Metal Deposition Diseases, Radioactive Metals, DTPA-Chelation, Understanding Medical Literature

In this blog I return to a topic I have not addressed in over 1 year, which is understanding medical literature. It is absolutely critical when trying to evaluate medical literature and a research study is to understand fully that a study design describes the results for that experimental model, and that it may not be extrapolatable to other settings ... unless you have a very good understanding what the limitations are and the scope of applicability.

I had in the past focused on rodent models for specific assessments like the results of comparative chelators. So for example comparing chelators using a rodent model with intraperitoneal administration of a chelator given a certain dose of a chelator in an animal with metal administered- the results pertain to that model, but may or may not extrapolate to the human situation.

An interesting aspect of the research on DTPA is the great majority deals with decorporation (the term used for radioactive metal removal) of plutonium, which is what the agent is FDA approved for (also amercium and curium). The toxicity that is focused on is radioactive toxicity, and not a metal deposition disease. So virtually all the clinical work, and animal work leading up to it, in advance of FDA approval ,was assessment of removing radioactive metals. In that circumstance much lower doses of the metal can be toxic and deterministically lethal, often directly based on dose. As such chelation with DTPA was performed to remove the radioactive metal as quickly as possible, which is daily chelation.

To my knowledge the only peer-reviewed work on the use of DTPA to remove Gd, was out original publication 3 years ago in Investigative Radiology, where we employed Ca-DTPA day 1 and Zn-DTPA day 2, with some of the patients treated on a weekly basis, but the majority every 4 weeks. We found in the blood work done that native metals (Mn, Mg, Zn) essentially restored to normal levels after one week. This speaks to the remarkable ability of the body to achieve homeostasis of its electrolyte components. Interesting research, that we have not done, is how quickly does this occur, my instinct is at day 3-4. What we found was that Ca-DTPA removes approximately twice as much Gd as Zn-DTPA, but by theory and early work (mentioned above) the lower stability constant of Ca-DTPA translates into greater removal of native metals, notably Mg, Mn, Zn. By contrast Zn-DTPA has higher stability then all the other native metals, so Zn-DTPA essentially leaves the other native metals alone and does not remove them.

So for daily administration of chelator it makes more theoretical sense to use Zn-DTPA, because daily use of Ca-DTPA does not allow the body to achieve homeostasis of native metals, and depletion of Mg, Mn, and Zn, if done long enough probably can be lethal. It is interesting that the radioactive protocols start with Ca-DTPA for the first day of daily therapy, which I assume is in recognition that it removes more Plutonium, so they start on a high note. What we have learned though from using both Ca-DTPA and Zn-DTPA for Gd, translated to the circumstance of exposure and incorporation of a radioactive heavy metal, it may make more sense to remove more radioactive metal more quickly. I would therefore look at a treatment of primarily Ca-DTPA, but then on alternate days or every third day administer iv solution containing isotonic Mg, Mn, Zn, and probably other native electrolytes (Cu, Fe). I would focus on getting more radioactive metal out quicker and accept some risk of electrolyte imbalance, this seems a better safety/risk analysis.

We first described and reported on Flare. with chelation of Gd, and specifically on DTPA chelation, but this occurs with all effective, even modestly effective chelators. What we found fascinating is the company that manufactures DTPA was surprised that such an event, Flare, would occur. Why would that be? That is because all the original work focused on Plutonium radioactive toxicity, and an entity such as Deposition Disease (essentially a T-cell immunogenic allergy) was never considered, because it was never observed. Two reasons for this: Metal Deposition Diseases are generally rare compared to Metal Storage Conditions (true for Gd-, Lead, mercury... and every metal) probably 1 in 10,000 for all of them (maybe higher occurrence for Mercury) and also generally a certain. dose of metal has to be in the body to cause Deposition Disease, which likely far exceeds the amount of Plutonium that would result in cell death and human death from radioactivity. So Plutonium Deposition Disease probably does not occur, because people would die from radioactive cell toxicity at lower dose than Deposition Disease develops at. If it did occur then probably only 1 in 10,000 would experience it.

A related interesting subject is that many skeptics about chelation for metals in general, and most discussions have regarded lead, is that it is difficult to know if a patient is sick from lead since lead presence in the body is so common- so a lot of chelation may be unnecessary because the metal is not causing the person to be sick. That is true from the perspective that for most people with lead in them (and probably 100% of americans have lead in them - our experience has shown this) how do we know if they are sick from it? Our experience with Gd also informs us how to tell if someone is toxic from a metal exposure. The simplest ofcourse if they have the symptoms described for the metal, but direct scientific evidence is: if they are sick from the metal, remobilizing the metal makes them transiently (hopefully transiently) sicker - this is the flare reaction. If you are sick from lead, chelating with DTPA that results in remobilizing lead in the circulation, should make the symptoms of concern worse- the flare.

I have to address another finding from an older report on chelation saying that if you chelate when a person is in an 'inflammatory state' it can make the symptoms worse. This observation again is the Flare. The problem with that observation are two monumental issues- 1) the only people who need to be chelated are in an inflammatory state from that metal, that is GDD, if they simply have the metal in them, GSC, they are not sick, hence don't need it removed. 2) It is not clear if a GDD individual is ever in a noninflammatory state (except in death). So the observation is true but the conclusion is ludicrous and dangerous. What has to be done is control the inflammatory state when chelating, which is what we do with steroids and antihistamines. In fact the only people who need to be chelated are in an inflammatory state.

Other critical points, almost all of the old papers on DTPA used for radioactive metal removal conclude: in the dosage used in humans the agent is safe. They would not be using this agent for chelating heavy metals if it was not safe, and in the case of DTPA safer than alternatives, combined with more effective. The other critical aspect is that DTPA is the chelator most commonly used for intravenous administration of many metals (many thousand times more stable, and hence more stable than EDTA). That is why nuclear medicine uses Tc- DTPA for bone scans, and not Tc-EDTA, and similarly Gd-DTPA and not Gd-EDTA. Scientists for decades have focused on the greater the stability and higher safety of DTPA as the chelator.

Almost everything is toxic if used in high doses (ofcourse even water) and this is usually the design for animal studies: using high doses.

I have heard in the past from radiologist GBCA contrast 'experts' that DTPA chelation is not safe. My response: "based on what data... there is no data showing that using the approach we used in humans". This is just misinformation based on the certainty that only comes with ignorance. If they do a study using the approach that we use, administering these chelators with 1 week intervals at least (we often use 3 week intervals). Perform that study and show me that it is not safe, and that our data on homeostasis of electrolytes is incorrect, then I believe it. But to use animal studies with high dose DTPA, or daily Ca-DTPA in. animals and even in humans, to state these agents are not safe is simply false, and what is worse it is dangerous because it misinforms patients against using the safest strategy to remove Gd and treat GDD. The fact that physicians and scientists seem ignorant on the subject of understanding methodology in studies is surprising to me, except that it probably fits with a devious narrative to deny GDD.

It has been brought to my attention that a patient with GDD, and not a physician antagonist to GDD is raising concern about DTPA. It is always important to evaluate, understand and explain and re-evaluate science and facts, So in some ways this alarm is useful even for me to look at again safety and knowledge. This has to be a constant process, just as I went through with GBCAs, I went from thinking it exceedingly safe, to now recognizing the importance of 3 adverse reactions: acute hypersensitivity reactions, GDD, and NSF (which can also occur in combination). I hope I do not have to write again for at least another year that DTPA is safe the way we perform it, which is essentially the way it is performed throughout the world (with some variations), but immune dampening is critical. If DTPA is not as safe as future agents, such as HOPO, or not as effective. I will report it. Right now, DTPA is the best we have..... by far. So be at peace if you are getting DTPA chelation, we have nothing better to treat GDD and it works well- if done appropriately.

In high dose or too frequent dose, as reported in many animal studies, DTPA can be deadly.... but the same is true of water.

Richard Semelka, MD.