The Industrial Treatment · Aug 8, 11:00 PM

Prof. Boyd Haley’s new chelator N,N’-bis (2-mercaptoethyl)isophthalamide, or “CT-01” — represented to the FDA as a “new dietary ingredient,” and now marketed as an antioxidant for consumption by autistic children under the trade name “Oxidative Stress Relief” (OSR) — is substantially similar if not identical in its chemical structure to one member of a family of industrial chelators developed by his colleagues at the University of Kentucky, and for which U.S. and international patents were awarded in 2003.

U.S. Patent No. 6,586,600, Multidentate Sulfur-Containing Ligands (issued July 2, 2003) (.pdf) names as its inventors chemists David A. Atwood, Brock S. Howerton and Matthew Matlock of Lexington, Kentucky. David Atwood is a Professor of Chemistry at the University of Kentucky, and Mr. Howerton and Mr. Matlock are graduate students. The rights to the patent are assigned to the University of Kentucky Research Foundation.

The patent describes methods for “binding, rendering insoluble, and precipitating a wide range of heavy metals,” including cadmium, lead, nickel, zinc, mercury, and copper, utilizing a new class of sulfur-containing ligands capable of bonding to these metals. These synthesized compounds are combined with a “starting material” such as soil or water; the mixture then forms a stable, insoluble complex which can either be separated from the starting material or can be allowed to rest over an extended time without concern that the metals will further leach into the environment.

In the patent and in numerous journal articles, Prof. Atwood and his colleagues discuss the industrial and environmental uses of the chelator 1,3-benzenediamidoethanethiol, also referred to by the abbreviation “BDETH2“ and by the trade name “MetX.” Applications include the decontamination of soil and water from waste treatment facilities, chemical and metal-finishing industrial sites, municipal landfills, and mines.

In Prof. Atwood’s Powerpoint presentation, Heavy Metal Binding with Thiolate Chelates (created in 2001 and last modified in 2007), BDETH2/MetX is depicted in a diagram.


Atwood Powerpoint, p. 18

In a poster presented at the November 2002 meeting of the Kentucky Academy of Sciences, Prof. Atwood and his colleagues describe the synthesis of BDETH2 using cystamine hydrochloride, isophthaloyl dichloride and triethylamine.

In his February 2008 submission notifying the FDA of his intention to market a new dietary ingredient, “CT-01,” Prof. Boyd Haley described his synthesis of a substance he assigned the chemical name N,N’-bis (2-mercaptoethyl)isophthalamide. Although details of the process have been redacted from the materials published by the FDA, Materials Safety Data Sheets included with the submission indicate that the main reactants which combine to make “CT-01” are cysteamine hydrochloride and isophthalic acid. These are essentially the same reactants used to synthesize BDETH2; isophthalic acid is nearly identical to albeit less toxic than isophthaloyl chloride. (Recent controversy surrounds the use of phthalates in the plastics industry; Congress is currently considering legislation to ban the use of six phthalates in the manufacture of products intended for children under 12, such as drink containers and toys. Manufacturers have protested similar bans enacted in Europe, California and Washington.)

In Powerpoint presentations displayed at the 2007 and 2008 Autism One conferences, Prof. Haley describes the “First Generation Mercury Chelating Agents” (later changed to “Antioxidant Chelating Agents”) that have been the subject of his recent investigations and product development efforts. Two molecules are depicted in diagrams.


Haley Autism One 2007 Powerpoint, p. 63


Haley Autism One 2008 Powerpoint, p. 58

The benzene-ring-based molecule depicted on the left of Prof. Haley’s slides is identical to BDETH2.

The pyridine-based molecule depicted on the right of Prof. Haley’s slides is nicknamed “PyDET” and described in Matlock, Atwood et al.‘s 2002 paper, Effectiveness of commercial reagents for heavy metal removal from water with new insights for future chelate designs (Journal of Hazardous Materials 92:2, 27 May 2002, pp. 129-142).

Both molecules depicted on Prof. Haley’s slides appear to fall within the scope of U.S. Patent No. 6,586,600.

Neither 1,3-benzenediamidoethanethiol nor N,N’-bis (2-mercaptoethyl)isophthalamide appears in the Chemical Abstracts Service (CAS) Registry. Neither chemical name has a corresponding Materials Safety Data Sheet; neither has been thoroughly tested to determine its toxicity and pharmacodynamics in human beings.

In neither their studies nor their patent do the inventors of BDETH2/MetX give any indication that they have ever intended their synthetic chelating compounds to be used on living organisms. Judging from the public record, it seems unlikely that either Prof. Atwood, his colleagues and students, or University of Kentucky administration ever envisioned that BDETH2/MetX or a variant thereof might ever be pressed into service as a “new dietary ingredient,” or that disabled children might ever be pressed into service as “starting material” for research on its toxicity and effects.

Nonetheless, as holder of the patent for Multidentate Sulfur-Containing Ligands, it would seem prudent for the University of Kentucky to investigate the possibility that BDETH2 has been perverted from its legitimate use in the decontamination of toxic waste and industrial sites to a more questionable use as an inadequately-tested chelation drug marketed as a “dietary supplement” for autistic children who have been dubiously diagnosed with chronic heavy metal poisoning.


(Thanks to commenter/chemist Jennifer for her assistance with this report.)

Comments


  1. I’m not sure I’m understanding this correctly. Is it fair to say that Haley took someone else’s heavy metal chelator (intended for industrial and environmental applications), claimed it as his own, and wants human beings to give it a try?

    — Joseph    Aug 8, 11:08 PM    #

  2. Wow. Just when one thought it was safe to go back to an Autism One conference.

    It will be interesting to see if University of Kentucky feels it can comment on Boyd Haley’s new chelator for autistic children.

    Thank you, again for making information available to people you don’t even know that can help them not to make the same horrible mistakes that others are making.

    — Ms. Clark    Aug 9, 12:06 AM    #

  3. Joseph, although both molecules depicted by Prof. Haley in his Autism One Powerpoints appear to fall within the scope of the UK patent, I wouldn’t go so far as to say that he “took someone else’s heavy metal chelator” unbeknownst to them. I’m not privy to his communications with Prof. Atwood or UK regarding development and testing of OSR. He doesn’t refer to the original developers and applications of the “new chelator concept” in his Powerpoints, but that doesn’t mean that he didn’t refer to them during his presentations. (I don’t have access to the audio recordings.) That said, it’s awfully hard to believe that any Institutional Review Board would approve a proposal to conduct pharma-qua-nutraceutical R&D the way Prof. Haley’s going about it.

    — Kathleen Seidel    Aug 9, 09:04 AM    #

  4. Why the MM isn’t too worried about pre-sales testing of efficacy or safety of alternative treatments:

    Josh, comment # 8 on the thread Boyd Haley—New Antioxidant

    Scientific studies are always unfairly biased against alt. treatments. If the antioxidant works, then it works. No point in having a bunch of college elitists try to disprove it.

    The mind reels.

    — Liz Ditz    Aug 9, 11:28 AM    #

  5. Kathleen

    Have you heard back from anyone at the University of Kentucky yet. I am interested to see what their comment will be to your letter

    — LULU    Aug 9, 06:36 PM    #

  6. Kathleen, while reading this I could almost feel the heat of your brain processing this information!

    I certainly hope somebody will inject some caution into this process.

    — isles    Aug 9, 07:47 PM    #

  7. Well, At least Dr. Wilke removed the misinformation from his Dental office website that OSR was “approved by the FDA”…somebody must have said something to him…
    Yet, he is still selling it..Go Figure.

    — Jeanette    Aug 9, 09:39 PM    #

  8. I’ve written a summary post of this and the previous article. I hope it helps in publicizing the potential harm in this approach to autism.

    — Liz Ditz    Aug 10, 03:05 PM    #

  9. Nice to see the additional material Kathleen. I have to say that one look at the chemical structures of the compounds immediately made me think of tetravalent co-ordination of metals ions. The two -SH and two -NH groups are identical to those used in proteins that tetrahedrally bind a zinc ion (e.g. CCHH zinc finger proteins). (In this case, the zinc is a structural, not enzymatic, component of the protein and tightly bound. These proteins aren’t found in the bloodstream.)

    Jeanette: Seems to me that if he was practising honest disclosure his website would state it hasn’t been approved by the FDA despite being received by them.

    — Heraclides    Aug 10, 06:36 PM    #

  10. Heraclides,

    In a related point, the metal complexes of BDET are insoluble in water. This is what makes BDET so attractive for waste water treatment.

    BDET itself is soluble in ethanol, but not in water. It’s not clear to me how this stuff is supposed to enter the bloodstream at all. And if it does, how the metal complexes are supposed to be excreted. Maybe by magically binding to gluathione?

    — Jennifer    Aug 11, 06:08 AM    #

  11. The precipitate (plot) thickens!

    I would also like to echo the concern about what avenue of excretion is involved, or if the precipitate(s) are just supposed to lie around “without concern that the metals will further leach into the environment.” Though that environment in this case would be ones own precious self/body.

    — Patrick    Aug 11, 12:45 PM    #

  12. Oh, I think that you can be sure that BDETH/OSR bound to mercury won’t just “sit around” in the body indefinitely. I imagine that some enzyme or another with break the molecule apart – probably stating at the amide bond – and release the mercury back into circulation.

    To echo what Jennifer and Patrick have mentioned, BDETH bound to mercury (or any metal) is much more insoluble in water than unbound BDETH, so excretion of mercury bound to BDETH in the urine seems unlikely.

    That would leave biliary excretion, although very little mercury-bound BDETH will be able to get from the brain to the liver because it is so poorly soluble in water. Most likely, BDETH-mercury complexes will sit in the lipid (fat) of the brain until the BDETH breaks down.

    At any rate, any BDETH-mercury complex that IS excreted in the bile will then be exposed to intestinal bacteria. These bacteria are amazing in their ability to break down complex organic molecules (like BDETH) and so can be expected to release the bound mercury. They will then methylate this released mercury (it’s how bacteria “detoxify” mercury) and it will be re-absorbed though the intestinal walls.

    BDETH was designed to immobilize mercury in soil, not to chelate mercury out of children. So far as I can tell, Dr. Haley hasn’t shown any data supporting his hypothesis that BDETH/OSR will actually remove mercury from experimental animals – or did I miss that part?

    Prometheus

    — Prometheus    Aug 11, 01:04 PM    #

  13. Jennifer: I’m all out of time… but a quick note:-

    About the (in)solubility: I was going to comment on this in the earlier thread, but for a different reason. In the “experiment” with the fish, I recall the article saying that the substance was put in the water. If its insoluble, and put in the water, it’d end up on the surfaces, not diluted, which you’d think would render this “experiment” worthless. An obvious problem with that is that’s such basic chemistry that a chemistry professor wouldn’t miss it. (Surely?!) So I thought there must be something more to it and I’d need to read exactly what he did. Perhaps he put it in the food, not the water? Perhaps he used a soluble variant. Although there is hte issue of how its taken in (gills v. mouth). And at that point, I thought I haven’t time for this and left it.

    In any event, fish would be a poor model organism to choose I would think. Since you’re testing v. human cardiovascular systems, you’d think you’d at least want a mammal. With that in mind whatever he did to the fish is probably more-or-less moot anyway. It also meant any concerns about this experiment would be rather moot too! (I’d be more interested in the mouse work.)

    My understanding is that solubility in drug development is complicated by the need for the compound(s) to pass through lipid membranes. Solubility is certainly important, though.

    In any event, all this, to me, points to a common theme: there needs to be testing in appropriate testing FIRST (including in appropriate model organisms) and these tests should be allowed to be examined by independent & competing groups before being accepted as safe and carrying out the intended function. Of course this is part of the what the FDA was set up for, but Boyd’s approach would appear to be to side-step this by trying to “relabel” it as “food supplement”.

    As a silly example, it needs to be shown that the compound can even enter the body or bloodstream, otherwise at best it’d be an expensive way of doing nothing! But like the solubility in water issue, this is very obvious too so its hard to imagine that its been overlooked.

    Because they haven’t released this information (assuming sound testing has been done), there seems to be no way for others to determine what, if any, real testing has been done and if it will stand up to wider criticism.

    — Heraclides    Aug 11, 06:34 PM    #

  14. Heraclides,

    fish, especially embryonic zebrafish, but also adults are often used as models for toxicity tests (see for example here http://toxsci.oxfordjournals.org/cgi/content/abstract/86/1/6). However, these are also experiments on vertebrates and need IACUC approval needs to be in place. You cannot just simply “try out the substance on some fish”. (not implying that this happened here, but it would be nice to know for sure).

    — Catherina    Aug 12, 04:06 AM    #

  15. I don’t know much about toxicity testing. All I can do is quote what is on Atwood’s slide:

    BDETH2 is soluble in water at only 5ppm, in water + ethanol at 20 ppm and in pure ethanol at 3g/100mL – so freely soluble in ethanol.

    The toxicity for minnows is listed as 292 ppm. I had assumed that this means that half the minnows swimming in a 229 ppm solution will die. But that doesn’t seem consistent with the low solubility.

    Other minnow toxicity testing (for different compounds, such as ethylene glycol) quotes the results in mg/Kg, which implies that they give a dose of a certain number of mg per Kg of weight of minnow. Like you, I’m not sure how one would dose a minnow! A solution of 1 mg/Kg (of solution) is the same as a 1 ppm solution. And likewise, feeding 292 mg to BDETH2 to 1Kg of minnow, and seeing half of them die might be the same as an LC50 of 292 ppm.

    One other thing to point out is that it is reasonable to test the toxicity of a chemical intended to treat contaminated water on fish. Not one intended to administration to children.

    Haley’s slides imply that binding with glutathione makes BDETH2 lipid soluble. I don’t know what to make of that.

    — Jennifer    Aug 12, 08:51 AM    #

  16. Catherina:

    Thanks for that. I was being a little simple and not very clear. I’m not a toxicologist (obviously!), but I am aware that fish and many other “model” organisms are used in toxicology, although being outside of that field, I’m not familiar with specifics. I guess my post reads badly to those working on fish toxicology! If so, I’m sorry—I wasn’t trying to say that fish toxicology studies are useless, but rather that the solubility (or not) in the fish tank was perhaps a moot issue given the mouse studies. Also, I was referring only to the CV system, not to, say, developmental issues, effects on other organs, etc., but I didn’t make that clear.

    Having said that, I have to admit to taking a naïve view that—generalising here, and bearing in mind I’m not a specialist—fish studies are more useful to rule something out, than rule something in, so to speak. Is this wrong?

    That is, if the fish being tested don’t look too well, you might say, “OK, maybe we’d best avoid this substance.” (Or from a budgetary or commercial point of view, think that the odds of main a usable product are getting longer, maybe we should spend our time and money looking at something else.) But if the fish are just fine, my thinking was that you would say “OK, might be worth studying more closely”, using more detailed studies or more closely-related model organisms, rather than “this stuff must be OK”. — ?

    (More, for my education: my naïve thinking would have fish embryo studies say something about if a compound was likely to be unsafe for the pre-natal case, not in a child or adult; and adult fish CV systems be too divergent to be meaningful in ruling a substance OK for humans? I realise specifics probably make this an impossibly difficult question!—I’m only after the general gist of it.)

    — Heraclides    Aug 12, 07:30 PM    #

  17. to properly test chelators you need to autopsy the brain and look for scythed large scale neural structures which actually may be a ten year research project in itself

    also the thyroid would need biopsing as well, though i am not sure what the mechanisim of damage there is, but certainly mobile mercury seems to do the thyroid in

    the fda standards of injury are incompedent, witness vioxx and thier being successfully sued over thier stance on amalgam filling toxicity

    lawsuit

    — Andrew    Aug 16, 12:33 AM    #

  18. just a word of caution against rushing to get amalgams removed, out of the frying pan into the fire so to speak

    my write up
    dentistry in the index

    — Andrew    Aug 16, 01:31 AM    #

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