologic fractures, seizures, encephalopathy, and death. Radiographs may be helpful in predicting aluminium toxicity without resorting to biopsy. Diagnostic findings include an increased frequency of fractures, a lack of osteosclerosis, a relative decrease in subperiosteal resorption compared with patients without aluminium toxicity, and a significant increase in osteonecrosis after transplantation (Fig.1).
The Encyclopaedia of Medical Imaging Volume III:1
http://www.emedicine.com/ped/topic1683.htm
Pathophysiology: Low bone density in children involves the net loss of bone. Bone density is currently a 2-dimensional measurement. It is the quotient of the bone mineral content (BMC) measured in grams by absorptiometry in a specified bone region (eg, hip, lumbar spine), divided by the bone area (BA) in cm2 to give a reading in g/cm2. This 2-dimensional method of assessing bone density is limited because changes in bone volume cannot be detected. This leads to an inaccurate estimation of the severity of bone loss or the skeletal response to treatment.

Pathways to decreased bone density all lead to an imbalance between the rate of bone formation and the rate of bone resorption. Thus, low-turnover conditions, such as hypoparathyroidism, burn injuries, or conditions that affect bone marrow (eg, malignancies) or their treatments, may result in a reduction of bone formation.
Other high-turnover states, such as Paget disease or hyperparathyroidism, can result in an increase in bone resorption. Interestingly, almost all preterm infants fall into this group. Since the majority of calcium is transmitted from mother to fetus during the third trimester, infants born prematurely do not receive all the calcium their body needs to mineralize normally. With rapid postnatal increase in bone turnover, there are fewer opportunities for the bones to mineralize, as recently shown by Naylor et al.

Furthermore, the majority of these children receive total parenteral nutrition (TPN) for at least the first 3 weeks of life. TPN solutions are contaminated with aluminum; therefore, these infants remain at risk for bone aluminum accumulation and consequent decreased mineralization. In addition, calcium and phosphorus requirements cannot be met by TPN, and the infant, especially the very premature infant, presents with hypophosphatemic metabolic bone disease.
Vaccine. 2004 Sep 9;22(27-28):3698-706.     Related Articles, Links    
 
Persistent itching nodules after the fourth dose of diphtheria-tetanus toxoid
vaccines without evidence of delayed hypersensitivity to aluminium.

Netterlid E, Bruze M, Hindsen M, Isaksson M, Olin P.

Swedish Institute for Infectious Disease Control, SE 171 82 Solna, Sweden.

Studies in Gothenburg, Sweden, reported an exceptionally high rate of persistent itching nodules at the site of injection of aluminium containing vaccines, usually with positive epicutaneous tests to aluminium. When a new booster diphtheria-tetanus vaccine was introduced we performed a prospective cluster randomised active surveillance in 25,232 10-year-olds. Parental reports 6 months after vaccination with Duplex((R)) or diTeBooster((R)) were collected for 22,365 (88%) pupils in 851 schools. We identified 3-6 children per 10,000 with a local itching nodule persisting for at least 2 months. There were no significant differences between the vaccine groups. Contact allergy to aluminium was not detected. The findings support the use of the vaccine presently available in the Swedish vaccination program. Continued surveillance of persistent itching nodules and aluminium contact allergy is, however, warranted for vaccines containing pertussis toxoid and aluminium.

PMID: 15315849 [PubMed - in process]   
 

http://www.emagazine.com/view/?2187
The Environmental Magazine, CT
January/February 2005
Vol. XVI, no. 1
Heavy Metal?
Exploring the Aluminum/Alzheimer's Link
by Melissa Knopper

In natural health circles, many people are tossing aluminum pans and using holistic underarm crystals instead of conventional antiperspirant. Their choices are fueled by an ongoing mystery surrounding aluminum. About 20 years ago, scientists first raised questions about a possible link between aluminum and Alzheimer's disease. Since then, researchers have gone back and forth on this question. As soon as one publishes a study showing a connection, another disproves it. These days, most of the top medical experts, from the Mayo Clinic to the Alzheimer's Association, say there really is no reason to panic.

But other agencies, including the National Institute of Environmental Health Sciences (NIEHS), continue to look into it because aluminum is so ubiquitous in our daily lives. We swallow it in foods like processed cheese and baked goods. Babies encounter it in formula, breast milk and vaccines. Since aluminum is both strong and lightweight, more auto manufacturers are relying on it to boost fuel efficiency. That means more aluminum byproducts will enter the air, water and, ultimately, the landfills.

"The Alzheimer's risk with aluminum hasn't been well defined," says Robert Yokel, a University of Kentucky pharmacy professor who is studying aluminum for the NIEHS. "You have to weigh risks and benefits. My personal opinion is if you can make simple choices to avoid it until we sort this thing out, why not?"

One certainty is that Alzheimer's disease is not going away. As the baby boom generation ages and more Americans live longer, this devastating illness is affecting more patients and their families. Currently, about five percent of people over age 60 will develop Alzheimer's disease. Some research shows a relationship between aluminum and other nervous-system disorders, such as Lou Gehrig's disease and Parkinson's Disease.

Pros and Cons

Scientists first became aware of aluminum's potential health risks 20 years ago, when a group of kidney patients came down with a similar form of dementia after being exposed to aluminum through dialysis. Another study found aluminum inside the plaques and tangles that appear in Alzheimer's patients' brains.

Meanwhile, a few epidemiological studies found that people with a high level of aluminum in their drinking water had a higher incidence of Alzheimer's. Other studies that followed, however, did not show the same correlation. Studies of cultures that drink large amounts of tea (which leaches a lot of aluminum) also did not show a link. After several decades, scientists have been unable to replicate the original studies showing aluminum deposits in a brain affected by Alzheimer's. "There was an aluminum scare 20 years ago, but it now looks like there is no connection," says Harvard Alzheimer's researcher Dr. Ashley Bush.

New research, by Bush and others, shows Alzheimer's to be a much more complex illness than anyone had imagined. Bush's laboratory is developing a promising new drug that prevents zinc from reacting with the proteins that form the abnormal deposits in brains attacked by Alzheimer's. Phase III clinical trials of the drug, developed by Prana Biotech (http://www.pranabio.com), will begin next year.

Experts now believe if aluminum does appear in an Alzheimer's brain, it's simply because it is so common in our environment. "It's a major component of the Earth's crust, so it shows up everywhere," Bush says. As for food and water contamination, aluminum probably isn't much of a threat because most of it passes right through the intestines without being absorbed.

Some natural health advocates disagree with this position. Suzan Walter is president of the American Holistic Health Association, and her mother died of Alzheimer's. She says many natural health experts advise patients to avoid aluminum based on the precautionary principle, and she takes steps to avoid it in her personal life. "We don't know what causes Alzheimer's, but why not stay away from aluminum just in case?" Walter asks. "It doesn't compromise my life to avoid it and it can't hurt."

Paul Schwartz, national policy coordinator for Clean Water Action, adds, "There is a valid concern to be raised about aluminum and health effects, but the science is not definitive."

Aluminum in Food and Medicine

While the metal is not easily absorbed, the government is still paying scientists like Yokel to make sure we are safe when it comes to dietary sources of aluminum. Currently, the U.S. Food and Drug Administration does not limit aluminum in food because it is "generally recognized as safe." At
the same time, no one knows the exact rate the body absorbs aluminum from food. Since food accounts for 95 percent of our aluminum intake, it's worth examining, Yokel says. "We're looking into whether this constant exposure in our diet is causing a problem," Yokel says. Yokel is also studying the rate of absorption for aluminum in drinking water. For years, municipal water treatment operators have added aluminum to their tanks to make bacteria settle out of the final product. If Yokel's ongoing experiments show our bodies absorb too much aluminum from tap water, the EPA may adopt stricter regulations.

Aluminum is so common that all of us have some background level in our bodies. For example, all mothers have traces of aluminum in their breast milk (about 40 micrograms per liter). Infant formula has about five times as much aluminum as breast milk (soy formula has the most). And the load just builds from there as a person ages.

"If aluminum does cause Alzheimer's, it's possible that lifelong exposure could contribute," Yokel says. "Sometime later in life, you could hit that threshold and develop a problem-but it's all speculation at this point." Certain over-the-counter medicines are loaded with aluminum. For example, the World Health Organization estimates antacid users swallow as much as five grams of aluminum per day. Buffered aspirin also has aluminum.

Vaccines are another little-known source of aluminum in our lives. The media has focused a great deal on mercury in childhood vaccines. But many vaccines also contain aluminum as an additive. That may be a concern because the body absorbs injected aluminum more easily. Vaccine critics also question whether mercury and aluminum might have a synergistic effect on the developing
nervous system.

Aluminum is an important part of vaccines, however, because it makes them work better, says Dr. Paul Offit, chief of infectious diseases at the Children's Hospital of Philadelphia. "It's used when you want to enhance the immune response," Offit says. The Hepatitis B, tetanus and DPT vaccines contain aluminum, as do some batches of the flu shot.

Some parent groups, such as the Virginia-based National Vaccine Information Center, have been critical of the government's childhood vaccine policies. They argue medical policy makers and drug companies should offer vaccines without additives like mercury and aluminum.

While most childhood vaccines no longer contain mercury, aluminum might be harder to replace, says FDA spokesperson Lenore Gelb. So far, no one has identified a safe alternative that can perform the same way. Even if researchers find a new substance, the testing and approval process would take years, she adds.  In pockets of the country, fears about these additives are causing an anti-vaccine backlash. Some parents are home schooling their kids to avoid government-mandated vaccines. And what about elderly patients who might skip their flu shot because they don't want an extra load of aluminum in their brains?

Offit believes the immediate benefits of vaccines outweigh any future risks. Right now, we have no definite proof that aluminum causes Alzheimer's, Offit argues. But each year, thousands of children and elderly people die of flu complications. "There is nothing theoretical about the flu," he says.

What About Antiperspirants?

Adults and teens who use antiperspirant every morning get another daily dose of aluminum. While the skin absorbs a very small percentage of the aluminum in antiperspirants, studies show, natural health advocates raise questions about the effects of constant exposure. Antiperspirants work by plugging sweat glands with aluminum salts.

Plenty of herbal alternatives are on the market at health food stores. But Yokel encourages shoppers to do their homework. A check of the label on one brand of crystal deodorant stone showed "alum" in the ingredients. That, Yokel advises, is simply a natural form of aluminum. Another option is to buy conventional deodorant, which should be aluminum-free as long as it
doesn't say "antiperspirant" on the label.

MELISSA KNOPPER is a Colorado-based science writer.

CONTACTS

http://www.vaccineinformation.org/
Immunization Action Coalition
Phone: (651) 647-9009

http://www.NVIC.org
National Vaccine Information Center
Phone: (703) 938-DPT3

http://www.alz.org/
Alzheimer's Association
Phone: (800) 272-3900

 

http://www.medscape.com/viewarticle/503821?src=mp
MEDSCAPE

Cutaneous Pseudolymphoma Tied to Vaccinations Containing Aluminum Hydroxide

NEW YORK (Reuters Health) Apr 25 - Vaccinations containing aluminum hydroxide may induce cutaneous lymphoid hyperplasia (CLH), also called cutaneous pseudolymphoma, according to a report in the April Journal of the American Academy of Dermatology.

"Long lasting cutaneous lesions occurring at the site of vaccination containing aluminum should lead to biopsy and the search for aluminum in the lymphocytic reaction," Dr. Herve Bachelez from Hopital Saint-Louis, Paris, France told Reuters Health.

Dr. Bachelez and colleagues investigated 9 patients presenting with late-onset, persistent CLH at the site of hepatitis B (8 patients) or hepatitis A (1 patient) vaccination. The vaccines were all aluminum hydroxide-adsorbed and the lesions appeared a median 3 months after a recall injection of the vaccine. Histologic evaluation of skin biopsies showed a pandermal dense lymphocytic infiltrate without evidence of cytonuclear atypia, consistent with the diagnosis of CLH.

Muscle biopsies years after the appearance of the skin lesions in 2 patients revealed focal lymphocytic microvasculitis in the muscle tissue in one case and lymphoid hyperplasia in perimuscular fat tissue in the second case. Electron microscopy and immunohistochemical studies identified aluminum hydroxide within the skin infiltrates in all cases, the researchers note. Four
patients had their lesions excised surgically, and two patients were treated successfully with intralesional steroid injection. These findings, the researchers conclude, warrant "further prospective studies to evaluate the incidence and the clinical course of CLH in the population
receiving aluminum hydroxide-containing vaccinations."

J Am Acad Dermatol 
April 2005 • Volume 52 • Number 4

Report
Vaccination-induced cutaneous pseudolymphoma

Abstract   

Background: Although mild early cutaneous transient reactions to vaccinations are common, late-onset chronic lesions have been scarcely reported. We report herein a series of 9 patients presenting with cutaneous and subcutaneous pseudolymphoma.

Observations: Nine patients presenting with late-onset, chronic skin lesions occurring at the site of antihepatitis B (8 cases) and antihepatitis A (one case) vaccination were reported. Histopathologic and immunohistochemic studies, and molecular analysis of clonality of skin biopsy specimens, were performed. Furthermore, the presence of vaccine products was investigated in skin lesions by using histochemical, microanalytic, and electronic microscopy techniques.

Results: Histopathologic studies showed dermal and hypodermal lymphocytic follicular infiltrates with germinal center formation. The center of follicles was mostly composed of B cells without atypia, whereas CD4+ T cells were predominant at the periphery. Molecular analysis of clonality revealed a polyclonal pattern of B-cell and T-cell subsets. Aluminium deposits were evidenced in all cases by using histochemical staining in all cases, and by microanalysis and ultrastructural studies in one case. Associated manifestations were vitiligo (one case) and chronic fatigue with myalgia (two cases).

Conclusion: Cutaneous lymphoid hyperplasia is a potential adverse effect of vaccinations including aluminium hydroxide as an adjuvant. Further prospective studies are warranted to evaluate the incidence of this complication in the immunized population.
 

 
Metals link to multiple sclerosis
Multiple sclerosis could be linked to difficulty in processing iron and aluminium, a study has suggested. Scientists at Keele University, Staffordshire, compared levels of the metals in the urine of people with MS and others without the condition.

Significantly higher levels than expected were found in those with MS. Experts said the research was interesting, but MS was a complex disease and more work was needed before a link could be confirmed.


These are interesting and unexpected findings
Dr Lee Dunster, MS Society

The study compared 10 MS patients with the relapsing-remitting form of the disease and 10 who had the more advanced secondary progressive form with 20 people who did not have MS.
They looked at iron levels because the metal has been linked with the facilitation and acceleration of oxygenated damage. It was found that iron levels were significantly higher in people with MS, particularly so in those with the secondary progressive form of the disease.

People with the relapsing-remitting form of the disease were found to have very high levels of aluminium - up to 40 times those seen in the group who did not have MS. The levels are as high as those seen in people with a condition known as aluminium intolerance.

Susceptibility

MS is an autoimmune disease caused by the immune system turning in on itself and attacking the body's own tissues. In MS, immune cells destroy the myelin sheath that surrounds nerve fibres in the brain and spinal cord and enables them to transmit impulses.

Dr Christopher Exley, a bio-organic chemist at Keele, who ran the study, said: "We know from animal studies that myelin is the preferred target for aluminium. "As myelin breaks down, something called myelin basic protein is found in urine. "It could be that aluminium is coming out with that. We are going to do further tests to see if that is the case."  The present understanding is that developing MS is due to a combination of having a genetic susceptibility and environmental factors. Dr Exley said: "We hypothesise that susceptibility genes may have something to do with how iron is metabolised in the body - something may be going wrong.

"And it may be that aluminium is a previously unrecognised factor that exacerbates that problem, which then manifests itself in some as MS." Dr Lee Dunster, head of research and information at the MS Society, said, "These are interesting and unexpected findings but MS is a highly complex, multi-factoral disease and further research in a larger study is needed to see how significant they may be."


Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/4724414.stm

Published: 2006/02/19 00:14:52 GMT

© BBC MMVI
 

Vaccines show sinister side
By pieta woolley

Publish Date: 23-Mar-2006
http://www.straight.com/Print_Page.cfm?id=16717

If two dozen once-jittery mice at UBC are telling the truth postmortem, the world's governments may soon be facing one hell of a lawsuit. New, so-far-unpublished research led by Vancouver
neuroscientist Chris Shaw shows a link between the aluminum hydroxide used in vaccines, and symptoms associated with Parkinson's, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's
disease), and Alzheimer's.

Shaw is most surprised that the research for his paper hadn't been done before. For 80 years, doctors have injected patients with aluminum hydroxide, he said, an adjuvant that stimulates immune response.  "This is suspicious," he told the Georgia Straight in a phone interview from his lab near Heather Street and West 12th Avenue. "Either this [link] is known by industry and it was never made public, or industry was never made to do these studies by Health Canada. I'm not sure which is scarier."

Similar adjuvants are used in the following vaccines, according to Shaw's paper: hepatitis A and B, and the Pentacel cocktail, which vaccinates against diphtheria, pertussis, tetanus, polio, and a type of meningitis. To test the link theory, Shaw and his four-scientist team from UBC  and Louisiana State University injected mice with the anthrax vaccine developed for the first Gulf War. Because Gulf War Syndrome looks a lot like ALS, Shaw explained, the neuroscientists had a chance to isolate a possible cause. All deployed troops were vaccinated with an aluminum hydroxide compound. Vaccinated troops who were not deployed to the Gulf developed similar symptoms at a similar rate, according to Shaw.

After 20 weeks studying the mice, the team found statistically significant increases in anxiety (38 percent); memory deficits (41times the errors as in the sample group); and an allergic skin reaction (20 percent). Tissue samples after the mice were "sacrificed" showed neurological cells were dying. Inside the mice's brains, in a part that controls movement, 35 percent of the cells were destroying themselves.

"No one in my lab wants to get vaccinated," he said. "This totally creeped us out. We weren't out there to poke holes in vaccines. But all of a sudden, oh my God—we've got neuron death!" At the end of the paper, Shaw warns that "whether the risk of protection from a dreaded disease outweighs the risk of toxicity is a question that demands our urgent attention."

He's not the only one considering that.

The charge that there's a sinister side to magic bullets isn't new. With his pen blazing, celebrity journalist Robert F. Kennedy Jr. popularized vaccine scepticism with his article arguing that mercury in vaccines causes autism, which ran in the June 2005 Rolling Stone and on-line at Salon.com. So did last year's vaccines-linked-to-autism bestseller, Evidence of Harm by David Kirby (St. Martin's Press). But there's a potential public-health cost to all the controversy, according to the B.C. Centre for Disease Control.

"Vaccines have been a victim of their own success," spokesperson Ian Roe told the Straight in a telephone interview from Ottawa. Diseases such as polio, which killed his father-in-law, are almost eradicated and therefore no longer serve as a warning to parents. But the epidemic threat is still real. "If everyone decided to not getvaccinated, we'd live in a very different world."

Canada's last national immunization conference, in December 2004, heard a report that vaccine coverage is sometimes low. For diphtheria, the Public Health Agency of Canada found that just 75
percent of two-year-olds are immunized; the target is 99 percent. For tetanus, just 66 percent of 17-year-olds are immunized, compared to a target of 97 percent. Dr. Ronald Gold, the former head of the infectious-disease division at Toronto's Hospital for Sick Children, told the conference
that "we will never be without an anti-vaccine movement," but "in reality, there is no scientific evidence for these myths."

Shaw acknowledges that there's a lot of pressure on parents to vaccinate their children. "You're considered to be a really bad parent if you don't vaccinate," he said—and your child can't attend
public school. "But I don't think the safety of vaccines is demarcated. How does a parent make a decision based on what's available? You can't make an intelligent decision." Conservatively, he said, if one percent of vaccinated humans develop ALS from vaccine adjuvants, it would still constitute a health emergency. It's possible, he said, that there are 10,000 studies that show
aluminum hydroxide is safe for injections. But he hasn't been able to find any that look beyond the first few weeks of injection. If anyone has a study that shows something different, he said,
please "put it on the table. That's how you do science."

Neuroscience research is difficult, Shaw said, because symptoms can take years to manifest, so it's hard to prove what caused the symptoms. "To me, that calls for better testing, not blind faith."
He pointed out that George W. Bush passed legislation that opens the door for the USA to order a nationwide anthrax immunization campaign, with the threat of bioterrorism.

Shaw's paper is currently undergoing a peer review.

 

http://www.wwns.com/sanders/gh/aluminum.htm
We have moved to http://www.prismiclight.com

--------------------------------------------------------------------------------
ALUMINUM
--------------------------------------------------------------------------------

Aluminum in the Human Diet
Aluminum: Contamination of Human Neurophysiology and Behavior
KEYWORDS: Aluminum in cookware, antacids, adjuvants in vaccines,toothpaste tubes,drink cans, cooking foil, baking powder,food containers,foods, pharmaceuticals,etc.

INTRODUCTION
The majority of the human population in the industrialized nations ingest a minimum of 30 to 50 milligrams of aluminum metal per day. An examination of labels on consumer products will reveal that many of them contain the metal. Most foods contain aluminum products. Beverage cans, aluminum foil in contact with food, aluminum pots and pans and aluminum in drugs (including most antacids) insure that the cumulative load of aluminum in the human body eventually reaches critical level.

Aluminum in consumer drugs is a big problem. Aspirin is commonly buffered with aluminum hydroxide, aluminum glycinate and other aluminum compounds. Vaginal douches contain potassium aluminum sulfate, ammonium aluminum sulfate, and alum. Antacids contain aluminum hydroxide, magaldrate, dihydroxyaluminum, and aluminum oxide. Antidiarrheal drugs contain aluminum magnesium silicate and kaolin, an aluminum salt. Cake mixes, self-rising flour, processed cheese, baking powder, food starch modifiers, pickling salts and anti-caking agents provide additional aluminum in the form of sodium aluminum, sodium aluminum sulfate, aluminum ammounium sulfate, and sodium aluminum silicate. Aluminum contaminates drinking water, milk and other products.

--------------------------------------------------------------------------------
The Problem of Aluminum Cookware
One wonders why aluminum cookware, as opposed to stainless steel, was introduced in the United States in the first place. Along with aluminum foil, cookware made of aluminum is a significant source of excess aluminum in the diet. Boiling water in aluminum containers, especially water containing acidic substances, causes aluminum to leach into the water and food. Water containing fluorides encourages the leaching process from aluminum cookware.

Water containing 1ppm fluoride[The usual level of fluoride in public water supplies.], boiled for ten minutes in an aluminum pot, will increase the concentration of aluminum to 200 ppm. Prolonged boiling can increase the concentration to 600 ppm.[Tennakone et al., "Aluminum leaching from cooking utensils" Nature, Vol 325, January 15-21, 1987.] Add acidic food (tomato sauce, for example) and it even goes higher. In addition, as we see in the chapter in fluorides, the presence of aluminum increases the negative effects of fluorides (which is why fluoride toothpaste comes in aluminum tubes). Since the scientific data has been around for some time on all these issues, it cannot be anything but intentional. Aluminum cookware has been around since the late 1920's.

--------------------------------------------------------------------------------
The Effect of Aluminum on the Human Brain
In order to prove that all of this is intentional, we have to prove that it was known early enough that aluminum causes a problem. One would assume that indications of negative effect would preclude introduction of aluminum cookware. Not in the United States. German experiments done in 1897 , where aluminum was analyzed for pathological reaction in animals, showed that aluminum is a selective neurotoxin and a nerve cell poison of specific affinity for the brain.[ Doellken, P. "Ueber die wirkung des aluminum mit sonder beruecksichtigung der durch das aluminum verursachten lasionen im zentralnervensystem" Naunyn-Schmiedebergs Arch Exper Path Pharmakol 40:58-120, 1897.] Exposure of the central nervous system to aluminum salts produces a progressive encephalopathy.[ Munoz-Garcia et al, "An immunocytochemical comparison of cytoskeletal proteins in aluminum-induced and Alzheimer-type neurofibrillary tangles." Acta Neuropathology Vol 70, 1986, p.243-248. Now we see that aluminum deposition produces encephalopathy, vaccines produce encephalopathy, fluorides and mercury amalgams produce encephalopathy, and they knew about all of it early on. Someone or some group in high position, more than 70 years ago, intentionally planned to use the United States as a testing ground for all of this, ultimately resulting in a sociopathic society pleading for totalitarian control. They knew about the effect of mercury and vaccines in 1926. It's in the medical literature. All of this is not an accident. Are you going to stand by and not take responsibility for your health and the health of those you love? The government isn't, because it's a conflict of interest.]

Earlier we mentioned the fact that a great number of cases of degenerative brain diseases in Guam drew the curiousity of researchers. Ten percent of the total population of native Guamanians die of brain disease. Fifteen percent of the natives in the Mariana Islands die of neurodegenerative disease. Why? Part of the answer is that there are high levels of aluminum in the drinking water. There are also high levels of aluminum in the food.[Perl, D., et al., "The association of aluminum, Alzheimer's disease, and neurofibrillary tangles" Journal of Neural Transmutation, Vol 24, 1987, pp.205-211; Dalton et al, "Aluminium and calcium in soil and food from Guam, Palau and Jamaica: implications for ALD and Parkinsonism-dementia syndromes of Guam", Brain, Vol 112, 1989, p. 45-53.]

--------------------------------------------------------------------------------
Aluminum Interaction With Brain Chemicals
Aluminum is a potent inhibitor of the uptake of choline and dopamine.[ Banks, W., et al., "Aluminum increases permeability of blood-brain barrier to labelled DSIP and beta-endorphin: possible implications for senile and dialysis dementias" Lancet Vol 26, Hov 1983, p.1227 ; Guest, J., et al., "The effects of aluminum on sodium-potassium-activated adenosine triphosphatase activity and choline uptake in rat brain synaptosomes" Biochemical Pharmacology, Vol 29, 1980, p.141; Davison, A., et al., "Differences in the inhibitory effect of aluminum 3+ on the uptake of dopamine by synaptosomes from forebrain and from striatum of the rat", Biochemical Pharmacology, Vol 30, 1981, p.3123-3125.] Both are vital chemicals released during nerve inpulse transmission, as well as nerve impulse conduction to muscles and various glands. As a result, the presence of aluminum ions in the brain has an adverse impact on thought and reasoning processes, as well as short-term memory. Furthermore, there is significant evidence that aluminum ions alter enzymes involved with acetylcholine metabolism,[ Wong, P.C., et al., "The effects of aluminum on the methylation of phospolipids in the rat brain synaptosomal membrane", Biochemical Pharmacology, Vol 30, 1981, p.1704; Simpson, J., et al, "Cholinergic enzymes in neurofibrillary degeneration produced by aluminum", Brain Research, Vol 197, 1980, p. 269-274. affecting interplay between thought processes and motor coordination, resulting in ataxia and other serious problems so obvious in those with Alzheimer syndrome and other "senile" degenerative conditions.
 

Babies Motor Better with Breast Milk Janet Raloff
http://www.sciencenews.org/articles/20061007/food.asp

{More of mothers milk and less of vaccines.............??}

Physicians have been advocating for years that breast milk is the best food for infants. Not only does it have the nutrition that babies need, but it also provides some antibodies and growth factors that speed maturation of the infant gut, thereby fending off disease. Now, a team of scientists in Britain offers strong evidence of another benefit. Mother's milk boosts early neurological development.

Social epidemiologist Yvonne J. Kelly of University College London and her colleagues were aware of studies that had suggested neurological benefits from breastfeeding. However, notes Kelly, those earlier analyses tended to be small and done in special populations—such as preemies. They also failed to rule out many factors that might account for differences in a child's developmental skills. Among such possible confounders: race, parent's education, family income, parenting attitudes, depression in the mother, characteristics of childcare, or the baby's overall health. Kelly and her coauthors had access to information on such features for the families of 18,000 infants from throughout the United Kingdom. The scientists also had motor-development data from in-home interviews with the families of those children when each baby was between 8 and 11 months old.

The data were collected as part of the still-ongoing Millennium Cohort Study begun in 2000. Among these children, 9 percent exhibited gross motor delays, which means being late in reaching such major milestones as sitting up, proficient crawling, or standing. Six percent also showed delays in fine-motor coordination—such as clapping hands, transferring an object from one hand to another, or efficiently using the thumb and forefinger like pincers to pick things up. Only 1 percent of the infants showed both types of delays, the scientists report in the September Pediatrics. When the researchers began their work, they were skeptical of a link between breastfeeding and motor skills. "Although we thought we'd initially see some kind of effect, we had expected to be able to later explain it all away when we [adjusted for] covariants," such as a family's income or mother's mental health, Kelly says. To the researchers' surprise, Kelly notes, children "were about 50 percent less likely to have a [developmental] delay if they had prolonged, exclusive breastfeeding when compared to those who were never breastfed." They defined breastfeeding as prolonged when it had lasted at least 4 months. Even babies receiving mother's milk for a short while—2 months or less—were 30 percent less likely to have a developmental delay than those who received solely infant formula, beginning right after birth.

 

Aluminum-induced mitochondrial dysfunction leads to lipid accumulation in human hepatocytes: a link to obesity
Mailloux R, Lemire J, Appanna V.
Cell Physiol Biochem. 2007;20(5):627-38.


Mitochondrial dysfunction is the cause of a variety of pathologies associated with high energy-requiring tissues like the brain and muscles. Here we show that aluminum (Al) perturbs oxidative-ATP production in human hepatocytes (HepG2 cells). This Al-induced mitochondrial dysfunction promotes enhanced lipogenesis and the accumulation of the very low density lipoprotein (VLDL). Al-stressed HepG2 cells secreted more cholesterol, lipids and proteins than control cells. The level of apolipoprotein B-100 (ApoB-100) was markedly increased in the culture medium of the cells exposed to Al. (13)C-NMR and HPLC studies revealed a metabolic profile favouring lipid production and lowered ATP synthesis in Al-treated cells. Electrophoretic and immunoblot analyses pointed to increased activities and expression of lipogenic enzymes such as glycerol 3-phosphate dehydrogenase (G3PDH), acetyl CoA carboxylase (ACC) and ATP-citrate lyase (CL) in the hepatocytes exposed to Al, and a sharp diminution of enzymes mediating oxidative phosphorylation. D-Fructose elicited the maximal secretion of VLDL in the Al-challenged cells. These results suggest that the Al-evoked metabolic shift favours the accumulation of lipids at the expense of oxidative energy production in hepatocytes. Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17762189
 

The Doctor's Corner
National Vaccine Information Center

Aluminum and Vaccine Ingredients:
What Do We Know? What Don’t We Know?

by Lawrence B. Palevsky, MD, FAAP
 

Thimerosal, which contains the organic compound ethyl mercury, is a known neurotoxin and used to be a major ingredient in childhood vaccines. There are over 15,000 articles in the medical literature describing the adverse health effects on the human body with exposure to varying amounts and forms of mercury.

In 1999 the American Academy of Pediatrics (AAP) urged government agencies to work rapidly toward reducing children's exposure to mercury from all sources. Because any potential risk was of concern, the AAP and the USPHS (United States Public Health Service) agreed that the use of thimerosal-containing vaccines should be reduced or eliminated.[1] The AAP recommended that it would be a good idea to remove thimerosal from vaccines, even though according to them, there was no evidence linking childhood health issues to thimerosal exposure from vaccines. In 2008, children are still being injected with thimerosal-containing vaccines, and old stocks of thimerosal-containing vaccines manufactured by 1999 continued to be administered to children up to 2003.

However, a growing number of physicians, scientists and parents maintain that thimerosal has played, and continues to play a large role in contributing to the emergence of multiple chronic illnesses in children and adults, including the neurological spectrum disorders. Aluminum, which is present in the environment and in many childhood vaccines, may be affecting the health of our children in ways that we have yet to understand.

Aluminum is a heavy metal with known neurotoxic effects on human and animal nervous systems. It can be found in the following childhood vaccines – DTaP, Pediarix (DTaP-Hepatitis B-Polio combination), Pentacel (DTaP-HIB-Polio combination), Hepatitis A, Hepatitis B, Haemophilus influenzae B (HIB), Human Papilloma Virus (HPV), and Pneumococcal vaccines.[2]

In 1996, the American Academy of Pediatrics issued a position paper on Aluminum Toxicity in Infants and Children which stated in the first paragraph, “Aluminum is now being implicated as interfering with a variety of cellular and metabolic processes in the nervous system and in other tissues.[3]

A review of the medical literature on aluminum reveals a surprising lack of scientific evidence that injected aluminum is safe. There is limited understanding of what happens to children when aluminum is injected into their bodies, including whether or not it accumulates in tissues and organs or is properly eliminated from the body. It is also unknown if genetic factors affect long term adverse health outcomes for those injected with aluminum containing vaccines.

One in 6 children under the age of 18 in this country has developmental/learning disabilities, although the numbers may be higher since this 1994 report was published.[4] Ten percent of all children have asthma.[5] Growing numbers of children are living with different types of allergies. That means they have impairment, or even irreversible damage to their nervous and immune systems. Isn’t it possible that injected aluminum plays a role in affecting the health of our children’s nervous and immune systems, as the science we do have seems to suggest?

What is even more concerning is the lack of accepted scientific data explaining whether injected aluminum interacts with other vaccine ingredients to cause harm to our children. Boyd Haley, PhD, Professor Emeritus of Chemistry at the University of Kentucky completed lab experiments showing the damaging effects on nerve cells when he exposed them to aluminum, especially in the presence of other vaccine ingredients like mercury, formaldehyde, and the antibiotic neomycin.[6] [7] His data, however, have been ignored by the scientific, medical and governmental institutions making vaccine policies.[8] The scientific community needs to be doing these experiments in the lab before shooting kids with these ingredients and declaring unequivocal vaccine safety for all children.

Aluminum is added to vaccines as an adjuvant so vaccines will produce a stronger antibody response and be more protective. It is this role as an adjuvant that may reveal to us the most significant relationship between aluminum in vaccines and the damage it imparts on the long term health of our children’s nervous and immune systems.

A Little Science Review

Children are born with a cellular mediated immune system (TH1 cells – T-helper 1), a humoral immune system (TH2 cells – T-helper 2), and a regulator immune system (TH3 cells – T-helper 3) as major pieces of their overall immune systems. These three arms are immature when babies are born, and begin to mature as children are exposed to their environments through their nervous systems, skin, airways and intestines. Antibiotics, poor nutrition, stress, exposure to heavy metals and other environmental toxins, and the use of vaccines, may interfere with the proper maturing process of these three arms of children’s immune systems. In theory, if the TH system is allowed to mature, and is not interfered with, children will develop a mature, balanced TH1, TH2 and TH3 immune system by age three.

TH1 and TH2 develop to protect children from the outside world, producing inflammation and anti-inflammation responses to foreign particles from the natural environment. TH3 immune cells develop to keep the TH1/TH2 arms of the immune system in check so the body only produces the amount of inflammation and anti-inflammation that is needed to protect itself from exposures in the natural environment.

When TH2 cells are activated properly, either directly via the natural environment, or through a direct signal from the TH1 system, the B cell arm of the immune system is then stimulated, leading to the production of the desired protective antibodies.[9] [10]

It’s important for the reader to know that the hallmark of a healthy, mature immune system in children is demonstrated by an equal and balanced TH1, TH2 and TH3 immune response to the natural environment. TH1, TH2 & TH3 do not work independently, and require a very important synergistic relationship to function properly in our bodies. As soon as one or more of these three arms begins to over or under work in relation to the other, chronic illness begins to express itself.

More on Aluminum

Aluminum is placed in the vaccines to selectively target the up-regulation of the humoral arm (TH2 cells) of children’s immune systems, to drive the production of antibodies. The medical community leads us to believe that this production of antibodies is what imparts for children a protective nature against vaccine-preventable illnesses. Yet, this outcome may come at a cost.

There are multiple articles in the medical literature demonstrating how chronic illnesses like allergies,[11] [12] asthma, [13] [14] [15] eczema,[16] lupus, [17] inflammatory bowel disease, [18] ADD/ADHD[19] and autism[20] all exhibit a skewed production and over-activity of the TH2 arm of the immune system.

Similarly, chronic illnesses like juvenile diabetes mellitus[21] [22] and rheumatoid arthritis,[23] multiple sclerosis,[24] uveits,[25] inflammatory bowel disease,[26] and autism[27] [28] all exhibit skewed production and over-activity of the TH1 arm of the immune system.

While aluminum in the vaccines is specifically targeting the over-activation of TH2 to encourage the body to produce antibodies, any direct or indirect effect of aluminum on the health or maturation of the TH1 or TH3 system is unknown. Yet, in many of these TH2 dominant chronic illnesses, TH1 and TH3 have also been shown to exhibit an impaired immune response to the environment.[29]

Any direct or indirect effect on the health or maturation of the TH1, TH2 and TH3 arms of children’s immune systems from any of the injected vaccine ingredients, either due to their individual action, or due to their combined interaction, is unknown as well.

The important synergistic, balanced activity of TH1, TH2 and TH3, in response to the environment is dysfunctional and impaired in all chronic illnesses. Children are not necessarily born with this dysfunction or impairment, although they may inherit the susceptibility from their parents. How then, do children develop the expression of these TH1, TH2, TH3 impairments, into what we describe as chronic illness?

What is clear is aluminum pushes the TH2 immune system to over perform, and multiple chronic illnesses in children show immune systems where the TH2 immune response over performs, while TH1 and TH3 responses are also impaired. Is there a connection? By having this type of effect on the TH2 system, is aluminum in any way contributing to the development of these chronic illnesses in children; especially in those children from families with a genetic history of the above mentioned chronic illnesses?

Does aluminum also affect the TH1 immune response, unbeknownst to scientists, clinicians and parents? Does aluminum play a role in impairing the overall synergistic, balanced activity of TH1, TH2 and TH3, which is a requirement for a healthy immune system response to the natural environment? There is no scientific evidence to clarify our understanding one way or the other, but the evidence may be right in front of us to conclude otherwise.

Aluminum forces the undeveloped and immature immune system of infants and children to produce greater amounts of humoral immune cells (TH2) and antibodies, before their immune systems have a chance to adapt to the world in which they’ve barely had a chance to live in.

Under these circumstances, the activity of aluminum appears to play a vital role in disrupting the maturation of the immune system in infants and children through its effects on TH2 and therefore, on TH1 and TH3.

What effect this has on their overall health in the short or long term is unknown, but this model appears to help us understand how we may be contributing to the development of chronic illness in infants and children with the use of aluminum in vaccines. We also have little understanding of what might happen to the overall health of their immune systems if parents wait until later in life to expose them to vaccines containing aluminum, or if they’re exposed in smaller doses one at a time.

How much of a role does injected aluminum play, either acting alone, or in conjunction with other vaccine ingredients and environmental toxins, in the selection and subsequent development of chronic illnesses, in a susceptible population of children, through the disruption of TH1, TH2, TH3? There is no science to answer this question because no one has investigated this issue.

We have no scientific studies in infants, children or adults to help us understand the nature of the progression of TH1, TH2 and TH3 immune responses to any of the injected materials in vaccines.

You cannot do research on questions that enough people don’t believe is worth asking, or are afraid of what the answers might show if the proper studies were done.

It is unfortunate that we continue to drag out this dialogue by singling out each individual vaccine ingredient as a detriment to the health of our children. First thimerosal needed to be removed, despite contentions from the medical community that there were any real medical reasons to do so, and now aluminum. According to Environmental Defense[30] (formerly known as the Environmental Defense fund), all the vaccine ingredients are poisonous, carcinogenic or potentially harmful to the skin, gastrointestinal, pulmonary, immune and neurological systems in our bodies.

What about formaldehyde? Are we going to wait until another brave physician or scientist writes about the damaging effects of injected vaccine-containing formaldehyde on our children’s brains before we are called to demand that formaldehyde be removed? Or about the problems associated with having Polysorbate-80 in the vaccines?

Polysorbate-80 is used in pharmacology to assist in the delivery of certain drugs or chemotherapeutic agents across the blood-brain-barrier. What viral, bacterial, yeast, heavy metal or other vaccine containing ingredient need to pass into the brains of our children? Do they belong in the brain? Is that part of the needed immune response to protect our children from disease? Do vaccine materials pass across the blood-brain barrier with the help of Polysorbate-80? If so, are there complications from being in the brains of our children? Is this another connection to help us get an understanding of why 1 in 150[31] children have autism, or 1 in 6 children has developmental/learning disabilities?

If we’re going to do justice to the topic of vaccine ingredients, we need to look at the potential harm of all the vaccine ingredients at once, and examine their individual effects on our children’s immune and nervous systems. Then, we can examine the interactive effects of the vaccine ingredients on human tissue, and evaluate the potential for harm, as Dr. Haley has already successfully done.

How many more children need to be potentially harmed before we invoke the precautionary principle and the Hippocratic Oath – First, Do No Harm? If there’s no adequate science, and we have positive evidence of toxicity from aluminum, injected alone or in conjunction with other ingredients, and we have a potential model to understand why certain chronic conditions may be developing in a susceptible population of children, then injecting aluminum containing vaccines into anyone should stop right now until we have the proper scientific proof we need to say otherwise. We need the same scientific proof of safety for all vaccine ingredients and their interactions, and we need parents, scientists and practitioners to stand up and demand nothing less before we make matters worse.

Lawrence B. Palevsky, MD, FAAP
Pediatrician

_______________________________________________________________________

1 PEDIATRICS Vol. 104 No. 3, September 1999, pp. 570-574 [Return]
2 MOTHERING No. 146, January-February 2008, pp. 46-53 [Return]
3 PEDIATRICS Vol. 97, 1996, pp. 413-416 [Return]
4 PEDIATRICS, Vol. 93 No. 3, 1994, pp 399-403 [Return]
5 AMA, Vol. 297, No. 24, June 27, 2007,pp. 2755-2759 [Return]
6 General Vaccine Issues: Mercury, Thimerosal and Neurodevelopmental Outcomes: Affidavit of Boyd E. Haley, PhD, Professor and Chair, University of Kentucky [Return]
7 http://www.whale.to/m/haley.html [Return]
8 http://www.safeminds.org/pressroom/press_releases/2005-07-01-Haley-IOM-Response.pdf [Return]
9 IMMUNOLOGY RESEARCH, Vol. 20, 1999, pp.147-161 [Return]
10 ALTERNATIVE MEDICINE REVIEW, Vol. 8, No. 3, August 2003, pp. 223-246 [Return]
11 CLINICAL OPINION IN CLINICAL ALLERGY and IMMUNOLOGY, Vol. 3, No. 3, 2003, pp.199-203 [Return]
12 JOURNAL of ALLERGY and CLINICAL IMMUNOLOGY, Vol. 113, No. 3, 2004, pp. 395-400 [Return]
13 JOURNAL of ALLERGY and CLINICAL IMMUNOLOGY, Vol. 111, 2003, pp. 450-463 [Return]
14 ANNUAL REVIEW OF MEDICINE, Vol. 53, 2002, pp. 477-498 [Return]
15 RESPIRATORY RESEARCH, Vol. 2, No. 2, 2001, pp. 80-84 [Return]
16 CLINICAL and EXPERIMENTAL ALLERGY, Vol. 32, No. 5, 2002, pp. 796-802 [Return]
17 SCANDANAVIAN JOURNAL of RHEUMATOLOGY, Vol. 27, No. 3, 1998, pp. 219-224 [Return]
18 WORLD JOURNAL of SURGERY, Vol. 22, No. 4, 1998, pp. 382-389 [Return]
19 ANNALS of ASTHMA, ALLERGY and IMMUNOLOGY, Vol. 6, No. 6 Suppl 3, 2003, pp. 71-76 [Return]
20 INTERNATIONAL REVIEW OF NEUROBIOLOGY, Vol. 71, 2005, pp. 317-341 [Return]
21 JOURNAL of AUTOIMMUNITY, Vol. 11, No. 6, 1998, pp. 635-642 [Return]
22 JOURNAL of IMMUNOLOGY, Vol. 162, No. 5, 1999, pp.2511-2520 [Return]
23 BAILLERE’S BEST PRACTICE & RESEARCH. CLINICAL RHEUMATOLOGY, Vol. 15, No. 5, 2001, pp. 677-691 [Return]
24 BRAZILIAN JOURNAL of MEDICAL and BIOLOGICAL RESEARCH, Vol. 31, No. 1, 1998, pp. 55-60 [Return]
25 IMMUNOLOGIC RESEARCH, Vol. 23, No. 1, 2001, pp. 59-74 [Return]
26 INFLAMMATORY BOWEL DISEASE, Vol. 12, Suppl 1, 2006, pp. S3-9 [Return]
27 JOURNAL of NEUROIMMUNOLOGY, Vol. 172, No. 1-2, 2006, pp. 198-205 [Return]
28 JOURNAL of PEDIATRICS, Vol. 146, No. 5, 2005, pp. 605-610 [Return]
29 CRITICAL REVIEWS in IMMUNOLOGY, Vol. 25, No. 2, 2005, pp. 75-102 [Return]
30 http://www.environmentaldefense.org [Return]
31 http://www.cdc.gov/ncbddd/autism/documents/AutismCommunityReport.pdf [Return]

Toxicol Lett. 2008 May 30;178(3):160-6. Epub 2008 Mar 27

Alumina nanoparticles induce expression of endothelial cell adhesion molecules.
Oesterling E, Chopra N, Gavalas V, Arzuaga X, Lim EJ, Sultana R,
Butterfield DA, Bachas L, Hennig B.

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, United States.

Nanotechnology is a rapidly growing industry that has elicited much concern because of the lack of available toxicity data. Exposure to ultrafine particles may be a risk for the development of vascular diseases due to dysfunction of the vascular endothelium. Increased endothelial adhesiveness is a critical first step in the development of vascular diseases, such as atherosclerosis. The hypothesis that alumina nanoparticles increase inflammatory markers of the endothelium, measured by the induction of adhesion molecules as well as the adhesion of monocytes to the endothelial monolayer, was tested. Following characterization of alumina nanoparticles by transmission electron microscopy (TEM), electron diffraction, and particle size distribution analysis, endothelial cells were exposed to alumina at various concentrations and times. Both porcine pulmonary artery endothelial cells and human umbilical vein endothelial cells showed increased mRNA and protein expression of VCAM-1, ICAM-1, and ELAM-1. Furthermore, human endothelial cells treated with alumina particles showed increased adhesion of activated monocytes. The alumina particles tended to agglomerate at physiological pH in serum-containing media, which led to a range of particle sizes from nano to micron size during treatment conditions. These data show that alumina nanoparticles can elicit a proinflammatory response and thus present a cardiovascular disease risk.

PMID: 18456438

 

http://sciencenow.sciencemag.org/cgi/content/full/2008/521/4
Vaccine Booster's Secret Revealed
By Martin Enserink
ScienceNOW Daily News
21 May 2008

For decades, scientists have known that they can make vaccines much more efficacious by adding aluminum compounds, but they never knew why. Now, a study reveals how, on a molecular level, these helpers spur the production of antibodies. The finding may help researchers develop better vaccines.
Many vaccines contain adjuvants, nonspecific agents that help jolt the immune system into action. "Alum," a term referring broadly to aluminum hydroxide and several aluminum salts, has this effect, as was accidentally discovered in the 1920s. It has been widely used in human vaccines since the 1950s, and it's still the only adjuvant allowed in the United States. "But we didn't really have a clue about how it worked," says immunologist Harm HogenEsch of Purdue University's School of Veterinary Medicine in West Lafayette, Indiana. The dominant theory held that alum particles bind the antigen--the vaccine's main ingredient--on their surfaces, presenting them more slowly to the immune system and thus ensuring a more thorough response.

But the situation is more complicated than that. Last year, HogenEsch's team and a group led by Fabio Re at the University of Tennessee Health Science Center in Memphis showed that in macrophages--white blood cells that gobble up pathogens and cellular detritus--alum triggers the production of interleukin 1β and interleukin 18, two key signaling molecules, or cytokines, known to stimulate the production of antibodies. Researchers knew that this duo is often released after the activation of so-called NOD-like receptors. "So then the race was on," says Re, to pinpoint which NOD-like receptor was involved.

That race was won by a team led by Richard Flavell of Yale University. In this week's issue of Nature, Flavell's group reports that aluminum adjuvants trigger a NOD-like receptor called the Nalp3 inflammasome--an intracellular protein structure that plays a key role in immune activation. When the group injected mice lacking Nalp3 with an alum-boosted vaccine, they produced almost no antibodies; but a vaccine with another adjuvant called Freund's resulted in the usual, vigorous immune response. Re says he will publish the same result in a paper accepted by the Journal of Immunology, which also shows that two other adjuvants--QuilA and chitosan--work in the same way.

The Nalp3 inflammasome is known to be activated by compounds of microbial origin and also by molecules that appear when cells die, such as uric acid. So researchers think that Nalp3 is like a "danger sensor," says Yale immunologist Stephanie Eisenbarth, the first author on the Nature paper. Alum-containing vaccines may simply "hijack" that response.

Knowing how alum works its magic may help researchers design more specific adjuvants that are more effective or have fewer side effects, HogenEsch says. Alum, for instance, is known to kill muscle cells when injected into muscles, as many vaccines are.
 

Macrophagic Myofasciitis in Children Is a Localized Reaction to Vaccination
Boleslaw Lach, MD, PhD, FRCPC1* and Edward J. Cupler, MD2
1 Department of Pathology and Laboratory, Medicine King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia


* To whom correspondence should be addressed. E-mail: lach@hhsc.ca.

Abstract
Macrophagic myofasciitis is a novel, "inflammatory myopathy" described after a variety of vaccinations, almost exclusively in adults. We examined the relevance of histological findings of this myopathy to the clinical presentation in pediatric patients. Muscle biopsies from 8 children (7 months to 6 years old) with histological features of macrophagic myofasciitis were reviewed and correlated with the clinical manifestations. Patients underwent quadriceps muscle biopsy for suspected mitochondrial disease (4 patients), spinal muscular atrophy (2 patients), myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All biopsies showed identical granulomas composed of periodic acid-Schiff–positive and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were identified by electron microscopy in 2 cases. The biopsy established diagnoses other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2), Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and cytochrome c oxidase deficiency (1). Three children with manifestations and/or a family history of mitochondrial disease had otherwise morphologically normal muscle. All children had routine vaccinations between 2 months and 1 year before the biopsy, with up to 11 intramuscular injections, including the biopsy sites. There was no correlation between histological findings of macrophagic myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic myofasciitis represents a localized histological hallmark of previous immunization with the aluminum hydroxide adjuvants contained in vaccines, rather than a primary or distinct inflammatory muscle disease.

 

Toxicol Lett. 2008 May 30;178(3):160-6. Epub 2008 Mar 27

Alumina nanoparticles induce expression of endothelial cell
adhesion molecules.
Oesterling E, Chopra N, Gavalas V, Arzuaga X, Lim EJ, Sultana R,
Butterfield DA, Bachas L, Hennig B.

Graduate Center for Toxicology, University of Kentucky,
Lexington, KY 40536, United States.

Nanotechnology is a rapidly growing industry that has elicited much concern because of the lack of available toxicity data. Exposure to ultrafine particles may be a risk for the development of vascular diseases due to dysfunction of the vascular endothelium. Increased endothelial adhesiveness is a critical first step in the development of vascular diseases, such as atherosclerosis. The hypothesis that alumina nanoparticles increase inflammatory markers of the endothelium, measured by the induction of adhesion molecules as well as the adhesion of monocytes to the endothelial monolayer, was tested. Following characterization of alumina nanoparticles by transmission electron microscopy (TEM), electron diffraction, and particle size distribution analysis, endothelial cells were exposed
to alumina at various concentrations and times. Both porcine pulmonary artery endothelial cells and human umbilical vein endothelial cells showed increased mRNA and protein expression of VCAM-1, ICAM-1, and ELAM-1. Furthermore, human endothelial cells treated with alumina particles showed increased adhesion of activated monocytes. The alumina particles tended to agglomerate at physiological pH in serum-containing media, which led to a range of particle sizes from nano to micron size during treatment conditions. These data show that alumina nanoparticles can elicit a proinflammatory response and thus present a cardiovascular disease risk.

PMID: 18456438

 

Aluminum Toxicity
(Aluminum Poisoning)
by Krisha McCoy, MS

http://www.med.nyu.edu/patientcare/library/article.html?ChunkIID=164929


Definition
Aluminum toxicity occurs when a person breathes in high levels of aluminum from the air, or stores high levels of aluminum in the body.

Aluminum is the most abundant metal in the earth’s crust, and is present in the environment combined with other elements (eg, oxygen, silicon, fluorine). Exposure to aluminum is usually not harmful, but exposure to high levels can cause serious health problems. If you suspect you have been exposed to high levels of aluminum, contact your doctor.

*
Causes
Because aluminum is found in virtually all food, water, air, and soil, people may be exposed to high levels of aluminum when they:

Eat foods containing high levels of aluminum
Breath aluminum dust in workplace air
Live in dusty environments
Live where aluminum is mined or processed
Live near certain hazardous waste sites
Live where aluminum is naturally high
Receive vaccinations containing aluminum
*
Risk Factors
Anyone can develop this condition, but certain people are more likely to develop aluminum toxicity. The following factors increase your chances of developing aluminum toxicity. If you have either of these risk factors, tell your doctor:

Age: older people
Diminished kidney function
*
Symptoms
If you experience any of these symptoms, do not assume it is because of aluminum toxicity. These symptoms may be caused by other, less serious health conditions. If you experience any one of them, see your physician, especially if you have kidney disease or are on dialysis .

Muscle weakness
Bone pain
Fractures that do not heal, especially in ribs and pelvis
Altered mental status
Premature osteoporosis
Anemia
Impaired iron absorption
Impaired immunity
Seizures
Dementia
Growth retardation in children
Spinal deformities: scoliosis or kyphosis
Red Blood Cells

These vital cells transport oxygen through the body. Symptoms of aluminum toxicity such as anemia and impaired iron absorption decrease the number of red blood cells.

© 2009 Nucleus Medical Art, Inc.

*
Diagnosis
Your doctor will ask about your symptoms and medical history, and perform a physical exam.

Tests may include the following:

Deferoxamine infusion test
X-ray of long bones
Blood test for anemia
Bone biopsy to measure aluminum levels
*
Treatment
Talk with your doctor about the best treatment plan for you. Treatment options include:

Medications
The medication, deferoxamine mesylate, may be given to help eliminate aluminum from your body. This substance works through a procedure known as chelation, which assists in ridding the body of poisonous materials.

Aluminum Avoidance
Your doctor can instruct you on how to avoid exposure to aluminum from your diet and other sources.

*
Prevention
To help reduce your chances of getting aluminum toxicity, take steps to avoid the following, which may contain aluminum:

Antacids
Antiperspirants
Dialysate (the solution of chemicals used in dialysis)
Immunizations
TPN (total parenteral nutrition) solutions
Last reviewed November 2008 by Marcin Chwistek, MD

Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.

Copyright © 2009 EBSCO Publishing. All rights reserved.

 

 Web address:
http://www.sciencedaily.com/releases/2007/08/
070831210302.htm

Aluminum In Breast Tissue: A Possible Factor In The Cause Of Breast Cancer
ScienceDaily (Sep. 2, 2007) — A new study has identified a regionally-specific distribution of aluminium in breast tissue which may have implications for the cause of breast cancer.

Scientists have found that the aluminium content of breast tissue and breast tissue fat was significantly higher in the outer regions of the breast, in close proximity to the area where there would be the highest density of antiperspirant.

Recent research has linked breast cancer with the use of aluminium-based, underarm antiperspirants. The known, but unaccounted for, higher incidence of tumours in the upper outer quadrant of the breast seemed to support such a contention. However, the identification of a mechanism of antiperspirant-induced breast cancer has remained elusive.

A team, led by Dr Chris Exley of the Birchall Centre for Inorganic Chemistry and Materials at Keele University in the UK, measured the aluminium content of breast tissue from 17 breast cancer patients recruited from Wythenshaw Hospital, Manchester, UK. Whether differences in the distribution of aluminium in the breast are related to the known higher incidence of tumours in the outer upper quadrant of the breast remains to be ascertained.

The major constituent of antiperspirant is aluminium salts which have long been associated with cancer, as well as other human disease. The daily application of aluminium-based antiperspirants should result in the presence of aluminium in the tissue of the underarm and surrounding areas, though there is almost no data on aluminium in breast tissue.

Breast cancer is the most common malignancy in women and is the leading cause of death among women aged 35-54. The cause of breast cancer is unknown and is likely to be a combination of generic and environmental factors.

Each of the patients in the study had undergone a mastectomy and biopsies from four different regions of the breast on a transect from the outer (axilla and lateral) to the inner (middle and medial) breast were collected.

Tests showed that while there were significant differences in the concentrations of aluminium between individuals they did show “a statistically higher concentration of aluminium in the outer as compared with the inner region of the breast”.

The report, published in the Journal of Inorganic Biochemistry, goes on: “We have confirmed the presence of aluminium in breast tissue and its possible regional distribution within the breast. Higher content of aluminium in the outer breast might be explained by this region’s closer proximity to the underarm where the highest density of application of antiperspirant could be assumed. There is evidence that skin is permeable to aluminium when applied as antiperspirant.

“However, we have no direct evidence that the aluminium measured in these breast biopsies originated from antiperspirant. An alternative explanation might be that tumourous tissue acts as a ‘sink’ for systemic aluminium”.

But it goes on to say that “aluminium in breast tissue might contribute” to breast cancer.

“Aluminium is a metalloestrogen, it is genotoxic, is bound by DNA and has been shown to be carcinogenic. It is also a pro-oxidant and this unusual property might provide a mechanistic basis for any putative carcinogenicity. The confirmed presence of aluminium in breast tissue biopsies highlights its potential as a possible factor in the aetiology of breast cancer”.


--------------------------------------------------------------------------------

Adapted from materials provided by Keele University, via AlphaGalileo.

Keele University (2007, September 2). Aluminum In Breast Tissue: A Possible Factor In The Cause Of Breast Cancer. ScienceDaily. Retrieved May 21, 2009, from http://www.sciencedaily.com­ /releases/2007/08/070831210302.htm

http://qjmed.oxfordjournals.org/content/55/2/127.full.pdf

 

Quarterly Journal of Medicine, New Series 55, No. 21 7, pp. 127-144, May 1985
The Pathogenesis of Renal Osteodystrophy: Role of Vitamin D, Aluminium, Parathyroid Hormone, Calcium and Phosphorus
C. R. DUNSTAN, ELLEN HILLS, A. W. NORMAN, JUNE E. BISHOP, E. MAYER,
S. Y. P. WONG, J. R. JOHNSON, C. R. P. GEORGE, P. COLLETT, S. KALOWSKI,
R. WYNDHAM, J. R. LAWRENCE and R. A. EVANS
From the Metabolic and Renal Units, Concord Hospital, Sydney the Renal Units,
Royal Prince Alfred Hospital and Mater Misericordiae Hospital, Syndey, Australia,
and the Department of Biochemistry, University of California, Riverside, USA
Accepted 15 October 1984
SUMMARY
Biochemical data and bone histology from 44 haemodialysis patients was compared using an
histologic technique capable of evaluating separately the individual components of osteodystrophy.
Hyperparathyroid bone disease was diagnosed by an elevated osteoclast count, and in
advanced disease there was also fibrosis and woven bone. Osteomalacia, defined as an impairment
in the rate of bone mineralisation, was present in two distinct forms: osteomalacia type I,
characterised by wide osteoid seams, and osteomalacia type II, characterised by extensive thin,
inactive osteoid. The histologic diagnoses were hyperparathyroid bone disease (15), osteomalacia
type I (3), osteomalacia type II (6), hyperparathyroid bone disease and osteomalacia type I
(12), hyperparathyroid bone disease and osteomalacia type II (6), normal (2). Aluminium was
evident histochemically in 17 biopsies.
Vitamin D metabolite levels were low in most patients and did not correlate with any biochemical
or histological parameter. Parathyroid hormone levels were highly correlated with
histological features of hyperparathyroid bone disease, and also correlated with plasma calcium,
suggesting a degree of autonomy of parathyroid hormone secretion. Urea and creatinine were
higher in the hyperparathyroid bone disease than the osteomalacia groups suggesting that poor
dialysis contributes to the former. Statistical analysis showed that osteomalacia type I was
associated with relatively low plasma calcium and phosphorus levels; osteomalacia type II was
associated with increased bone aluminium and with the uraemic process itself, as reflected in
the plasma creatinine level.
This study shows relationships between renal osteodystrophy and plasma calcium and phosphorus
levels, but no relationship with vitamin D metabolites. Aluminium appears to impair
mineralisation even at relatively low levels of accumulation. However there are other unidentified
factors associated with the uraemic process, contributing to all three components of renal
osteodystrophy.
Correspondence to: Dr. R. A. Evans; Metabolic Unit, Concord Hospital, NSW 2139, Australia.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
128 C. R. Dunstan and others
INTRODUCTION
The major bone disorders associated with chronic renal failure are hyperparathyroid bone disease
and osteomalacia which occur either alone or in combination. Effective treatment of renal bone
disease commenced in 1943 when Liu and Chu showed that pharmacologic doses of vitamin D
healed renal osteomalacia(l)suggesting that vitamin D resistance was important in its aetiology.
This phenomenon seemed to be explained by the observation that the vitamin D metabolite,
1,25-dihydroxycholecalciferol (1,25(OH)jD), is synthesised in the kidney (2) and that the
levels of 1,25(OH)2 D are reduced in uraemia (3). Following the synthesis of this metabolite (4),
it was administered to uraemic patients in the hope of curing osteomalacia without the problems
of vitamin D resistance, prolonged hypercalcaemia and ectopic calcification which can accompany
treatment with the standard preparations of vitamin D (5, 6). However, even in early
studies it was apparent that the benefits of 1,25(OH)2D were most marked in the treatment of
secondary hyperparathyroidism (5, 7). Also, Slatopolsky et al. produced convincing evidence
that secondary hyperparathyroidism was caused by phosphorus retention (8). In animals,
secondary hyperparathyroidism can be prevented by dietary phosphorus restriction (9), and
reversed by the use of aluminium hydroxide (10). In humans, however, phosphorus restriction
does not reverse established secondary hyperparathyroidism (11), though it does reduce hyperphosphataemia
and hence the likelihood of ectopic calcification.
One major problem with the use of aluminium hydroxide is that aluminium can induce
osteomalacia. This toxicity was first suggested by Ward et al. in 1978 (12), demonstrated
chemically by Alfrey in 1979 (13), and definitively described in 1982 (14-16). Aluminium
enters the body from the dialysing fluid (17), and also from aluminium hydroxide taken orally
(18). Other causes, including a deficiency of 24/?,25-dihydroxcholecalciferol (24,25(OH)2D)
(19) and calcitonin (20), have also been implicated in the development of renal bone disease.
The interpretation of bone histology is central to an understanding of these disorders, and
histologic techniques have improved in recent years. The introduction of tetracycline as a
dynamic marker of bone formation (21), has corrected earlier beliefs that osteomalacia can be
diagnosed by osteoid area alone, and that the extent of bone formation can be simply measured
as osteoid surface. Osteoid-forming surfaces can now be identified by active osteoblasts, and
bone formation (i.e. osteoid mineralisation) is measured by double labelling with tetracycline.
The adequacy of mineralisation can be assessed by relating mineralisation rate to the amount
of osteoid as the 'mineralisation lag time' (22—24). Active bone resorption is now assessed by
osteoclast surface in many laboratories (25—28), though some still accept crenated bone surface,
which reflects both active and previously active resorbing surfaces. Simple histochemical techniques
for identification of aluminium have been shown to correlate well with chemically
measured bone aluminium (15,29), and have become routine practice in many bone laboratories.
With the use of these techniques, hyperparathyroid bone disease is characterised by increased
osteoblast and osteoclast levels and, in the more severe forms, by increased woven bone and
marrow fibrosis. We have found the osteoclast count, which correlates well with parathyroid
hormone level (28) to be the most sensitive method of diagnosis of hyperparathyroid bone
disease. Osteomalacia is characterised by a mineralisation rate which is low in relation to the
amount of unmineralised matrix present. We have previously demonstrated two clearly differing
types: osteomalacia type I, in which osteoid width is increased relative to mineral apposition
rate, and osteomalacia type II, in which the mineralising surface is small relative to the osteoid
surface (30). Osteomalacia type I and osteomalacia type II can co-exist, and can be associated
with hyperparathyroid bone disease, so it is necessary that the histological techniques can
evaluate the three components separately.
Though there are many published studies of bone histology in chronic renal failure, most
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
Pathogenesis of Renal Osteodystrophy 129
have not used tetracycline and few have included specific histochemical stains for osteoclasts
and osteoblasts. There has also been a lack of uniformity of methodology and of histologic
criteria for the different disease patterns. In this study bone biopsies from 44 patients established
on chronic haemodialysis were examined and the findings were compared with the levels of
calcium-regulating hormones and standard plasma biochemistry. The primary aim of the study
was to determine the relationships between postulated aetiologic factors and the differing
histological components of renal osteodystrophy.
METHODS
PATIENTS
Forty-four patients were studied. The patients were aged between 20 and 71 (mean ± SD 52 ± 12)
years; 29 were male and 15 female. They had been treated by chronic haemodialysis for periods
ranging from two to 94 months (mean ± SD 24 ± 22). Bone pain was present in three patients,
of whom two had severe osteomalacia, and the other severe hyperparathyroid bone disease. No
patient was anephric. Thirty patients were dialysed by Redy machines (D31 cartridge) with
Gambro Lundia dialysers (3x6 h/week). The other 14 patients were dialysed by Drake Willock
machines with Travenol hollow fibre dialysers (2x6 h/week). The blood flow was 200—250 ml/
min and dialysate flow 200ml/min. The tap water used for the Drake Willock machines had an
aluminium level of 14±9Mg/l (31), and was not softened. With the Redy cartridge in use at the
time of the study the dialysate aluminium level has been reported to vary between 8 and
38/ig/l (32). The dialysate calcium concentration was 1.6 mmol/1 and magnesium 0.25 mmol/1.
There was no dietary protein restriction. Hyperphosphataemia was treated by the oral adminstration
of aluminium hydroxide. No patient had received vitamin D preparations for at least
one year before study. Two patients had undergone subtotal parathyroidectomy more than one
year before biopsy. The controls for bone histology were six healthy hospital employees, aged
23—43 years (33). The controls for plasma chemistry were 30 healthy hospital employees aged
between 19 and 45 years(mean ± SD 30±8), 11 of whom were male.
BONE BIOPSIES
Tetracycline hydrochloride, 1.5 g, and demeclocycline, 1.2 g, were given orally 24 and three
days respectively before the biopsy, which was taken from the posterior superior iliac spine
with an 8 G Jamshidi trephine (34), on the day following dialysis. The bone sample was fixed
in cold 10 per cent formalin pH 7.0, dehydrated in ethanol and embedded in a methyl
methacrylate—glycol methacrylate medium (28). Four consecutive sections were taken: a 5/xm
section for histochemical staining for acid phosphatase activity (28), a 7jnn section mounted
unstained for tetracycline fluorescence a 5^im section for pyronin staining to show ribonucleic
acid (33), and a 5^im section for staining by the aurin tricarboxylic acid method to show
aluminium accumulation (35). Aqueous toluidine blue was used as a counterstain for the first
and third sections. A further four consecutive sections were taken 200/an further in the block
so that a total section area of 50 mm2 was measured. Osteoclasts were identified by their red
granular cytoplasm in the section stained for acid phosphatase activity (Fig. 1) (28). Osteoblasts
were defined as cells (plump or flat) forming a continuous lining on bone surfaces and showing
intense cytoplasmic pyronin staining (33). Osteoid was defined as unmineralised matrix visible
when viewed at a magnification of x 100. Aluminium was identified as bright red staining along
the bone—osteoid interface and cement lines (Fig. 2) (35). A microscope with a camera lucida
attachment was used to prepare a tracing (magnification x 100) of the superimposed images of
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
130 C. R. Dunstan and others
FIG. 1. Osteoclasts (OC) are readily identifiable by their dark cytoplasm, indicating high acid
phosphatase activity. B = bone. Acid phosphatase stain with toluidine blue counterstain, green
filter, x 500.
FIG. 2. Aluminium deposition shown by histochemical stain. The aluminium is present at the
bone-osteoid interface. Al = aluminium, O = osteoid, B = bone. Green filter, x 100.
the four consecutive sections and the tracing was quantitated with a Hewlett—Packard 9864A
digitiser interfaced to a Hewlett—Packard 9815A desk-top computer (33).
Although methods of calculation have been described previously (33) some aspects should
be explained. Resorption was expressed as osteoclast count per mm2 section area, osteoclast
count per mm bone surface, and as resorbing surface (percentage of bone surface actually in
contact with osteoclasts). The two tetracyclines fluoresced with different colours and it was
possible to identify first and second markers except where they merged. Tetracycline surface was
measured only where the second marker or merged bands were present; single bands of the first
marker were not included. Bone formation rate was determined by multiplying the tetracycline
surface by the mean mineral apposition rate. Osteoid width was measured in two ways: (a)
directly, at lOO^m intervals when both osteoblasts and tetracycline were present (active osteoid
width); (b) indirectly, as osteoid area divided by osteoid surface (mean osteoid width). Similarly
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
Pathogenesis of Renal Osteodystrophy 131
the mineralisation lag time (MLT) was calculated in two ways: (a) directly (MLTd), as previously
described (22, 23), by dividing osteoid width by mineral apposition rate where osteoblasts
and double tetracycline labels were present ;(b) indirectly (MLTi), as described by Nielsen
et al. (24), by dividing osteoid area by bone formation rate.
From the measured variables the biopsies were classified as:
1. Hyperparathyroid bone disease if osteoclast count exceeded the control mean by more
than two standard deviations, i.e. a count of more thanO.7/mm trabecular surface. This measurement
was used because it corrects for surface area and permits inclusion of osteoclasts not in
apposition to the bone surface in the plane of the section.
2. Osteomalacia if the MLTd or MLTi exceeded the control mean by more than two standard
deviations. Two distinct types of mineralisation defect could be identified by this approach:
FIG. 3. Osteomalacia type I, showing wide osteoid seams. O = osteoid, B = bone. Acid phosphatase
stain with toluidine blue counterstain, green filter, X 100.
FIG. 4. Osteomalacia type II, showing narrow osteoid seams with no surface osteoblasts. O:
osteoid, B = bone. Acid phosphatase stain with toluidine blue counterstain, green filter, x 100.
5
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
132 C. R. Dunstan and others
(a) Osteomalacia type I (Fig. 3) where the MLTd was greater than 24 days (i.e. control
mean + 2 SD). In its most severe form, seen in two patients in this study, the osteoid
was very wide and the tetracycline labels merged. For calculation of MLTd in these two
biopsies, a normal mineral apposition rate of 1.0/jm/day was assumed, though in both
cases it was less and the MLTd was underestimated. The MLTi was always increased in
osteomalacia type I.
(b) Osteomalacia type II (Fig. 4) where the MLTi was greater than 67 days (i.e. control
mean + 2 SD), and the MLTd normal. Here the osteoid, though often extensive, was
not wide and the mineral apposition rate was usually normal. The mineralising surface
and osteoblast surface were small relative to the osteoid surface (30).
3. Combined hyperparathyroid bone disease and osteomalacia. This group of patients was
then further classified as hyperparathyroid bone disease + osteomalacia type I, or hyperparathyroid
bone disease + osteomalacia type II.
PLASMA BIOCHEMISTRY
Fasting plasma samples were taken for standard biochemistry at the time of bone biopsy.
Calcium, inorganic phosphorus and alkaline phosphatase were measured on a Technicon autoanalyser
by standard methods, and the plasma calcium was corrected for albumin concentration
(36). A Nova 2 ionised calcium analyser was used to measure ionised calcium in whole blood.
Parathyroid hormone level was measured by radioimmunoassay with a predominantly carboxyterminal-
specific antibody obtained from Dr. E. Slatopolsky, Washington University, St Louis.
The human hyperparathyroid serum used as standard was assigned an arbitrary concentration of
1000jLdEq/ml. By this method, parathyroid hormone is detectable at 1/jLEq/ml, which corresponds
to approximately lOpg/ml of bovine parathyroid hormone. Inter- and intra-assay coefficients
of variation are 13.4 and 17.1 per cent respectively. Calcitonin was measured by radioimmunoassay
(37). The vitamin D metabolites 25-hydroxycholecalciferol (25(OH)D),
1,25(OH)7D and 24,25(OH)3D were measured by previously published methods (38). AU
samples were obtained over an eight-week period in November—January (spring—summer in
Australia).
STATISTICAL ANALYSIS
This was carried out on a PDP 11/03 computer with 'Minitab' (Pennsylvania State University)
programs.
Differences between groups were determined by one-way analysis of variance, with log transformations
carried out on data not showing a normal distribution. For variables with significant
F values, the significance of differences between groups, was determined by a Bonferroni r-test
(39). Because 15 possible comparisons existed between means of the six groups, the level of
significance was set at p< 0.003 (0.05-H 5). Correlations between variables were tested for
significance by linear regression. Multiple linear regression was used to determine the interdependence
of several variables correlating with a pre-selected dependent variable.
RESULTS
HyperparathyToid bone disease alone was present in 15 patients, whilst nine patients had osteomalacia
alone (osteomalacia type I, three; osteomalacia type II, six). Eighteen patients had
hyperparathyroid bone disease + osteomalacia (osteomalacia type I, 12; osteomalacia type II,
six). Two patients had normal bone histology, and their data are excluded from Tables 2—3.
Aluminium deposition was seen in 17 biopsies. Figs. 1—4 show the typical histologic patterns.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
Pathogenesis of Renal Osteodystrophy 133
TABLE 1. Age, dialysis and renal disease in the patient population
Age (years)a
Sex
Male
Female
Dialysis machine
Redy
Drake-Willcock
Dialysis duration (months)a
Renal disease
Analgesic nephropathy
Glomerulonephritis
Diabetic nephropathy
Nephrocalcinosis
Hypernephroma
Reflux nephropathy
Pyelonephritis
Unknown
HPT
( i = 1 5 )
49 ±13
87
10
5
1 7 ± 1 2
7
4

1
-
1
1
1
OMI
(n=3)
45 ±20
i
1
2
1
24 ±6
-
——

1
1
-
1
OMII
(/i =6)
52 ± 1 1
5
1
4
2
24±35

32
1
-



HPT + OMI
(n = 12)
59±4
10
2
8
4
31 ±23
5
5

1
-
1
HPT + OMII
(n =6)
5O±12
2
4
4
2
36 ±26

2
1
-
-
-
-
3
Normal
(n = 2)
54, 71
1
1
i
0
8, 7
-
2
-

-
—-

a Results expressed as mean ± SD. HPT = hyperparathyroid bone disease, OMI = osteomalacia type I; OMII = osteomalacia type II. Table 1 shows patient ages, dialysis type and duration, and underlying renal disease for the different histological appearances. Dialysis method and renal disease did not influence the histological appearance.
Plasma chemistry is shown in Table 2. Calcium levels were similar in all groups. Hyperphosphataemia was most marked in the hyperparathyroid bone disease and hyperparathyroid bone disease + osteomalacia type II groups, which therefore also had the highest calcium-phosphorus product. However, when the groups with hyperparathyroid bone disease were combined they also had higher levels of urea and creatinine than the remaining groups (p < 0.005) (Fig. 5). Phosphorus was low (0.7 and 0.8mmol/l) in the two patients with severe osteomalacia type I, who had been taking moderately large amounts of aluminium hydroxide (4.8, 6.0g/day).
Alkaline phosphatase and parathyroid hormone levels were higher in the groups with hyperparathyroid bone disease than in the other groups. The mean levels of all vitamin D metabolites were low compared to control means, but were similar in all histologic groups. There were no differences in plasma calcitonin levels in the various subgroups, or between all hyperparathyroid bone disease groups combined and the other patients.

Quantitative bone histology is shown in Table 3. The bone was most active metabolically in the hyperparathyroid bone disease groups, where formation, resorption, woven bone and marrow fibrosis increases were seen. Osteoid surface was increased in all groups, and osteoid width was increased in the two osteomalacia type I groups. In the osteomalacia type II group, the osteoblast surface and bone formation rate were low to normal. Of the 17 patients with histochemically detectable aluminium, one had osteomalacia type I, four osteomalacia type II, five hyperparathyroid bone disease + osteomalacia type I, six hyperparathyroid bone disease +
osteomalacia type II and one had hyperparathyroid bone disease. There was no difference in frequency or extent of aluminium deposition in patients treated by the Redy or Drake WUlock
dialysis machines. No double tetracycline label was present at sites of aluminium deposition.
The maximum extent of aluminium deposition was 19.5 per cent of the trabeculai surface.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
TABLE 2. Biochemical data
Calcium (mmol/1)
Phosphorus (mmol/1)
Alkaline phosphatase (iu/l)e
Parathyroid hormone OilEq/ml)e
25(OH)D(ng/ml)
24,25(OH)2D(ng/ml)
l,25(OH),D(pg/ml)
Calcium X phosphorus
Creatinine (mmol/1)
Urea (mmol/1)
Ionized calcium (mmol/1)
Calcitonin (pg/ml)
HPT
(n = 15)
2.43 10.25°
2.310.5"
251±292"
3821325
1617
1.U0 7
23 112
5.6111.24"
0.8410.27"
26.517.9"
1.1710.12"
156151
OMI
(H = 3)
2 38 ±0.19
1.4±0.4c-d
96 ±51
70130
22114
1.411.0
23 ± 1 3
3.2H0.63c ' d
0.56±0.12"
17.414.8"
1.1 U0.18
283 + 248
OM1I
(n =6)
2.48 + 0.27"
1.610.4"'c
89 + 1 1
49126
1216
1.0±0.3
24+14
3.95 ±1.24b-c-
0.62±0.16"
17.8 + 3.6"'°
1.2010.13
184 184
d
HPT + OMI
('i = 12)
2.36 10.20
1 7±0.7"'
279±339b
245 ±262
17112
0.910.5
29110
3.8911 50"
0.8510.25"
23.4 18.4"
1.1610.09"
223 + 112
HPT+OMII
(/> = 6)
Control
c, d
2.5310.21"
2.3 + 0 5 "
3491418"
4091 534
1618
1.2±0 5
20±l 1
5.7O±I.32"
0.75 ±0.14"
24.4 1 7 0"
1.16 10.13
250173
2.30 + 0 04
1.010.2
591 22
0- 15
42110
3.7 ± 1 2
4711 1
2.3010.3 8
0.07 1 0 02
5.311.0
1 221005
0-400
a Results expressed as mean 1 standard deviation;"significantly different from controls; Significantly different from HPT group; dsignificantly
different from HPT + OM2 group;eLog transformed data used for Mest. Abbreviations as in Table 1.
g
s
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
TABLE 3. Quantitative bone histology
HPT
(n = 15)
0M1 OMII
(n =6)
HPT + OMI
(n =12)
HPT + OMII Control
(n=6) («=6)
Area
Bone (% section area)
Woven bone (% bone area)
Fibrosis (% section area)g
Osteoid (% bone area)8
Formation and mineralisation
Osteoid surface (% total surface)*
Tetracycline surface (% osteoid surface)
Osteoblast surface {% total surface)*
Osteoid width-mean (Aim)
Osteoid width-active (nm)
Osteoblasts/osteoclasts
Mineral apposition rate (jim/day)
MLTd (days)
MLTi (days)B
Bone formation rate (jim7 /mm2 /day)E
Resorption
Osteoclasts (per mm2 section area)*
Osteoclasts (per mm total surface)*
Resorbing surface (% total surface)*
Resorption velocity (/L/m/day)
Aluminium
Histochemical stain (% bone surface)*
18±7a
19±15
2.5 ±3.3
5.2±9.3b
46 + 22b
38 ± 13b
19±15
18±5
20 ±5
5.7 ±3.3
1.2 ±0.2
15±5
42 ±12
735±630
5.4±2.6b
1.8 ± 0.7b
3.2±1.0b
7.0±3.9
7 l)h(1V
15+3
13±18
0
23.5 ±12.9b
55 ± 22b
l l ± 1 0 b ' c
5±2
24 ±3
39 + 1 l b - c . d
3.2 ± 1.6
1.1 ±0.3
4 9 ± 2 i b , c , d , e
352 ± 1 52b> c> d
146 + 153
1.5±0.4c
0.6 ±0.1c
1.6 ±0.4
3.7 ±3.9
(13.9)h(l)J
I 5 ± 7
10 + 9
0
8.8±3.1e
3 2 ± l l b ' e
10±7b ' c
2 ± 2 c ' d ' e
15±3e
20±4e - f
3.0 ±1.6
1.1 ±0.3
18 ± 4 e - f
166±74b>c
7 4 ± 6 , c , d , e
0.7±0.4c ' d - e
0.3±0.2c - d - e
0 . 7 ± 0 . 4 c ' d ' e ' f
4.6±2.9
2.7±3.6
(4.0±3.9)h(4)J
23 ±9
22±19b
4.4 ±9.8
27.6 ±9.7b>c
71±15b - c
17±l3b,c
14 ± 12
26±9C
3 6 ± 1 2 b , c , d
6.8±5.5
1.1 ±0.3
3Q± 5 b , c , d
209±90b - c - d
424±610
4.0±2.6b
l . l ± 0 . 5 b
2.1 ± 0.8b-c
4.3 ±2.9
3.4 ±6.1
(8.3 ± 7.3)h (5)J
22 ± 1 2
8±8
3 3±4.8
18.0 ±9.8b
52±20b
2O±5b - c
13 ± 8
22 ± 10
22±5
4.3±2.2
1.3 ±0.3
1 6 ±4
94 ± 2 lb> c
453 ±415
5.9±5.7b
1.6 ± 0.9b
3.0±1.4b
4 0±0.6
1.9±2.6h
(6)J
17 ±4
0
0
3.8 ± 2.5
14 ± 7
62 ± 14
6±3
17±3
19±4
6.2±3.2
1.0±0.2
18 ±3
35 ± 16
220±170
1.0± 0.5
0.4±0.1
1.0 ±0.3
8.3 ±4.1
0
I
a.
"5 a
o
!t
3
a Results are expressed as mean ± 1 SD. All significant group differences,p < 0.003 ;bsignificantly different from controls; csignificantly different
from HPT group; dsignificantly different from HPT + OMII group; esignificantly different from HPT + OM1 group; fsignificantly different from
OMI group; glog transformed data used for f-test; h mean ± SD for biopsies containing aluminium ^number containing aluminium. Abbreviations
as in Table 1.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
136 C. R. Dunstan and others
Table 4 shows linear correlations for the entire patient group. Plasma urea and creatinine
were highly correlated (Fig. 5), and phosphorus correlated with both. Parathyroid hormone
level correlated positively with calcium (Fig. 6), but did not correlate with phosphorus, even
in multiple linear regression which included urea and calcium as independent variables. When
calcium was considered as the dependent variable in multiple linear regression, it correlated
positively with parathyroid hormone level (p < 0.01) and negatively with both MLTd (p < 0.01)
TABLE 4. Linear correlations between histologic and biochemical variables3
Dependent variable
Plasma parathyroid hormone vs.
Plasma alkaline phosphatase vs.
Plasma 25(OH)D vs.
Plasma phosphorus vs.
Plasma calcium vs.
Plasma urea vs.
Osteoclasts/mm surface vs.
Osteoblast surface (% total) vs.
MLTi vs.
Aluminium (% osteoid) vs.
Independent variable
Plasma calcium
Plasma phosphorus
Plasma alkaline phosphatase
Plasma calcitonin
Osteoclasts/mm surface
Resorbing surface (% total)
Osteoblast surface (% total)
Tetracycline surface (% total)
Mineral apposition rate (active)
Bone formation rate
Marrow fibrosis
Osteoid area
Osteoid width (mean)
Osteoblast surface (% total)
Bone formation rate
Plasma 24,25(OH)2D
Plasma albumin
Plasma parathyroid hormone
Plasma calcium
Plasma creatinine
Plasma urea
Osteoid width (active)
MLTd
MLTi
Ionised calcium
Plasma creatinine
Plasma parathyroid hormone
Plasma calcium
Osteoclasts/mm surface
Resorbing surface (% total)
Osteoblast surface (% total)
Bone formation rate
MLTi
Tetracycline surface (% total)
Bone formation rate
MLTd
Dialysis duration
Tetracycline surface (% osteoid)
MLTi
MLTd
r
0.40
0.20
0.60
-0.07
0.75
0.71
0.64
0.59
0.47
0.70
0.52
0.44
0.49
0.74
0.85
0.36
0.31
0.20
-0.15
0.56
0.63
-0.46
-0.45
-0.39
0.68
0.83
0.29
~0.U
0.38
0.49
0.77
0.83
-0.40
0.88
-0.39
0.54
0.36
-0.41
0.42
0.14
P
0.01
NS
0.001
NS
0.001
0.001
0.001
0.001
0.01
0.001
0.001
0.01
0.001
0.001
0.001
0.05
0.05
NS
NS
0.001
0.001
0.01
0.01
0.01
0.001
0.001
NS
NS
0.01
0.001
0.001
0.001
0.01
0.001
0.01
0.001
0.05
0.01
0.01
NS
a Controls were excluded from these calculations.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
PLASMA
UREA
(mmol/l)
50n
40-
30H
20-
0.2 0.6 1.0 1.4 1.8
PLASMA CREATININE (mmol/l)
FIG. 5. Types of bone disease at differing levels of plasma urea and creatinine. r = 0.82, p < 0.001,
• = hyperparathyroid bone disease, A = osteomalacia type I, • = osteomalacia type II, A = hyperparathyroid
bone disease + osteomalacia type I, • = hyperparathyroid bone disease + osteomalacia
type II, o= normal bone. Plasma urea and creatinine were higher in patients with hyperparathyroid
bone disease than in those without (p < 0.005).
PLASMA
CALCIUM
(mmol/l)
3.0-,
2.8-
2.6-
,
2.2-
2.0-
400 loo 1200 1600
PLASMA PARATHYROID HORMONE (JJI eq/mO
FIG. 6. Relationship between parathyroid hormone and plasma calcium. The positive correlation
indicates a degree of parathyroid autonomy in established secondary hyperparathyroidism.
r = 0.40, p < 0.01. • = hyperparathyroid bone disease, ^ = osteomalacia type I, n = osteomalacia
type II, A= hyperparathyroid bone disease + osteomalacia type I, • = hyperparathyroid bone
disease + osteomalacia type II, o= normal bone.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
138 C. R. Duns tan and others
and phosphorus (p<0.01). There were no correlations between indices of osteomalacia and
those of resorption. Parathyroid hormone level was most highly correlated with osteoclast
count, and also correlated well with most variables of bone formation and resorption. Osteoclast
count (but not parathyroid hormone level) correlated with plasma urea, but not with phosphorus
or creatinine. Parathyroid hormone level also correlated with osteoid area and with
mean osteoid width. The levels of vitamin D metabolites did not correlate with any histologic
or biochemical parameter, other than albumin, in simple or multiple linear regression. Osteoblast
surface and tetracycline surface were highly correlated and the two were closely related
anatomically. The extent of aluminium deposition correlated positively with duration of dialysis
and negatively with the uptake of tetracycline at the calcification front. In addition to the
correlation between MLTi and aluminium deposition in the whole patient group, there was a
strong correlation when only the 10 osteomalacia type II patients with stainable aluminium
were considered (r = 0.73, p< 0.05).
With multiple linear regression MLTd correlated negatively with plasma calcium (p< 0.01)
and phosphorus (p < 0.001), the combined correlation coefficient being 0.58 (p< 0.001). MLTi
correlated negatively with phosphorus (p< 0.001) and positively with creatinine (p < 0.05) and
bone aluminium (p < 0.01), the combined correlation coefficient being 0.55 (p < 0.001).
DISCUSSION
Diagnosis of hyperparathyroid bone disease
Hyperparathyroid bone disease is easily identified histologically by increases in osteoclasts and
osteoblasts accompanied by marrow fibrosis and extensive woven bone in the more severe
forms. Parathyroid hormone appears to initially stimulate osteoclast activity (40), with a subsequent
local stimulation of osteoblasts (41), though there is evidence for a primary stimulation
of osteoblasts (42); the fibrosis and woven bone are manifestations of the increased rate of
bone turnover. The osteoclast count correlates well with parathyroid hormone levels both in
uraemic patients and in subjects with normal renal function (28). It therefore provides a useful
means of quantitating the severity of hyperparathyroid bone disease.
Pathogenesis of hyperparathyroid bone disease
Though short-term studies suggest that phosphate retention is the major stimulus to hyperparathyroid
bone disease, the matter is less clear in the chronic situation. Phosphorus administration
increases parathyroid hormone secretion, probably by inducing hypocalcaemia (43), and
phosphorus retention induces secondary hyperparathyroidism in uraemic dogs (8). However, in
such studies, phosphorus restriction does not completely inhibit the increase in parathyroid
hormone secretion, unless mild hypercalcaemia is induced with vitamin D in addition (44), and
it does not reverse established secondary hyperparathyroidism in uraemic humans (11). In our
study the hyperparathyroid bone disease patients had higher plasma levels of phosphorus, urea
and creatinine than did the other groups. Phosphorus levels did not correlate with parathyroid
hormone levels, as reported by Fournier et al. (45), but plasma urea did correlated with osteoclast
count, the most sensitive histologic index of hyperparathyroid bone disease. Thus inadequate
dialysis is a factor in the maintenance of secondary hyperparathyroidism, and though this may
be mediated by hyperphosphataemia, such mediation was not shown by our data. Furthermore,
parathyroid hormone was positively correlated with calcium, as previously observed by Fournier
et al. (45). This implies a degree of autonomy of parathyroid hormone secretion in the established
disease rather than simply a response to phosphorus-induced hypocalcaemia. The findings are
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
Pathogenesis of Renal Osteodystrophy 139
consistent with stimulation of the parathyroid glands by unidentified factors associated with
the uraemic condition.
The importance of reduced levels of vitamin D metabolites in the pathogenesis of secondary
hyperpaiathyroidism in chronic renal failure, has not been clearly defined. The simplest mechanism
for such a role is an inappropriate decrease in 1,25(OH)2D levels as renal failure develops,
leading to reduced gut calcium absorption and thus increased parathyroid hormone secretion to
maintain the level of plasma calcium. Such a mechanism is consistent with long-term experiments
with the dog where suppression of parathyroid hormone secretion by phosphate restriction and
administration of 1,25(OH)2D was associated with mild hypercalcaemia (44). In humans, the
decrease in serum parathyroid hormone levels following 1,25(OH)2D therapy correlated well
with the increase in serum calcium levels (46). Decreases in serum parathyroid hormone levels
have been observed when the plasma calcium level was elevated by increasing dialysate calcium
in one study (47) but not in others (48,49). There is also evidence of inhibition of parathyroid
cell activity by vitamin D metabolites (50—52). In our study, the levels of vitamin D metabolites
were similar in the patients with hyperparathyroidism and those in the other groups. Neither
parathyroid hormone levels nor osteoclast counts correlated with the levels of any vitamin D
metabolite, either in simple linear regression, or in multiple linear regression which included
calcium, phosphate and urea. Thus we found no evidence to suggest that secondary hyperparathyroidism
is related to abnormal vitamin D metabolism in chronic renal failure.
Diagnosis of osteomalacia
Whilst the histologic definition of hyperparathyroid bone disease is straightforward, that of
osteomalacia has long been a matter of contention (53). Osteoid width and area have been used
in many studies as sole diagnostic criteria for osteomalacia, but they both correlate with parathyroid
hormone level, and are therefore inadequate when considered alone. Osteoid must increase
if its rate of mineralisation decreases, as in osteomalacia, or if its formation rate increases, as in
hyperparathyroid bone disease. Uraemic patients frequently have hyperparathyroid bone disease
with osteomalacia type I and osteomalacia type II, and all three can increase osteoid surface
and area. The MLT, by relating osteoid to mineralisation, permits the diagnosis both of mild
osteomalacia and of osteomalacia in the presence of hyperparathyroid bone disease, which can
be diagnosed independently by an increased osteoclast count. In the present study both MLTd
and MLTi were used, as neither alone provides adequate differentiation of osteomalacia type I
and osteomalacia type II. A prolonged MLTd identified osteomalacia type I, which results from
impaired mineralisation in osteoid seams lined by active osteoblasts, and implies a disorder of
transport of calcium and/or phosphate through these cells. The close relationship between
osteoblast and tetracycline surfaces suggests that osteoblasts are involved in the initiation of
mineralisation. In osteomalacia type II, MLTd is normal but MLTi is prolonged. This reflects
a small mineralising surface relative to osteoid surface, and results from a delay in mineralisation
of maturing seams.
Pathogenesis of osteomalacia
There is a complex relationship between osteomalacia and plasma levels of vitamin D metabolites,
calcium and phosphorus(54). Vitamin D deficiency is a major cause of osteomalacia in nonuraemic
patients but did not appear to be important in our uraemic patients. In vitamin Ddeficiency
osteomalacia the levels of all vitamin D metabolites are usually extremely low (55)
though normal 1,25(OH)2D levels have been reported (56). The mean levels of vitamin D metabolites
in our patients were approximately half normal, but were considerably higher than those
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
140 C. R. Dunstan and others
reported in vitamin D-deficiency osteomalacia by Papapoulos et al. (55). No relationship could
be demonstrated between the plasma levels of their metabolites and any histologic criterion of
osteomalacia. This finding is not surprising, as vitamin D has not been shown to stimulate
mineralisation (57), though osteoblasts do appear to be target cells for 1,25(OH)2D (58). Our
results are consistent with those of Christiansen et al. (59), but differ from those of Mason et al.
(60), who found a negative correlation between the severity of osteomalacia (assessed by osteoid
area) and levels of 25(OH)D and 24,25(OH)2D.
The negative correlation between MLTd and plasma calcium and phosphorus levels is consistent
with previous observations of low plasma calcium and phosphorus levels in renal osteomalacia
(61, 62). Calcium deficiency (63, 64) and phosphorus deficiency (62, 65—67) can
induce osteomalacia in humans and rats, and the disease has been related to a low calciumphosphate
ion product rather than to a low 1,25(OH)2D level (68). In vitamin D-deficient rats
both the hypocalcaemia and osteomalacia can be corrected by a high calcium diet (69). However,
renal osteomalacia is not improved by oral calcium (70) or by high calcium dialysate (71),
and in our osteomalacia type I patients the plasma calcium level was usually normal. The plasma
phosphorus level was frequently slightly elevated, and only in the two cases with severe osteomalacia
type I was hypophosphataemia present. Thus, although plasma calcium and phosphorus
levels influence the relationship between osteoid formation and its mineralisation in osteomalacia
type I patients, a further factor associated with the uraemic state must also be involved. There
is evidence that osteomalacic bone does not release calcium into the extracellular fluid in a
normal manner (72), suggesting that hypocalcaemia may be, at least in part, an effect of the
osteomalacia. However, this is unlikely to be caused by a reduction in bone surface available for
resorption, as in our study, active resorbing surface was highly correlated with parathyroid
hormone level, and did not further correlate with osteoid surface. Available data does not
exclude the possibility that impaired bone membrane calcium transport may reduce the
plasma calcium level, but the weight of evidence favours a primary effect of plasma levels of
calcium and phosphorus on bone mineralisation (osteomalacia type I). They do not appear to
play a role in osteomalacia type II.
Aluminium accumulation can occur in uraemia and has been implicated in the aetiology of
severe osteomalacia type I (12—16), often with normal or slightly elevated plasma levels of
calcium and phosphorus (14, 16). Our study did not include such patients, but the negative
correlation between aluminium deposition and tetracycline uptake, and the absence of tetracycline
at sites of aluminium deposition, suggest that mineralisation is impaired by even a
moderate increase in aluminium. The alternative explanation, that aluminium is deposited coincidentally
at inactive bone-osteoid interfaces is less likely in view of the induction of osteomalacia
in normal (73) or uraemic (74) rats by the administration of aluminium. A moderate
increase in bone aluminium level, as found in the present study, thus appears to impair mineralisation
in maturing osteoid seams, and so contributes to osteomalacia type II, whilst high levels
of aluminium must also inhibit mineralisation in actively growing osteoid seams, thus inducing
osteomalacia type I. The mechanism could be a direct inhibition of mineralisation, or a toxic
effect on osteoblasts; in another study (29), which included chemical measurement of bone
aluminium, we also found evidence suggesting that aluminium causes a direct reduction in
osteoblast numbers.
CONCLUSIONS
The relationship between bone histology and metabolic factors in renal failure is extremely
complex, and the histological patterns cannot be fully accounted for by other measurable
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
Pathogenesis of Renal Osteodystrophy 141
factors, even when considered in combination. Phosphate retention is clearly a major initial
stimulus to secondary hyperparathyroidism and, though the evidence is less clear, may be
important in the chronic state. Poor dialysis is also related to hyperparathyroid bone disease,
perhaps mediated in part by hyperphosphataemia, though this was not demonstrable in our
study. However, the positive correlation between parathyroid hormone and calcium suggests
some degree of autonomy of the parathyroid glands in established secondary hyperparathyroidism
in chronic uraemia. Osteomalacia does not appear to result from abnormal vitamin D metabolism.
Mineralisation in actively growing osteoid seams is influenced by plasma calcium and phosphorus
levels, but not levels of vitamin D metabolites. Aluminium accumulation impairs mineralisation
in both active and maturing seams. However, in all subgroups of renal osteodystrophy, the data
indicate a major influence of other factors dependent on the uraemic state, or perhaps a nonspecific
effect of uraemia.
ACKNOWLEDGEMENTS
This study was supported by the Australian Department of Veterans' Affairs, the National
Health and Medical Research Council, the Postgraduate Medical Foundation of the University of
Sydney, and Roche Products Australia. We are grateful to Graham F. Bryce, PhD, Hoffman-
La Roche, Nutley, for performing the parathyroid hormone assays. We are also grateful to RN
Mary Evans for nursing supervision of this study, to Mrs. V. Macallister, Mrs. M. Herft and Miss
D. Spears for secretarial assistance, and Qantas Airways for rapid shipment of blood plasma to
the USA.
REFERENCES
1. Liu SH, Chu HI. Studies of calcium and phosphorus metabolism with special reference to
pathogenesis and effect of dihydrotachysterol (AT10) and iron. Medicine (Baltimore)
1943;22:103-161.
2. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biologically active vitamin D
metabolite. Nature 1970; 228: 764-766.
3. Brumbaugh PF, Haussler DH, Bressler R, Haussler MR. Radioreceptor assay for la,25-
dihydroxyvitamin D. Science 1974; 183: 1089-1091.
4. Norman AW, Midgett RJ, Myrtle JF, Nowicki HG. Studies on calciferol metabolism: I.
Production of vitamin D metabolite 4B from 25-OH-cholecalciferol by kidney homogenates.
Biochem Biophys Res Commun 1971 ;42: 1082-1987.
5. Brickman AS, Sherrard DJ, Jowsey J et al. 1,25-Dihydroxycholecalciferol effect on
skeletal lesions and plasma parathyroid hormone levels in uremic osteodystrophy. Arch
Intern Med 1974; 134: 883-888.
6. Henderson RG, Russell RGG, Ledingham JGG et al. Effects of 1,25-dihydroxycholecalciferol
on calcium absorption, muscle weakness, and bone disease in chronic renal failure.
Lancet 1974;1: 379-384.
7. Massry SG, Goldstein DA, Malluche HH. Current status of the use of 1,25(OH)3D3 in the
management of renal osteodystrophy. Kidney Int 1980; 18: 409—41 8.
8. Slatopolsky E, Caglar S, Pennel JP et al. On the pathogenesis of hyperparathyroidism in
chronic experimental renal insufficiency in the dog. J Clin Invest 1971; 50: 492—499.
9. Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary
hyperparathyroidism in chronic renal disease. Kidney Int 1973; 4: 141 — 145.
10. Kaplan MA, Canterbury JM, Bourgoignie JJ et al. Reversal of hyperparathyroidism in response
to dietary phosphorus restriction in the uremic dog. Kidney Int 1979; 15: 43—48.
1 1. Biswas CK, Arze RS, Ramos JM et al. Effect of aluminium hydroxide on serum ionised
calcium, immunoreactive parathyroid hormone, and aluminium in chronic renal failure. Br
Med J 1982; 284: 776-778.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
142 C. R. Dunstan and others
12. Ward MK, Feest TG, EUis HA et al. Osteomalacic dialysis osteodystrophy: evidence for a
water-borne aetiological agent, probably aluminium. Lancet 1978; 1: 841-845.
13. Alfrey AC, Hegg A, Miller N, Berl T, Berns A. Interrelationship between calcium and
aluminum metabolism in dialyzed uremic patients. Miner Electrolyte Metab 1979; 2: 81 —
87.
14. Hodsman AB, Sherrard DJ, Alfrey AC et al. Bone aluminum and histomorphometric
features of renal osteodystrophy. J Clin Endocrinol Metab 1982; 54. 539—546.
1 5. Ott SM, Maloney NA, Coburn JW, Alfrey AC, Sherrard DJ. The prevalence of bone aluminum
deposition in renal osteodystrophy and its relation to the response to calcitriol therapy N
Engl J Med 1982; 307: 709-713.
16. Boyce BF, Fell GS, Elder HY et al. Hypercalcaemic osteomalacia due to aluminium toxicity.
Lancet 1982;2:1009-1013.
17. Kaehny WD, Alfrey AC, Holman RE, Shorr WJ. Aluminum transfer during hemodialysis.
KidneyInt 1977; 12: 361-365.
1 8. Kaehny WD, Hegg AP, Alfrey AC. Gastrointestinal absorption of aluminum from aluminumcontaining
antacids. N Engl J Med 1977;296: 1389-1390.
19. Kanis JA, Cundy T, Bartlett M et al. Is 24,25-dihydroxycholecalciferol a calcium-regulating
hormone in man? Br Med J 1978; 1: 1382-1386.
20. Heynen G, Kanis JA, Oliver D, Ledingham JGG, Russell RGG. Evidence that endogenous
calcitonin protects against renal bone disease. Lancet 1976; 2: 1322-1326.
21. Frost HM. Tetracycline-based histological analysis of bone remodelling. Calcif Tissue Res
1 969; 3: 211-237.
22. Baylink D, Stauffer M, Wergedal J, Rich C. Formation, mineralization, and resorption of
bone in vitamin D-deficient rats. J Clin Invest 1970; 49: 1112-1134.
23. Sherrard DJ, Baylink DJ, Wergedal JE, Maloney NA. Quantitative histological studies on
the pathogenesis of uremic bone disease. J Clin Endocrinol Metab 1974; 39: 1 19-135.
24. Nielsen HE, Melsen F, Christensen MS. Interrelationships between calcium—phosphorus
metabolism, serum parathyroid hormone and bone histomorphometry in non-dialyzed
patients with chronic renal failure. Miner Electrolyte Metab 1980;4: 113-122.
25. Bordier PJ, Tun Chot S. Quantitative histology of metabolic bone disease. Clin Endocrinol
1972; 1: 197-215.
26. Teitelbaum SL, Russell JE, Bone JM, Gilden JJ, Avioli LV. The relationship of biochemical
and histometric determinants of uremic bone. Arch Pathol Lab Med 1979; 103: 228-
230.
27. Malluche HH, Ritz E, Lange HP et al. -Bone histology in incipient and advanced renal
failure. Kidney Int 1976; 9: 355-362.
28. Evans RA, Dunstan CR, Baylink DJ. Histochemical identification of osteoclasts in undecalcified
sections of human bone. Miner Electrolyte Metab 1 979; 2: 1 79 — 1 85.
29. Dunstan CR, Evans RA, Hills E, Wong SYP, Alfrey AC. Effect of aluminum and parathyroid
hormone on osteoblasts and bone mineralisation in chronic renal failure. Calcif Tissue Int
1984;36: 133-138.
30. Evans RA, Flynn J, Dunstan CR, George CRP, McDonnell GD. Bone metabolism in chronic
renal failure. Miner Electrolyte Metab 1982; 7: 207-218.
31. Odell RA, Yang J, George CR, Farrell PC. Aluminum kinetics during sorbent (Redy)
dialysis. Contemp Dialysis 1982; 3: 57-62.
32. Branger B, Ramperez P, Marigliano N, Mion H, Shaldon S, Mion C. Aluminium transfer in
bicarbonate dialysis using a sorbent regenerative system: an in vitro study. Proc Eur Dial
Transplant Ass 1980; 17: 213-218.
33. Dunstan CR, Evans RA. Quantitative bone histology: a new method. Pathology 1980; 12:
255-264.
34. Jamshidi K, Swaim WR. Bone marrow biopsy with unaltered architecture: a new biopsy
device. J Lab Clin Med 1971; 77: 335-342.
35. Buchanan MRC, Ihle BU, Dunn CM. Haemodialysis related osteomalacia: a staining method
to demonstrate aluminium. J Clin Pathol 1981 ;34:1352-1354.
36. Berry EM, Gupta MM, Turner SJ, Burns RR. Variation in plasma calcium with induced
changes in plasma specific gravity, total protein and albumin. Br Med J 1 973; 4: 640—643.
3 7. Hudson J, Posen S, Clifton-Bligh P. The measurement of calcitonin in human serum. Proc
Endocr Soc Aust 1977; 20: 57 (Abstr).
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
Pathogenesis of Renal Osteodystrophy 143
38. Bishop JE, Norman AW, Coburn JW, Roberts PA, Henry HL. Studies on the metabolism
of calciferol. XVI. Miner Electrolyte Metab 1980;3: 181-189.
39. Miller RG. Simultaneous Statistical Inference, 67. New York: McGraw-Hill, 1966.
40. Parfitt AM. The actions of parathyroid hormone on bone: relation to bone remodeling and
turnover, calcium homeostasis, and metabolic bone diseases. Metabolism 1976; 25: 909-
955.
41. Parfitt AM. The coupling of bone formation to bone resorption: a critical analysis of the
concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone Dis Relat Res
1982;4: 1-6.
42. Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption - a
hypothesis. Calcif Tissue Int 1981; 33: 349-351.
43. Reiss E, Canterbury JM, Bercovitz MA, Kaplan EL. The role of phosphate in the secretion
of parathyroid hormone in man. J Clin Invest 1970; 49: 2146-2149.
44. Rutherford WE, Bordier P, Marie Petal. Phosphate control and 25-hydroxycholecalciferol
administration in preventing experimental renal osteodystrophy in the dog. J Clin Invest
1977,60: 332-341.
45. Fourmer AE, Arnaud CD, Johnson WJ, Taylor WF, Goldsmith RS. Etiology of hyperparathyroidism
and bone disease during chronic hemodialysis. J Clin Invest 1971; 50.
599-605.
46. Goldstein DA, Malluche HH, Massry SG. Management of renal osteodystrophy with
1,25(OH)2D3. Miner Electrolyte Metab 1979; 2: 35-47.
47. Johnson WJ, Goldsmith RS, Beabout JW, Jowsey J, Kelly PJ, Arnaud CD. Prevention and
reversal of progressive secondary hyperparathyroidism in patients maintained by hemodialysis.
Am J Med 1974; 56: 827-832.
48. Drueke T, Bordier PJ, Nguyen KM, Jungers P, Marie P. Effects of high dialysate calcium
concentration on bone remodelling, serum biochemistry, and parathyroid hormone in
patients with renal osteodystrophy. Kidney Int 1977; 1 1. 267-274.
49. Regan RJ, Peacock M, Rosen SM, Robinson PJ, Horsman A. Effect of dialysate calcium
concentration on bone disease in patients on hemodialysis. Kidney Int 1976; 10: 246-
255.
50. Chertow BS, Baylink DJ, Wergedal JE, Su MHH, Norman AW. Decrease in serum lmmunoreactive
parathyroid hormone in rats and in parathyroid hormone secretion in vitro by
1.25-dihydroxycholecalciferol. J Clin Invest 1 975; 56: 668-678.
5 1. Canterbury JM, Lerman S, Claflin AJ, Henry H, Norman A, Reiss E. Inhibition of parathyroid
hormone secretion by 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol
in the dog. J Clin Invest I 978; 61 : 1375-1383.
52. Cloix JF, Ulmann A, Monet JD, Funck-Brentano JL. Human parathyroid gland adenylate
cyclase activity: inhibition by 24,25-dihydroxycholecalciferol in vitro Clin Sci 1981; 60:
339-341.
53. Harter HR, Laird NM, Teehan BP. Effects of dialysis prescription on bone and mineral
metabolism: the National Cooperative Dialysis Study. Kidney Int 1983; 23. S73-S79.
54. Kanis JA, Brown CB, Cameron EC et al. The role of vitamin D metabolites in the osteomalacia
of renal disease. Curr Med Res Opin 1981 ; 7: 294-314
55 Papapoulos SE, Clemens TL, Fraher LJ, Gleed J, O'Riordan JLH. Metabolites of vitamin D
in human vitamin-D deficiency: effect of vitamin D3 or 1,25-dihydroxycholecalciferol
Lancet 1980; 2: 612-615.
56. Eastwood JB, De Wardener HE, Gray RW, Lemann JL. Normal plasma-1,25-fOH)2-vitamin-
D concentrations in nutritional osteomalacia. Lancet 1 979; 1: 1377- 1378.
57. Stern PH. A monolog on analogs, in vitro effects of vitamin D metabolites and consideration
of the mineralization question. Calcif Tissue Int 1981; 33: 1—4.
58. Narbaitz R, Stumpf WE, Sar M, Huang S, Deluca HF. Autoradiographic localization of
target cells for 1 a,25-dihydroxyvitamin D3 in bones from fetal rats. Calcif Tissue Int
1 983;35: 177-182.
59. Christiansen C, Christensen MS, Melsen F, Rodbro P, Deluca HF. Mineral metabolism in
chronic renal failure with special reference to serum concentrations of 1,25(OH)2D and
24,25(OH)2D.Clin Nephrol 1981 ; 15: 18-22.
60. Mason RS, Lissner D, Wilkinson M, Posen S. Vitamin D metabolites and their relationship
to azotaemic osteodystrophy. Clin Endocrinol 1980; 13: 375-385.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011
144 C. R. Dunstan and others
61. Stanbury SW, Lumb GA. Parathyroid function is chronic renal failure. Q J Med 1966; 35:
1-23.
62. Ahmed KY, Varghese Z, Wills MR et al. Persistent hypophosphataemia and osteomalacia
in patients not on oral phosphate-binders- response to dihydrotachysterol therapy. Lancet
1976; 2:439-442.
63. Stauffer MD, Baylink DJ, Wergedal J, Rich C. Decreased bone formation, mineralization
and enhanced resorption in clacium deficient rats. Am J Physiol 1973; 225: 269-276.
64. Marie PJ, Pettifor JM, Ross FP, Glorieux FH. Histological osteomalacia due to dietary
calcium deficiency in children. N Engl J Med 1 982; 307: 584-588.
65. Ludwig GD, Kyle GC, De Blanco M. 'Tertiary' hyperparathyroidism induced by osteomalacia
resulting from phosphorus depletion. Am J Med 1967,43: 136—140.
66. Schwartz GH, David DS, Riggio RR et al. Hypercalcemia after renal transplantation. Am J
Med 1970; 49: 42-51.
67. Baylink D, Wergedal J, Stauffer M. Formation, mineralization, and resorption of bone in
hypophosphatemic rats. J Clin Invest 1971; 50: 2519-2530.
68. Rasmussen H, Baron R, Broadus A, De Fronzo R, Lang R, Horst R. 1,25(OH)2D3 is not
the only D metabolite involved in the pathogenesis of osteomalacia. Am J Med 1980; 69-
360-368.
69. Howard GA, Baylink DJ. Matrix formation and osteoid maturation in vitamin D-deficient
rats made normocalcemic by dietary means Miner Electrolyte Metab 1 980; 3: 44—50.
70. Eastwood JB, Bordier PJ, Clarkson EM, Tun Chot S, De Wardener HE. The contrasting
effects on bone histology of vitamin D and of calcium carbonate in the osteomalacia of
chronic renal failure. Clin Sci Molec Med 1974; 47: 23-42.
7 1. Evans RA, Somerville PJ. The use of high calcium dialysate in the treatment of renal osteomalacia.
Aust NZ J Med 1976;6- 10-15.
72. Jowsey J. Calcium release from the skeletons of rachitic puppies. J Clin Invest 1972; 51:
9-15.
73. Ellis HA, McCarthy JH, Hemngton J. Bone aluminium in haemodialysed patients and in
rats injected with aluminium chloride: relationship to impaired bone mineralisation. J Clin
Pathol 1979; 32: 832-844.
74. Chan YL, Alfrey AC, Posen S et al. Effect of aluminum on normal and uremic rats: tissue
distribution, vitamin D metabolites, and quantitative bone histology. Calcif Tissue Int
1983; 35: 344-351.
Downloaded from qjmed.oxfordjournals.org by guest on February 2, 2011



Back to page