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In the Pipeline
Autism


June 27, 2005

Thimerosal, AgainEmail This EntryPrint This Article

Robert F. Kennedy, Jr. has helped to put this issue right back on the front pages again. I spoke a lot about thimerosal in vaccines, and its putative link to autism, back in late 2002, which is when the controversy last flared to this degree. (I've put those old posts over into the Autism category on the right for reference.)

I've read Kennedy's Rolling Stone / Salon article, and it's quite a piece of work. Kennedy is no stranger to exaggeration and to outright misrepresentation, and he's in typical form here. (Try checking out the corrections that have already run, and be sure to check back for updates. A keyboard macro that says "Salon and Rolling Stone regret the errors" would come in handy, no doubt.)

I'd like to refer everyone to the Blissful Knowledge blog and to Orac for thorough coverage of this issue. These folks have done all the heavy lifting, and there's a lot of stuff to lift here. I'm in debt to them.

The short take-home? There is still no persuasive evidence linking thimerosal to autism, no matter what Robert Kennedy tells you. But this story will take years to die - ah, what am I talking about? It never will. The New York Times ran an excellent article last weekend by Gardiner Harris, making just that point. There are people who will live the rest of their lives convinced that thimerosal has caused thousands of cases of autism, no matter what amount of evidence piles up to the contrary.

I remember reading posts on this on Blissful Knowledge back in late 2002, when I was writing mine. My children, 4 and 2 years old at the time, have been fine since then. But the author of that site discovered a year later that his own son was autistic, a diagnosis that causes me physical pain each time I just hear about it. As a parent, I cannot imagine what it must be like to deal with the reality, and I have deep sympathy and respect for those who have to. I hope that my profession can eventually do something to help. I do not think, based on the evidence we have, that my profession is to blame.

March 10, 2004

A Mechanism for ThimerosalEmail This EntryPrint This Article

There's some fresh news in the (quite possibly endless) debate about the vaccine preservative thimerosal. The Institute of Medicine is working on another report, due in several months. Their last report, in 2001, found no evidence to support a link, but didn't dismiss the possibility, either.

I've written about this topic before. My belief, then and now, is that autism and thimerosal are very unlikely to be related. I haven't seen any data that make me lean the other way, and the evidence against a link has continued to pile up. One of my objections to the hypothesis has been that it's hard to rationalize, mechanistically. Mercury compounds are certainly neurological bad news, but autism hasn't generally been noted as a symptom of developmental mercury exposure. (There's a different set of effects, instead.) It's hard to come up with an explanation for why thimerosal's effects would be different and specific, while still partaking of the general toxicity of mercury compounds. (Why no rising epidemic of, say, cerebral palsy?) And there's the matter of the low dose, too.


But now there's a paper in Molecular Psychiatry by a team of researchers (from Northeastern and several other schools) which suggests a mechanism. They're looking at the synthase enzyme that produces the amino acid methionine, which is an important source of methyl groups for other enzymatic systems. DNA methylation is particularly important in gene expression, and many cellular growth factor pathways seem to have a methylation requirement in them as well. They've found that thimerosal is a powerful inhibitor of two particular growth-factor driven methylation reactions, with an IC50 of about 1 nanomolar.

Single-digit nanomolar is the kind of inhibitory constant that we look for in a new drug, too, so it's certainly plausible that that could have effects in vivo (if the pharmacokinetic behavior - blood and tissue levels of the compound - go along.) The paper points out that the ethylmercury blood levels produced by thimerosal-containing vaccines are in the 4 to 30 nM range, which is enough of a multiple of the IC50 to keep the hypothesis going (but see below.) So is this the proof against thimerosal, or not?

Well, on one level, this could answer some of my mechanistic objections. But I still have the same questions as before. This could be a refinement, but not enough by itself to establish a link. We're still in the same place: It's not that I can't imagine that thimerosal could be toxic, it's that I have trouble with it being toxic in just such a way as to produce only autism. Methylation pathways are ubiquitous - how does such a specific phenotype show up from this? (More such scepticism from an immunologist at McGill is here.


The authors do suggest some possible answers. Perhaps some individuals have a less robust methylation system than others, especially in specific brain development pathways, and are thus predisposed to thimerosal-induced damage. That's definitely a hypothesis worth investigating. If that looks like it's the case, I'll have to upgrade my take on the whole idea, subject to the 800-pound-gorilla in the last paragraph below.

And they suggest some limitations to their work. For one thing, they're working on cultured cell lines, which are tumor-derived and may well respond quite differently than primary cells in vivo. They also point out the potential complication that their cells have not fully differentiated into neurons. It's responsible of them to mention these factors.

I also wonder what the hit rate is in this assay - if we run a few thousand natural products or other environmental-exposure compounds through, how many are positive at nanomolar levels? I could also add that the ethylmercury blood levels they quote might not mirror the levels in the brain. That's been a battleground in the whole thimerosal debate, because we don't have definitive mercury pharmacokinetics in the brains of human children (and I sure can't think of an acceptable way to get 'em, either. The methods we use for that kind of data in rodent studies are clearly not going to apply!)

But my biggest objection to a thimerosal/autism link is epidemiological. So far, there seems to have been no change in the autism rate in response to the discontinuation of thimerosal. Data continue to be collected, of course, but there's no apparent connection, even from countries that eliminated the compound before the US did (and thus have a longer baseline.) The real-world numbers trump any amount of biochemical speculation. That goes for my own ideas as well, as my research projects demonstate to me regularly.

January 13, 2004

Here and ThereEmail This EntryPrint This Article

I wanted to take a moment to mention some interesting posts around Blogdom that readers may not have seen. In a response to the news on secretin for autism (see my post below), Dwight Meredith writes on what it was like at its peak of interest:


Human secretin, swine secretin, herbal secretin (which as far as I can tell is an oxymoron) and synthetic secretin were all hawked relentlessly to the parents of autistic children. The price of secretin skyrocketed. People were paying $2,000 for an amount of secretin that before the buzz had cost about $30. It is not an exaggeration to say that parents were mortgaging their homes to purchase secretin for their kids. We now know that a sugar pill would have been equally effective.


Please note that all of that buzz was generated by the fact that a few autistic children had improved after being given secretin for digestive problems. The autism community could not wait for double blind and placebo tested trials. We wanted our miracle and we wanted it now.


This is a man who writes from personal experience, I should note. And I can understand the desperation (well, as much as anyone in my position can - I have two small children, neither of whom have - thus far - shown any neurological abnormalities.) What I have trouble imagining, though, is what goes through the mind of someone who peddles "herbal secretin" to parents who are begging for something to help their autistic child.


Herbal secretin? They didn't even bother making it sound like anything but a heartless scam. Figured the customer base would be too desperate to care, I suppose. I'm ashamed to be in the same phylum with creatures who would do something like this.


There's a larger point about the wait for double-blinded trials, too, of course, which I should save for a longer post. The short form is that I can see the point that some people make, that it would be better to require safety (Phase I) trials, then stand back and let efficacy be sorted out in the marketplace. (SMU's Steve Postrel and I had a long e-mail exchange on that subject a year or so ago.) But then I hear about this sort of thing, and start to think that this is one of those sensible ideas that would only work on some other species than humans.


The other post I wanted to mention is over at Colby Cosh's site. Talking about medical progress, he hits on the idea of looking at the causes of death in the records of ballplayers from the old days, who were in their physical prime. It's an alarming list, and most of the things on it are, fortunately, in the process of disappearing from the world. And good riddance. As Cosh says: "I don't know how anybody kept from just going insane before antibiotics existed, with death lurking around every corner."


One final note - I've forgotten to mention that Charles Murtaugh is back blogging again. There's lots of good new stuff; just start at the top and work your way down.

January 06, 2003

Compare and ContrastEmail This EntryPrint This Article

Dwight Meredith over at PLA pointed out to me that the UC-Davis study on the prevalence of autism in California is online. It hasn't been published in a journal yet, and the JAMA paper I mentioned last week doesn't reference it. But the editorial comment in the same issue does.

As it should, since there's certainly an issue to be resolved. The Davis authors feel that their evidence makes it more likely that autism is actually increasing, even after correcting for wider diagnostic criteria, and so on. They still couldn't correct for all the potential differences in case finding, though, and it's unknown how much this has affected the final numbers. The JAMA editorial points out a recent paper analyzing the same California data which concluded that "diagnostic substitution" had occurred - a decrease in the "mental retardation" category had been taken up by an increase in the autism category.

Dwight's view, I believe, is that there has indeed been a real increase in autism - although short of the epidemic that some in the press have spoken of. I look forward to seeing how more data prove or disprove this - if there really is an increase, it's a tragedy, of course, but it could also provide a rare chance to uncover some important facts about the etiology of the condition. You don't get many good shots at the causes of a complex syndrome like this.

I think that's one reason the thimerosal provision that worked its way into the Homeland Security bill upsets me. Unlike many, I don't see it as evidence of a conspiracy to cover up wrongdoing (although one of the worst parts is that it provides spectacular ammunition to those who do.) I think that the less political maneuvering and grandstanding there is on this topic, the better. Most things would be improved that way, come to think of it. I did a quick Google search while writing this post, and since it had "autism" as a search term, up popped a sponsored link on the right-hand side of the page: "Child vaccines are linked to autism. Free case review by our lawyers." I'm glad these guys are so certain.

It's going to be hard enough to figure all this out without all the bricks flying through the air. As I've said, I think that thimerosal is a red herring. But if autism really is on the increase - and I'm still on the fence about that - then finding the real cause would be the most important research priority in the whole field.

January 02, 2003

The Rate of AutismEmail This EntryPrint This Article

There's a new study out in JAMA (free full text here) on the incidence of autism in the US population. Before getting to what the article actually says, it's worth seeing what the media are saying it says. The New York Times headlines it "Study Shows Increase in Autism", and Yahoo runs it as "Study Confirms Marked Rise in Autism."

The AP ("CDC Study Finds Autism To Be Less Rare") and Reuters ("Atlanta Study Finds Rise in Autism Diagnoses" do better. That's because it's very hard to tell if there's a real rise taking place or not. The numbers are going up, but the interpretation isn't as easy as it sounds. To quote the authors:

Debate continues about whether the overall prevalence of autism has increased or whether past rates underestimated true prevalence. This debate is difficult to resolve retrospectively.

It's difficult for these reasons:

In the United States, the increase in the number of individuals receiving services for autism may be attributed to several factors. Changes in diagnostic criteria have expanded the concept of autism to a spectrum of disorders. Heightened public awareness of autism also has had an effect, due in large part to efforts of parent and advocacy groups, availability of more medical and educational resources, increased media coverage of affected children and families, and more training and information for physicians, psychologists, and other service providers. Also, in 1991, the US Department of Education added autism as a category for special education services, possibly leading to increases in the number of children classified with autism because of the availability of these services. The mandate for early intervention services for children with DDs, including autism, also has contributed to greater attention being placed on autism. At the same time, studies are suggesting that some children with autism respond well to early, intense educational intervention. The combined influence of these factors has probably contributed to the identification of more individuals with autism. However, it remains unclear whether specific environmental, immunologic, genetic, or unidentified factors also have contributed to these higher reported prevalence rates.

I think that's a very fair statement. Some environmental factor might be at work, if the increase is a real one. If so, tracking it down is going to be a major undertaking, because instead of one smoking gun, there might be several - insufficient by themselves, but adding up to something. These things are very hard to unravel, because it's almost impossible to get statistically meaningful samples that represent the range of variables that you're trying to check.

As for clues to any environmental causes, one footnote from the article that I have access to is from 2000, in Environmental Health Perspectives (Medline abstract here.)

Epidemiologic studies indicate that the number of cases of autism is increasing dramatically each year. It is not clear whether this is due to a real increase in the disease or whether this is an artifact of ascertainment. A new theory regarding the etiology of autism suggests that it may be a disease of very early fetal development (approximately day 20-24 of gestation). This theory has initiated new lines of investigation into developmental genes. Environmental exposures during pregnancy could cause or contribute to autism based on the neurobiology of these genes.

I find this idea somewhat more plausible than the thimerosal hypothesis, or any other environmental factor acting in the first years after birth. For what it's worth, it makes more sense to me that any causative agent would be something that's present in very small amounts, which would overall have greater leverage to cause broad-based harm earlier in brain development. That's an Occam's razor approach, which doesn't always cut the right way, but that's how I'd call it now - if there's an environmental cause at all, and if there is indeed a rise in autism. And we're still not sure about either one.

December 22, 2002

Clearance SaleEmail This EntryPrint This Article

While I'm on the subject, I'll mention some details that will be familiar to my fellow medicinal chemists. The body has a lot of mechanisms to deal with foreign substances. We assume that all our drugs are going to be handled by them, one way or another, and we just try to keep the stuff around long enough to work. (And that's usually the case - once in a while you'll come across a compound that binds to some protein so tightly that it doesn't disappear until that population of protein molecules is metabolically recycled, and that's bad news. Altering a protein that permanently can cause more effects than you're looking for, the worst of which is setting off an immune response.)

The two sorts of systems that clear out unrecognized molecules are divided into Phase I and Phase II enzymes. The Phase I crowd rips into anything that fits into their active sites, which are biased toward greasy structures, and tears the molecules up in ways to make them more water-soluble. The so-called P450 enzymes in the liver are the big players here, and they can oxidize just about anything that comes their way. If the newly torn-up substance is sufficiently water-soluble, out it goes into the urine next time it hits the kidneys.

If it isn't, it hangs around long enough for a Phase II enzyme to get ahold of it. These attach what are basically disposal tags to molecules, groups that are made to be pulled out of the blood and into the urine. A sugar called glucuronic acid is a common tag, and another molecule called glutathione does a lot of this, too. Sometimes Phase II pathways are the main way a drug is eliminated - depends on its structure. One way or another, the body finds a way to get rid of things.

And if it doesn't, that can mean trouble. If the body's exposed multiple times to something that isn't cleared well, the stuff can accumulate in one tissue or another. And while that's not always harmful, there's no way it can help, either. This is the problem with heavy metals like lead or mercury. They're not the sort of thing that can fit well into the P450 enzymes, and they're generally already oxidized as far up as they can be, anyway. Compared to drugs, they're handled poorly. Metals are often excreted bound to sulfur-containing proteins, or as the salt with cysteine itself (the amino acid unit that contains the reactive SH group.) There's a lot of oxidation-reduction chemistry involved - a dose of a metal salt may end up being excreted as the reduced element itself.

That takes us back to tonight's thimerosal theme. The recent Lancet study found that most of the mercury was eliminated through the GI tract, mostly as inorganic (elemental) mercury. The faster it gets converted to that, the better, I'd say, because doses of mercury metal itself are virtually harmless. It's just too insoluble to get into trouble. They also found much quicker excretion than they expected, which was good news, too (as I mentioned on December 4, below.) The follow-up study is going to look at the early pharmacokinetics of thimerosal, to see if there's some sort of maximum-concentration spike that's being missed.

As has been pointed out, if thimerosal is a cause of autism (I'll reiterate that I doubt it,) then it only happens in a few children. So the criticism can always be made that a small study would likely miss testing the sort of child that might be affected. This is true, but if the levels are low, with little variation in the individuals studied, then you have to assume that there's a subpopulation that is quite different. If you have to string together enough assumptions, then you start to rule out the hypothesis - that's as close to proving a negative as you can get in science. We'll see what the numbers have to say.

Thimerosal - A Chemical PointEmail This EntryPrint This Article

I haven't posted on this issue recently (although I'm working on a column for TechCentral Station,) but Dr. Manhattan has been writing some good pieces on it (check the comments sections for more.)

There's one thing I'd like to add, as an organic chemist. A persistant statement that I see about thimerosal is that it's "49% ethylmercury by weight." This makes it sound like it's a mixture of components, one of which is ethyl mercury, which really isn't the case. Thimerosal is a single compound, a mercury with an ethyl group and a thiosalicylate (the mercury is in the +2 oxidation state.) When sulfur is bonded to mercury, its reactive characteristics change quite a bit. A dose of thimerosal would not be expected to be the same as a dose of ethyl (more correctly, diethyl) mercury. And it isn't.

Thimerosal - a Chemical PointEmail This EntryPrint This Article

I haven't posted on this issue recently (although I'm working on a column for TechCentral Station,) but Dr. Manhattan has been writing some good pieces on it (check the comments sections for more.)

There's one thing I'd like to add, as an organic chemist. A persistant statement that I see about thimerosal is that it's "49% ethylmercury by weight." This makes it sound like it's a mixture of components, one of which is ethyl mercury, which really isn't the case. Thimerosal is a single compound, a mercury with an ethyl group and a thiosalicylate (the mercury is in the +2 oxidation state.) When sulfur is bonded to mercury, its reactive characteristics change quite a bit. A dose of thimerosal would not be expected to be the same as a dose of ethyl (more correctly, diethyl) mercury. And it isn't.

Clearance SaleEmail This EntryPrint This Article

While I'm on the subject, I'll mention some details that will be familiar to my fellow medicinal chemists. The body has a lot of mechanisms to deal with foreign substances. We assume that all our drugs are going to be handled by them, one way or another, and we just try to keep the stuff around long enough to work. (And that's usually the case - once in a while you'll come across a compound that binds to some protein so tightly that it doesn't disappear until that population of protein molecules is metabolically recycled, and that's bad news. Altering a protein that permanently can cause more effects than you're looking for, the worst of which is setting off an immune response.)

The two sorts of systems that clear out unrecognized molecules are divided into Phase I and Phase II enzymes. The Phase I crowd rips into anything that fits into their active sites, which are biased toward greasy structures, and tears the molecules up in ways to make them more water-soluble. The so-called P450 enzymes in the liver are the big players here, and they can oxidize just about anything that comes their way. If the newly torn-up substance is sufficiently water-soluble, out it goes into the urine next time it hits the kidneys.

If it isn't, it hangs around long enough for a Phase II enzyme to get ahold of it. These attach what are basically disposal tags to molecules, groups that are made to be pulled out of the blood and into the urine. A sugar called glucuronic acid is a common tag, and another molecule called glutathione does a lot of this, too. Sometimes Phase II pathways are the main way a drug is eliminated - depends on its structure. One way or another, the body finds a way to get rid of things.

And if it doesn't, that can mean trouble. If the body's exposed multiple times to something that isn't cleared well, the stuff can accumulate in one tissue or another. And while that's not always harmful, there's no way it can help, either. This is the problem with heavy metals like lead or mercury. They're not the sort of thing that can fit well into the P450 enzymes, and they're generally already oxidized as far up as they can be, anyway. Compared to drugs, they're handled poorly. Metals are often excreted bound to sulfur-containing proteins, or as the salt with cysteine itself (the amino acid unit that contains the reactive SH group.) There's a lot of oxidation-reduction chemistry involved - a dose of a metal salt may end up being excreted as the reduced element itself.

That takes us back to tonight's thimerosal theme. The recent Lancet study found that most of the mercury was eliminated through the GI tract, mostly as inorganic (elemental) mercury. The faster it gets converted to that, the better, I'd say, because doses of mercury metal itself are virtually harmless. It's just too insoluble to get into trouble. They also found much quicker excretion than they expected, which was good news, too (as I mentioned on December 4, below.) The follow-up study is going to look at the early pharmacokinetics of thimerosal, to see if there's some sort of maximum-concentration spike that's being missed.

As has been pointed out, if thimerosal is a cause of autism (I'll reiterate that I doubt it,) then it only happens in a few children. So the criticism can always be made that a small study would likely miss testing the sort of child that might be affected. This is true, but if the levels are low, with little variation in the individuals studied, then you have to assume that there's a subpopulation that is quite different. If you have to string together enough assumptions, then you start to rule out the hypothesis - that's as close to proving a negative as you can get in science. We'll see what the numbers have to say.

December 05, 2002

A Quick Tour Through the MudholeEmail This EntryPrint This Article

Before leaving this subject (for now,) I thought I'd take a look at some of the sites I mentioned that pop up when you do a Google search for thimerosal. I hope you all will pardon me for not directly linking these people. I'm not particularly interested in sending them any traffic.

From a law firm:

Recently evidence has surfaced linking Asperger's Disorder and other pervasive developmental disorders associated with Autism to mercury poisoning in infants as a result of childhood vaccines containing thimerosal. Thimerosal is preservative that pharmaceutical companies added to vaccines in order to mass package them, which is far less expensive then individually packaging each vaccine dose. Unfortunately this attempt to save money appears to have endangered thousands children in the United States.

And from another, under the heading "Have You Been Injured by a Thimerosal Vaccine?":

Symptoms of mercury toxicity in young children are extremely similar to those of autism. This can explain the recent increase in the numbers of children diagnosed with autism since the early 1990's. The numerous amount of children diagnosed with autism seems to directly correlate with the recommendation of both the hepatitis B and HIB vaccine to infants in the early 1990s.

Here's a whole group of legal firms, with a corresponding rise in the amount of misinformation:

The high mercury content of Thimerasal (sic) poses a serious health risk for children. In the first few months of a baby's life, an infant may have already received up to 15 vaccinations. The levels of toxic mercury in these vaccinations can cause lasting and serious developmental and neurological problems in these children. The Centers for Disease Control and Prevention has linked mercury-containing vaccines and developmental disorders.

And one more, just to get the flavor of the business:

A full generation of children in America was exposed to dangerous doses of highly toxic ethyl mercury from 1990 through 2000. Children were injected with the toxic mercury that was a major ingredient in a chemical product called thimerosal. . .With each dose of vaccine that contained thimerosal, a child would also get an injection of toxic mercury. Each one of those mercury injections exposed the child to levels of toxic mercury in excess of the federal government's own safety guidelines. Mercury is widely known to cause neurological damage, often permanent. Current clinical and epidemiological research suggests that the mercury-laden thimerosal so widely given to children by the drug companies in the 1990's might cause a range of neurological and neurodevelopmental injuries, including autism. Compounding this public health disaster is that the toxic exposure was entirely avoidable. . .Thimerosal had nothing to do with vaccine safety, and everything to do with the profits and convenience of packaging for the pharmaceutical companies.

All right, enough. I hardly need to say that I find the above excerpts to be full of misinterpretations, half-truths, distortions, and out-and-out falsehoods, and that's just the beginning of what's out there. You'd think the drug industry was full of Mengeles, high-fiving each other when another child gets sick and another nickel drops into the hopper.

I hope that I've been able to show (or at least point people to) some of the complexities of the whole thimerosal question (that Institute of Medicine report I've linked to will really give you the authentic scientific experience, I can tell you.) But tort lawyers have no need of complexity. All they need are desperate clients and a deep-pocketed defendant or two. . .

More on Autism (And Mercury)Email This EntryPrint This Article

After reading my post below, I thought I should clarify a couple of things. I realize that some who believe in a thimerosal-autism link probably don't argue for a specific brain lesion effect (which spent yesterday's post argues against.) Rather, the general effects of organomercury toxicity could be the cause. I don't think that this argument holds up - see this section of the Institute of Medicine report on thimerosal. Mercury causes a wide variety of neurological symptoms, and it generally causes them all at once.

Autism is probably too specific a condition to ascribe to a general organomercury effect. But, as I argued yesterday, it's still too general a condition to ascribe to some specific MPTP-like thimerosal toxicity. That doesn't close out the possible explanations; there's still room in there. But it does set bounds on them, and the size of the space that's left - coupled with the Rochester data that I mentioned previously - make it increasingly likely that this isn't the answer.

More on Autism and MercuryEmail This EntryPrint This Article

After reading my post below, I thought I should clarify a couple of things. I realize that some who believe in a thimerosal-autism link probably don't argue for a specific brain lesion effect (which spent yesterday's post argues against.) Rather, the general effects of organomercury toxicity could be the cause. I don't think that this argument holds up - see this section of the Institute of Medicine report on thimerosal. Mercury causes a wide variety of neurological symptoms, and it generally causes them all at once.

Autism is probably too specific a condition to ascribe to a general organomercury effect. But, as I argued yesterday, it's still too general a condition to ascribe to some specific MPTP-like thimerosal toxicity. That doesn't close out the possible explanations; there's still room in there. But it does set bounds on them, and the size of the space that's left - coupled with the Rochester data that I mentioned previously - make it increasingly likely that this isn't the answer.

A Quick Tour Through the MudholeEmail This EntryPrint This Article

Before leaving this subject (for now,) I thought I'd take a look at some of the sites I mentioned that pop up when you do a Google search for thimerosal. I hope you all will pardon me for not directly linking these people. I'm not particularly interested in sending them any traffic.

From a law firm:
Recently evidence has surfaced linking Asperger's Disorder and other pervasive developmental disorders associated with Autism to mercury poisoning in infants as a result of childhood vaccines containing thimerosal. Thimerosal is preservative that pharmaceutical companies added to vaccines in order to mass package them, which is far less expensive then individually packaging each vaccine dose. Unfortunately this attempt to save money appears to have endangered thousands children in the United States.

And from another, under the heading "Have You Been Injured by a Thimerosal Vaccine?":
Symptoms of mercury toxicity in young children are extremely similar to those of autism. This can explain the recent increase in the numbers of children diagnosed with autism since the early 1990's. The numerous amount of children diagnosed with autism seems to directly correlate with the recommendation of both the hepatitis B and HIB vaccine to infants in the early 1990s.

Here's a whole group of legal firms, with a corresponding rise in the amount of misinformation:
The high mercury content of Thimerasal (sic) poses a serious health risk for children. In the first few months of a baby's life, an infant may have already received up to 15 vaccinations. The levels of toxic mercury in these vaccinations can cause lasting and serious developmental and neurological problems in these children. The Centers for Disease Control and Prevention has linked mercury-containing vaccines and developmental disorders.

And one more, just to get the flavor of the business:
A full generation of children in America was exposed to dangerous doses of highly toxic ethyl mercury from 1990 through 2000. Children were injected with the toxic mercury that was a major ingredient in a chemical product called thimerosal. . .With each dose of vaccine that contained thimerosal, a child would also get an injection of toxic mercury. Each one of those mercury injections exposed the child to levels of toxic mercury in excess of the federal government's own safety guidelines. Mercury is widely known to cause neurological damage, often permanent. Current clinical and epidemiological research suggests that the mercury-laden thimerosal so widely given to children by the drug companies in the 1990's might cause a range of neurological and neurodevelopmental injuries, including autism. Compounding this public health disaster is that the toxic exposure was entirely avoidable. . .Thimerosal had nothing to do with vaccine safety, and everything to do with the profits and convenience of packaging for the pharmaceutical companies.

All right, enough. I hardly need to say that I find the above excerpts to be full of misinterpretations, half-truths, distortions, and out-and-out falsehoods, and that's just the beginning of what's out there. You'd think the drug industry was full of Mengeles, high-fiving each other when another child gets sick and another nickel drops into the hopper.

I hope that I've been able to show (or at least point people to) some of the complexities of the whole thimerosal question (that Institute of Medicine report I've linked to will really give you the authentic scientific experience, I can tell you.) But tort lawyers have no need of complexity. All they need are desperate clients and a deep-pocketed defendant or two. . .

December 04, 2002

NeurotoxinsEmail This EntryPrint This Article

One reason that I have doubts about thimerosal as a cause of autism goes back to mechanism of action. Are there any specific compounds that are know to cause specific neurological problems? (There are plenty that cause more diffuse symptoms, often motor-related, such as tardive dyskinesia.)

Well, there's one prominent example: MPTP, known to the trade as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. It's a reasonably simple organic molecule, and to a medicinal chemist it certainly looks like a central nervous system agent (if I had a dollar for every CNS-active piperidine or piperazine that's been reported in the patent literature, I could retire.) But no one could have predicted what it actually does.

The compound gets oxidized by monoamine oxidase B, which is a common fate for molecules of its type. That produces a pyridinium compound which is the real problem. As fate would have it, it's a fine substrate for the dopamine transporter protein, which imports dopamine into cells that require it. And in a further stroke of bad luck, the same compound is also an inhibitor of a key enzyme in mitochondria - and you don't want to do anything to your mitochondria. Cell death follows in short order if you shut them down too hard.

So everything's set up for a disastrous cascade: MPTP's turned into something dangerous, which is taken up selectively into cells that import a lot of dopamine, which process then kills them. Unfortunately, the cells that import the most dopamine are those in the substantia nigra, up in the forebrain. Which is why in the late 1970s and early 1980s, a number of young drug users started showing up in emergency rooms on the west coast with what appeared to be some sort of catatonia. They didn't move; they weren't responsive - everyone waited for whatever it was to wear off so they could start to recover.

It didn't, and they didn't. At first, no one recognized what was going on, mainly because no one had ever seen a twenty-year-old with advanced Parkinson's disease before. These patients had taken batches of some sort of home-brewed meperidine (better known as Demerol) or a derivative, and the synthetic route had produced some MPTP as a contaminant. Quality control isn't a big feature of the basement drug industry.

The affected users improved slightly when given L-Dopa, as you'd expect from a Parkinson's patient. But not much, and not for long. The damage is permanent - they skipped years of the normally slow progression of the disease and went straight to its worst phase in one night. Is this what's happening with thimerosal and autism?

I strongly doubt it. Here's why: Parkinson's is caused by a lesion in a specific area of the brain, in a specific (and unusual) cell type. MPTP is toxic to some specific and unusual cell types, and it's just a terrible stroke of misfortune that they happen to overlap. But despite a tremendous search, no one has been able to tie autism to primary lesions in a specific region of the brain, much less down to certain cells. I'm not saying that it's impossible - just that it's been looked for strenuously, and thus far in vain. Studies of brain activity in autistic patients show a variety of differences, but nothing that can be pinned down as a cause.

The other half of the story is the reactivity of thimerosal itself. There's nothing known about the compound that would suggest that it has a particular affinity (or particular toxicity) to any one type of cell over another. Organomercury compounds are (in high doses) pretty bad news in general, causing all sorts of neurological problems. They just don't seem to be specifically toxic.
So there's no evidence, mechanistically, on either side of the hypothesis. That doesn't disprove it, of course - it's not impossible that there would be some sort of subtle effect that we've missed so far. It's just that I believe that the odds are very much against it. We'd have to string together too many (big) assumptions in a row, and the evidence isn't nearly compelling enough to make us do that.
If thimerosal is cleared as a possible agent for autism, that'll be good news and bad news. The good news is, of course, that we haven't been damaging children without realizing what we're doing. The bad news will be that we still won't know why some children become autistic and others don't, a lack of knowledge that's hard to bear.

The only other good news I can think of - and a hard, sour piece of good news it is - would be that parents of autistic children who have feared that they were the cause of their children's condition - just by having them vaccinated - could at least put that part of their burden down. It's not enough, but it's something. Believe me, I have two small kids myself, and the thought of either of them showing signs of neurological trouble makes me start to double over. I can't even imagine what it must be like. But to those in that situation, all I can say is that I really don't think that some doctor did it to your child. Or that some drug company did it to your child. Or that you did, either. For what it's worth.

NeurotoxinsEmail This EntryPrint This Article

One reason that I have doubts about thimerosal as a cause of autism goes back to mechanism of action. Are there any specific compounds that are know to cause specific neurological problems? (There are plenty that cause more diffuse symptoms, often motor-related, such as tardive dyskinesia.)

Well, there's one prominent example: MPTP, known to the trade as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. It's a reasonably simple organic molecule, and to a medicinal chemist it certainly looks like a central nervous system agent (if I had a dollar for every CNS-active piperidine or piperazine that's been reported in the patent literature, I could retire.) But no one could have predicted what it actually does.

The compound gets oxidized by monoamine oxidase B, which is a common fate for molecules of its type. That produces a pyridinium compound which is the real problem. As fate would have it, it's a fine substrate for the dopamine transporter protein, which imports dopamine into cells that require it. And in a further stroke of bad luck, the same compound is also an inhibitor of a key enzyme in mitochondria - and you don't want to do anything to your mitochondria. Cell death follows in short order if you shut them down too hard.

So everything's set up for a disastrous cascade: MPTP's turned into something dangerous, which is taken up selectively into cells that import a lot of dopamine, which process then kills them. Unfortunately, the cells that import the most dopamine are those in the substantia nigra, up in the forebrain. Which is why in the late 1970s and early 1980s, a number of young drug users started showing up in emergency rooms on the west coast with what appeared to be some sort of catatonia. They didn't move; they weren't responsive - everyone waited for whatever it was to wear off so they could start to recover.

It didn't, and they didn't. At first, no one recognized what was going on, mainly because no one had ever seen a twenty-year-old with advanced Parkinson's disease before. These patients had taken batches of some sort of home-brewed meperidine (better known as Demerol) or a derivative, and the synthetic route had produced some MPTP as a contaminant. Quality control isn't a big feature of the basement drug industry.

The affected users improved slightly when given L-Dopa, as you'd expect from a Parkinson's patient. But not much, and not for long. The damage is permanent - they skipped years of the normally slow progression of the disease and went straight to its worst phase in one night. Is this what's happening with thimerosal and autism?

I strongly doubt it. Here's why: Parkinson's is caused by a lesion in a specific area of the brain, in a specific (and unusual) cell type. MPTP is toxic to some specific and unusual cell types, and it's just a terrible stroke of misfortune that they happen to overlap. But despite a tremendous search, no one has been able to tie autism to primary lesions in a specific region of the brain, much less down to certain cells. I'm not saying that it's impossible - just that it's been looked for strenuously, and thus far in vain. Studies of brain activity in autistic patients show a variety of differences, but nothing that can be pinned down as a cause.

The other half of the story is the reactivity of thimerosal itself. There's nothing known about the compound that would suggest that it has a particular affinity (or particular toxicity) to any one type of cell over another. Organomercury compounds are (in high doses) pretty bad news in general, causing all sorts of neurological problems. They just don't seem to be specifically toxic.

So there's no evidence, mechanistically, on either side of the hypothesis. That doesn't disprove it, of course - it's not impossible that there would be some sort of subtle effect that we've missed so far. It's just that I believe that the odds are very much against it. We'd have to string together too many (big) assumptions in a row, and the evidence isn't nearly compelling enough to make us do that.

If thimerosal is cleared as a possible agent for autism, that'll be good news and bad news. The good news is, of course, that we haven't been damaging children without realizing what we're doing. The bad news will be that we still won't know why some children become autistic and others don't, a lack of knowledge that's hard to bear.

The only other good news I can think of - and a hard, sour piece of good news it is - would be that parents of autistic children who have feared that they were the cause of their children's condition - just by having them vaccinated - could at least put that part of their burden down. It's not enough, but it's something. Believe me, I have two small kids myself, and the thought of either of them showing signs of neurological trouble makes me start to double over. I can't even imagine what it must be like. But to those in that situation, all I can say is that I really don't think that some doctor did it to your child. Or that some drug company did it to your child. Or that you did, either. For what it's worth.

December 03, 2002

Doing Justice to Thimerosal, And the StoryEmail This EntryPrint This Article

Like Charles Murtaugh, I've been trying to get around to writing something about the thimerosal issue for some time. There are so many angles to the story that it's hard to know where to begin. They are, in no particular order:
Is thimerosal safe?
Was it safe when kids didn't get so many vaccines, but became less so as the exposures multiplied?
If it isn't safe, what does it do?
Is it a cause of what some people call an autism epidemic?
Is there a rise in autism, or just a rise in its diagnosis?
If there was harm done, who bears the blame for it?
Who put the paragraphs into the homeland security bill that seem to let Eli Lilly off the hook for thimerosal lawsuits?
When and how should vaccine makers be insulated from legal action, anyway?

And that's just off the top of my head. But I wanted to point out that some new data may be helping to clear things up, at least those first couple of points. Last year, the Institute of Medicine issued a lengthy report that basically said that there was no evidence that thimerosal, even when given in multiple vaccine doses, was harmful. But there was no evidence that it couldn't cause harm, either, and organomercury compounds are known to be trouble, in principle. Thus the recommendation that it be phased out, under the better-safe-than-sorry principle.

The University of Rochester studied 61 children who had received thimerosal-containing vaccines. Blood levels of mercury were lower than expected, well under the toughest EPA standards. And the mercury was found to be cleared much more quickly from the children's system than had been expected (a week versus the predicted 45 days.) This goes a way toward clearing things up, because it makes it less likely that there's an accumulation of mercury with multiple vaccinations. A key part of the anti-thimerosal case has been that exposure to it was allowed to creep up over the years - the hypothetical autism epidemic is much more recent than the use of thimerosal per se.

Anti-thimerosal groups point out that we still don't know what the peak levels of mercury are in the blood after dosing, which is true (although there are studies in the works to check that.) But the entire story, to my medicinal chemist's eye, is based on the med-chem properties of clearance and area-under-the-curve (AUC,) rather than Cmax (peak concentration.) And that is addressed well by the Rochester work. I look forward to seeing more data, but I think that the odds are heavy that thimerosal isn't doing harm. (I'll reserve judgment on whether some people are possibly much more sensitive to it than others - not impossible, but not proven.)

And I'll close by mentioning a not-unrelated fact: when you search "thimerosal" on Google, the first ad that appears on the right-hand side of the screen is for "Thimerosal attorneys." I'm not saying that inserting the stuff into the Homeland Security bill was a good idea, because it wasn't. It makes everyone look guilty, like there's something to hide. And I really don't think there is. The industry has enough problems without bringing more down on its head.

Doing Justice to Thimerosal, and the StoryEmail This EntryPrint This Article

Like Charles Murtaugh, I've been trying to get around to writing something about the thimerosal issue for some time. There are so many angles to the story that it's hard to know where to begin. They are, in no particular order:

Is thimerosal safe?
Was it safe when kids didn't get so many vaccines, but became less so as the exposures multiplied?
If it isn't safe, what does it do?
Is it a cause of what some people call an autism epidemic?
Is there a rise in autism, or just a rise in its diagnosis?
If there was harm done, who bears the blame for it?
Who put the paragraphs into the homeland security bill that seem to let Eli Lilly off the hook for thimerosal lawsuits?
When and how should vaccine makers be insulated from legal action, anyway?

And that's just off the top of my head. But I wanted to point out that some new data may be helping to clear things up, at least those first couple of points. Last year, the Institute of Medicine issued a lengthy report that basically said that there was no evidence that thimerosal, even when given in multiple vaccine doses, was harmful. But there was no evidence that it couldn't cause harm, either, and organomercury compounds are known to be trouble, in principle. Thus the recommendation that it be phased out, under the better-safe-than-sorry principle.

The University of Rochester studied 61 children who had received thimerosal-containing vaccines. Blood levels of mercury were lower than expected, well under the toughest EPA standards. And the mercury was found to be cleared much more quickly from the children's system than had been expected (a week versus the predicted 45 days.) This goes a way toward clearing things up, because it makes it less likely that there's an accumulation of mercury with multiple vaccinations. A key part of the anti-thimerosal case has been that exposure to it was allowed to creep up over the years - the hypothetical autism epidemic is much more recent than the use of thimerosal per se.

Anti-thimerosal groups point out that we still don't know what the peak levels of mercury are in the blood after dosing, which is true (although there are studies in the works to check that.) But the entire story, to my medicinal chemist's eye, is based on the med-chem properties of clearance and area-under-the-curve (AUC,) rather than Cmax (peak concentration.) And that is addressed well by the Rochester work. I look forward to seeing more data, but I think that the odds are heavy that thimerosal isn't doing harm. (I'll reserve judgment on whether some people are possibly much more sensitive to it than others - not impossible, but not proven.)

And I'll close by mentioning a not-unrelated fact: when you search "thimerosal" on Google, the first ad that appears on the right-hand side of the screen is for "Thimerosal attorneys." I'm not saying that inserting the stuff into the Homeland Security bill was a good idea, because it wasn't. It makes everyone look guilty, like there's something to hide. And I really don't think there is. The industry has enough problems without bringing more down on its head.