Wednesday, August 10, 2011

Ancestry of Pink Disease and Autism

A study was published a few weeks ago that took a look at whether having a family history of pink disease (Infantile Acrondynia) leads to an increased risk of autism.  Pink disease is, as most of you probably know, a form of mercury poising linked to use of teething powders that used to be commonly seen in infants and toddlers.  And so, as would be expected when someone mentions the words "autism" and "mercury" together in the same sentence, this study has produced some rather strong opinions from all corners of the autism world.

I didn't want to write anything about this one until I had the chance to read what the study did and did not say (unlike some other people).  But after reading it, I don't really understand what the big deal is.  The data contained in the paper is interesting, if very limited, but outside of the typical theories that fill the introduction and conclusion sections of almost every paper, there is no direct link made between mercury and autism.

Or to put it another way, even if every bit of actual data in the study is 100% true and having a parent or grandparent who survived pink disease does increase the risk of having autism, it does not speak to why the relationship is there.  So this is just a simple association study saying that A might be associated with B, and a very tenuous one at that.

The core of the data is quite simple.  The researchers sent out surveys via mail and e-mail to approximately 2,300 survivors of pink disease.  The surveys indicated that they were collecting data on the general health outcomes in the descendants of survivors of pink disease instead of identifying the interest in autism specifically.

The surveys asked questions about the number of biological children and grandchildren that each survivor had that lived until at least their fifth birthday.  It asked how many of the children and grandchildren had one or more of the following conditions : autism, Asperger's, ADHD, epilepsy, fragile X, intellectual disability, or Down syndrome.

Out of all of the surveys sent out, only 522 completed, non-duplicate surveys were received back.  If you are looking for problems with the study, this is one of the first ones.  Only a small fraction of the surveys were returned leading to the very real possibility that people who chose to respond were biased in some way.

The breakdown of the responses is as follows.  I am only going to report the autism and ADHD numbers as those are the interesting ones.

There were a total of 1,103 children who had a mean age of 37.1 years old.  In this group, there were 11 children with any form of autism (3 autism, 8 Asperger) and 38 children with ADHD.

There were a total of 1,366 grandchildren who had a mean age of 11.3 years old.  In this group, there were 34 grandchildren with autism (12 autism, 22 Asperger) and 29 grandchildren with ADHD.

The researchers then compared the rates of autism in the grandchildren against other published estimates of autism prevalence from Australia.  There are some other sites out there (some of which didn't read the paper) that are claiming that this is one of the problems with this paper.  The claim is that there is no accepted autism prevalence number so there is nothing to compare against.

These claims are largely baseless as the prevalence estimates used in the paper are from other published research that specifically looked at autism prevalence in Australia in and around the age of the grandchildren.  Furthermore, the estimates used are in line with other published estimates in other countries during the same time period.

Personally, I don't find these comparisons to other prevalence estimates all that useful or meaningful.  I think the raw numbers speaks for themselves even in terms of the most recent autism prevalence estimates.

The bottom line is that there were far more cases of autism in grandchildren than would be expected in a group of this size.  The total rate in this population would be almost 2.5%, or more than double what would be expected even in the youngest children today.  When the grandchildren are grouped according to age, the autism prevalence are -

1 in 25 for 6-12 year olds (398 kids)
1 in 35 for 13-16 year olds (141 kids)
1 in 60 for 16+ year olds (827 kids)

That last point is my own extrapolation from the data included in the study.  As a point of comparison, the accepted expected rate of autism today is about 1 in 110, or at least it is in the US.

The study doesn't go into details about the children, but simple math would show you that about 1 in 100 of the direct children had a form of autism.  That number is far larger than would be expected considering that the majority of these people were born before 1980.  Back then the expected rate would have been something like 4 in 10,000 - not 100 in 10,000.

But as shocking as these numbers are, you can't read too much into them because they are based on a survey.  No one went out and actually verified that the people had the condition that they said they did.  No one checked for any sort of response bias in the data.  No one even checked that the people who responded did actually survive pink disease.

So the results are interesting but hardly earth-shattering.

There are also two interesting artifacts in the data that give me pause.

First, the proportion of people with autism compared to Asperger's is out of balance.  Normally you find one person with Asperger's for each 9 with classic autism or pdd-nos.  Yet in both the children and grandchildren Asperger's made up almost two thirds of the autism group.

Perhaps the survivors whose children had autism were less likely to have grandchildren or were less likely to be included in the sample.  This could especially be true since the response to autism back them was to stick people in an institution for the rest of their lives.

Second, there is something interesting going on with the total number of autism and ADHD cases.  In the children, the percent with either form of autism or ADHD was about 4.5%.  In the grandchildren, this percent was about almost identical at 4.6%.  The two populations aren't the same size but it looks like about half of the increase in the autism group could have come from the decrease in the ADHD group.

But again, this is just survey data, so we can't read too much into these quirks just like we can't read too much into the autism rates.

I am not going to go into the mercury/autism theories as there isn't too much point.

Any possible relationship between pink disease and autism is purely hypothetical at this point.  If you wanted to prove some sort of relationship you would have to do a much better job with data collection and analysis.

And on the flip side, we know almost nothing about the relationship between the type of mercury associated with pink disease and autism.  It is a different type of mercury delivered in different doses in a different way.  You can't look at the existing data on  intramuscular ethyl mercury exposure and draw conclusions about ingested mercury chloride.


Shandley, Kerrie, and David W Austin. 2011. “Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders.” Journal of toxicology and environmental health. Part A 74(18):1185-94.
PMID : 21797771 


  1. Thanks for the overview of this study. I have not seen the full-text of the paper yet but have read the press release from Swinburn University which states the authors intentions of this study showing that genes and environment might share centre-stage, at least in their described cohort. I like the fact that they are continuing this work to look at the "cellular and genetic characteristics" which should definitely be worth a look when it eventually arrives on the research scene.

  2. Hi MJ
    The point is that I , at least, disagree with any kind of extreme position. I do think that the finding may be a begining of a deep study about predisposition and impact of nature of exposure, and the correlation is important; BUT CLINICAL studies are needed IMO- and also different genetic ones.
    I disagree with the kind of questions done by the critics and with a correlation extrapolated to causation with this kind of data, but the work is not meaningless in an objetive context.
    If you want, I may elaborate more.

  3. If the researchers could tie these numbers back to an actual genetic/environmental risk factor or if they replicated the study in another population using more rigorous methods then that would definitively give their findings more weight.

    If there is something to these findings, I have to wonder whether it would be a susceptibility to Hg or genetic/epigenetic damage caused by pink disease (or both) that makes the difference.

  4. Now, there are several published manuscripts on biochemical and metabolic problems with management of xenobiotics found in autistic children.
    One of them
    Biol Trace Elem Res. 2011 Jul 14. [Epub ahead of print]
    Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder.
    Obrenovich ME, Shamberger RJ, Lonsdale D.
    Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6 years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-approaches and avenues of exploration for this devastating and growing disease.

    Mutat Res. 2010 Oct;705(2):130-40.
    The relevance of the individual genetic background for the toxicokinetics of two significant neurodevelopmental toxicants: mercury and lead.
    Gundacker C, Gencik M, Hengstschläger M.
    The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metalsand (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized.

  5. The analysis should be done IMO considering the pediatric management of the childhood for the grandparents, from food to other medications used before the pink disease in grandparents appeared. Remember the cod liver oil for example, given to children decades ago to avoid ricketts? At the best of my knowledge breast feeding was a rule- sometimes for years- and even when there were other problems, food had a much higher quality in terms of nutrients for mothers- generally at home. Mothers were not vaccinated with tetanus/flu for example or Rh shots.

    The primary mistake is to assume that thimerosal or Hg is an only cause, without the consideration of the accumulative/additional impact of environment. Without careful analysis of the medical prenatal and postnatal history and xenobiotics (tylenol use for fever for example) /infections/gut flora status/vaccines/others in grandparents, children- and grandchildren the exposure can not be properly analyzed in context, Without the consideration of other factors such as glutathione status in the context of the work of James et al. the questions are ill conceived.

    For the critics is a matter of the same path of potential damage in susceptible people from pink disease and in ASD. BUT to do so it has to equate two completely different exposures in terms of mechanism of action- with differences only in the supposed dose. The question is centered on the doses in absence of anything else

  6. We have to analyze calomel exposure or other similar compound by ingestion at an age when teeth are present ( near 6 months when calomel was used), with previous medical history in grandparents in terms of biochemical, BBB and immune status and gut flora status vs thimerosal exposure by injection - with coexposure with Alum and other compounds – in accumulative way since birth for an important part of the grandchildren (since the year of the hepatitis B vaccine introduction in USA) and taking into account prenatal exposure in grandchildren.Therefore
    a) the path of the exposure is different (ingestion vs injection)
    b) the chemical related to the exposure is different ( calomel vs thimerosal) and therefore metabolism in susceptible people is not (necessarily) similar.
    c) the presentation of the impact is different (acrodynia vs potential contribution from an encephalopatic state related to ASD to tics- a finding recently reported in thimerosal analysis impact)
    d) the metabolic management is individualized and different in susceptible people .(ingestion - through the gut and with the modifications related to the status of the gut flora vs injected without contact with gut flora and modifications related to). It is known from long time ago that gut flora modulates mercury speciation and methylation. It is also known that antibiotics pretreatment increases the accumulation from studies in rats.
    e) the exposure to Hg compound is concomitant to other coexposures and affected by previous xenobiotics (for example antibiotics or tylenol) at a completely different developmental window- powder teeth were used when children have teeth , even when they could be used daily. Even more, the previous history at 6 months of age- when in general calomel was used – is completely different in grandchildren vs grandparents in terms of pediatric management of childhood (and therefore predisposition to adverse effects of low doses of Hg).