Thursday, 24 July 2014

Prenatal valproate exposure and brains

The paper by Amanda Wood and colleagues [1] (open-access) makes a potentially very important contribution to the growing literature looking at how prenatal exposure to sodium valproate (VPA) may affect some children. Authors reported on: "regional structural cortical brain changes in humans exposed to VPA in utero" and specifically, increased cortical thickness in the left inferior frontal gyrus.

Lightning and lava @ Oliver Spalt @ Wikipedia 
In case you need any background on the story behind pregnancy exposure to VPA, I would direct you to a few previous posts where the topic has been covered on this blog (see here and see here) with an autism slant. You might also read my small contribution to a more formal article on this topic here.

Outside of any reported elevated risk of offspring autism or autistic traits associated with prenatal VPA exposure, I'm also minded to bring in some interesting work on intestinal inflammation being reported in a VPA mouse model (see here) to further highlight that important gut-brain axis which I seem to be a little obsessed with.

The Wood paper is open-access and has some accompanying media coverage but a few pointers might be useful...

Allowing for the relatively small participant groups studied and the lack of any other research parameter such as looking at accompanying brain chemistry which may be important [6], the Wood paper offers some intriguing insights into how pregnancy VPA use might affect infant brain development. The very important detail of analysis being based on real human children and not rat offspring also invites some further examination of previous results based on rodents [7]. Rats are rats, children are children.

I'm going to leave you with a quote from the authors about their study: "VPA remains an important medication for people with epilepsy. What this study really tells us is that further research is required so that all women with epilepsy can make informed decisions about their medication use during pregnancy". I couldn't agree more, and as per the Treating for Two initiative, I'm not the only one.

Music then... HRH Gaga and Just Dance.


[1] Wood AG. et al. Altered cortical thickness following prenatal sodium valproate exposure. Annals of Clinical and Translational Neurology. 2014. July 3. doi: 10.1002/acn3.74

[2] Nadebaum C. et al. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011 Feb 22;76(8):719-26.

[3] Powell HWR. et al. Hemispheric asymmetries in language-related pathways: A combined functional MRI and tractography study. NeuroImage. 2006; 32: 388-399.

[4] Shallcross R. et al. In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. Neurology. 2014 Jan 21;82(3):213-21.

[5] Vajda FJE. et al. The teratogenicity of the newer antiepileptic drugs – an update. Acta Neurol Scand. 2014. July 18

[6] Almeida LE. et al. Increased BDNF expression in fetal brain in the valproic acid model of autism. Mol Cell Neurosci. 2014 Mar;59:57-62.

[7] Mychasiuk R. et al. Effects of rat prenatal exposure to valproic acid on behaviour and neuro-anatomy. Dev Neurosci. 2012;34(2-3):268-76.

---------- Wood, A., Chen, J., Barton, S., Nadebaum, C., Anderson, V., Catroppa, C., Reutens, D., O'Brien, T., & Vajda, F. (2014). Altered cortical thickness following prenatal sodium valproate exposure Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.74

Wednesday, 23 July 2014

Trauma and PTSD raise risk of autoimmune disorders?

I admit to some head scratching when I first read the paper by Aoife O’Donovan and colleagues [1] reporting that among war veterans of the Iraq and Afghanistan campaigns, "trauma exposure and PTSD [post-traumatic stress disorder] may increase risk of autoimmune disorders".

It wasn't that I didn't believe the results, but rather that the idea that a physical event with a psychological consequence could impact on a somatic condition with an autoimmune element to it seemed to open up some new avenues particularly pertinent to this blog and its focus on psychology and biology intersecting. That there may be consequences for other conditions from the O'Donovan findings was something else that piqued my interest.
Sunset in Rio @ BBC 1

Anyway, a few details first:

  • A retrospective study based on the analysis of several thousands of medical records of US troops deployed into active theatre in Iraq or Afghanistan was the study starting point. The idea being that outside of PTSD being "associated with endocrine and immune abnormalities" [2] there may be more to see when it comes to autoimmune disease - conditions characterised by a breakdown in the immune system distinguishing self from other. The types of autoimmune disorder included for study ranged from inflammatory bowel disease (IBD) to lupus erythematosus.
  • From an initial cohort of 666,269 veterans, 203,766 (30%) were diagnosed with PTSD and just shy of 20% were diagnosed with a psychiatric disorder other than PTSD. Comparing those with PTSD with those without, authors reported a "significantly higher adjusted relative risk (ARR) for diagnosis with any of the autoimmune disorders alone or in combination compared to veterans with no psychiatric diagnoses... and compared to veterans diagnosed with psychiatric disorders other than PTSD".
  • Both men and women with PTSD seemed to be equally affected by autoimmune disorders. Military sexual trauma exposure was also "independently associated with increased risk in both men and women" of autoimmune disorders.

The first thing that struck me about the O'Donovan findings was the observation that nearly a third of all veterans were diagnosed with PTSD. I've talked before about concepts like shell shock and how thousands of troops suffered psychological trauma during the First World War (see here). In the modern era where trench warfare has to some extent been overtaken by the digital battlefield, it appears that the psychological harms of war still persist and still inflict a terrible burden.

As intrigued as I was about the PTSD - autoimmune disorder connection included in the O'Donovan paper, a quick trawl through some of the other research in this area tells me this is not the first time that such an association has been made. The results from Boscarino [3] hinted that "chronic sufferers of PTSD may be at risk for autoimmune diseases" based on an analysis of Vietnam war veterans. The comparison between veterans who operated in different theatres of conflict (Iraq/Afghanistan vs. Vietnam) also to some degree negates any individual geographical effect from the war zone itself as influencing the results. The paper by Zung and colleagues [4] looking at paediatric type 1 diabetes frequency and psychological stress associated with the 2006 Lebanon War concluded that war trauma might play a role in the increased numbers of cases situated near the conflict. One wonders what the outcome of current events might be too. Such data also implies that age and occupation (i.e. a military career) are not going to be able to account for the PTSD - autoimmunity link either.

So then to the question of what mechanism might be driving this association. Outside of the general area of immune response and something like inflammation [5], the paper by Sommershof and colleagues [6] reported data pointing to a "profoundly altered composition of the peripheral T cell compartment [which] might cause a state of compromised immune responsiveness" in relation to traumatic stress and physical health. I'm no expert on T cells but I gather that they do play an important role in the issue of autoimmunity [7] (open-access) so perhaps there is more research to do there. O'Donovan et al also list "lifestyle factors" as also influencing the trauma exposure / PTSD - autoimmune disease relationship which brings into play a whole host of issues ranging from drug and/or alcohol abuse to less extreme environmental factors. I'd also be minded to suggest that culturally-related issues might also play a role in any relationship as per studies like the one from Whealin and colleagues [8] talking about "risk and resilience correlates of PTSD" as a function of ethnicity. I might also draw your attention to the important paper by Alessio Fasano on gut permeability and autoimmune disease [9] which might very well link PTSD to other physiological events as per other descriptions [10].

Whichever way you look at the O'Donovan paper, their findings present some stark facts about caring for war veterans. They also emphasise how war really can be hell.


[1] O'Donovan A. et al. Elevated Risk For Autoimmune Disorders In Iraq And Afghanistan Veterans With Posttraumatic Stress Disorder. Biological Psychiatry. 2014. June 28.

[2] Pace TW. & Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011 Jan;25(1):6-13.

[3] Boscarino JA. Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci. 2004 Dec;1032:141-53.

[4] Zung A. et al. Increase in the incidence of type 1 diabetes in Israeli children following the Second Lebanon War. Pediatr Diabetes. 2012 Jun;13(4):326-33.

[5] Tursich M. et al. Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis. Translational Psychiatry. 2014. July 22.

[6] Sommershof A. et al. Substantial reduction of naïve and regulatory T cells following traumatic stress. Brain Behav Immun. 2009 Nov;23(8):1117-24.

[7] Dejaco C. et al. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. Mar 2006; 117: 289–300.

[8] Whealin JM. et al. Evaluating PTSD prevalence and resilience factors in a predominantly Asian American and Pacific Islander sample of Iraq and Afghanistan Veterans. J Affect Disord. 2013 Sep 25;150(3):1062-8.

[9] Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012 Feb;42(1):71-8

[10] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.

---------- O’Donovan, A., Cohen, B., Seal, K., Bertenthal, D., Margaretten, M., Nishimi, K., & Neylan, T. (2014). Elevated Risk For Autoimmune Disorders In Iraq And Afghanistan Veterans With Posttraumatic Stress Disorder Biological Psychiatry DOI: 10.1016/j.biopsych.2014.06.015

Tuesday, 22 July 2014

Medical comorbidities in autism

A very quick micropost to direct you to the second version of the document: 'Medical comorbidities in autism spectrum disorders' published by Treating Autism, a group based here in Blighty.

Covering a fair chunk of the peer-reviewed science examining the various medical comorbidities which seems to crop up with some regularity when a diagnosis of autism spectrum disorder (ASD) is made, this free document (complete with a 6 page reference list) is pretty comprehensive.

The message is quite a clear one: under-diagnosis of medical comorbidity and the prospect of barriers to accessing appropriate healthcare represent significant challenges to those diagnosed on the autism spectrum. Hence, receipt of a diagnosis of autism "should represent the beginning of medical investigation and assessment, not the end".

Congratulations go to all those who contributed to this document and in particular, Natasa, for her hard-work in bringing this important primer to fruition. So, please, disseminate far and wide...

Common variation and the genetics of autism

The paper by Trent Gaugler and colleagues [1] reporting that the genetic architecture of the autism spectrum disorders (ASDs) seems in the most part to be due to "common variation" over and above "rare variants or spontaneous glitches" adds to the quite voluminous literature in this area.
Everything in proportion? @ Wikipedia 

Based on an analysis of "a unique epidemiological sample from Sweden" researchers looked at DNA variations in some 3000 individuals with autism and asymptomatic controls. They were able to model their findings "based mostly on combined effects of multiple genes and non-shared environmental factors" including some "synthesis of results from other studies".

Their results: "Most genetic risk for autism comes from common inherited gene variations that can be found in many individuals without the disorder" as per one write-up of the study results. Spontaneous mutations - those so-called de novo mutations which seem to be of growing interest to autism research - were reported to only 'modestly' increase risk of the condition (2.6% of the total risk). About 40% of the risk was unaccounted for, but combined with those common inherited gene variations, made up about 90% of the total risk or liability for ASD.

Quite a lot of the discussion about these results has focused on the issue of tiny genetic effects which many people not on the autism spectrum have present in their genome adding up into something with "substantial impact" when present together. Other research has hinted at similar things as for example, in the paper by St Pourcain and colleagues [2] looking at the genetics of social communication issues.

Whilst I do think that the Gaugler paper is an important one, I am minded to suggest a few words of caution. First and foremost is the reliance on observed genetic variation in the current paper. Although no expert in genetics, my very basic knowledge is that such variations are structural in nature as per issues like single-nucleotide polymorphisms (SNPs). The presence of such mutations (which we all have by the way, dotted around our genomic landscape) whilst of interest, don't actually though tell you an awful lot about the function of particular genes as a consequence of those point mutations unless further studies are conducted. Genes for example expressing protein can be affected by such mutations but, as we've come to realise in the past few decades, gene expression is also to some degree affected by other variables, as per the rise and rise of the science of epigenetics and the focus on non-structural effects on the genome. It's beyond the scope of this post to go too heavily into epigenetics and autism, but the research forays so far have provided some interesting data on issues like DNA methylation and autism (see here) and potential knock-on effects (see here). Importantly, structural variations might not necessarily be the same, or have the same effects, as epigenetic variations although the two may work synergistically.

Second, and I hate to bang on about this, but autism or ASD does not normally appear in some sort of diagnostic vacuum. As per the Gillberg work on the ESSENCE of autism (see here) or the 'big data' studies from the likes of Kohane and colleagues (see here), not only is autism an extremely heterogeneous condition in terms of presentation, but also a condition more than likely to co-exist alongside some heightened risk of certain comorbidity. It's all well and good saying that cumulative common genetic variants raise the risk of autism but, as per other biomarker discussions, we might very well replace the word autism with something like attention-deficit hyperactivity disorder (ADHD) or epilepsy or even something more somatic along the lines of the various work looking at autoimmune conditions appearing alongside autism. In short, genetic risk might be related to other things outside of just autism or its individual traits, and as I was reminded recently: "correlation is not the same as causation" (thanks Natasa). Oh, and then there is the RDoC initiative to consider...

Finally, it is a glaring omission in quite a bit of the coverage of this paper that the 41% of risk "unaccounted for" does not receive more interest than it has. I don't want to speculate on what might be included in the array of factors involved in this category (outside of my previous chatter on possible epigenetic factors) but will again draw your attention to other work on the old genetics-environment relationship with autism in mind and the question of heritability (see here and see here). That also one media piece talking about the Gaugler study is quoted as saying: "On their own, none of these common variants will have sufficient impact to cause autism" is an important detail which implies both cumulative effects and possibly the input of some external force(s). And those effects may very well cross the nature-nuture debate in some instances as per the results from Mitchell and colleagues talked about in a previous post.

Deciphering the genetic architecture of autism is still very much a work in progress. This latest contribution to the issue is important not least for the conclusions arrived at with talk of an additive model and it's intersection with common genetic mutations present in the general population. That being said, I still want to see more from the discipline. I'd like to see a more comprehensive analysis taking into account both genetic and epigenetic factors crossing environmental contributions too. I'd also like to see more focus on smaller groups on the autism spectrum as a function of things like developmental trajectory (see here) or response to certain interventions (see here). And for those who seem to be using this work as a hammer against environment being related to cases of autism, just remember, there may be many, many routes towards a clinical diagnosis...


[1] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

[2] St Pourcain B. et al. Common variation contributes to the genetic architecture of social communication traits. Mol Autism. 2013 Sep 18;4(1):34.

---------- Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, & Buxbaum JD (2014). Most genetic risk for autism resides with common variation. Nature genetics PMID: 25038753

Monday, 21 July 2014

Autism and asthma yet again

"Asthma is approximately 35 % more common in autistic children".

Pipe down @ Wikipedia 
That was the finding reported by Stanley Kotey and colleagues [1] based on their analysis of the 2007 National Survey of Children's Health (NSCH) dataset, a resource looking at "the physical and emotional health of children ages 0-17 years of age" resident in the United States. I don't intend to dwell too much on the Kotey findings aside from pointing out: (a) the reported prevalence of autism came in at 1.8% which is not a million miles away from the latest US estimate made by the CDC and, (b) although the unadjusted odds ratio (OR) for asthma in cases of autism was 1.35 (CI: 1.18-1.55), the adjusted OR taking into account factors such as "age, gender, body mass index, race, brain injury, secondhand smoke and socio-economic status" dropped down to 1.19... so perhaps it was more accurate to conclude that asthma is approximately 20% more common in kids with autism. Oh and that OR and relative risk might not necessarily be one and the same [2].

The NSCH is a valuable resource which provides snapshots for lots of different aspects of child health and wellbeing (see here). A quick trawl of the sections pertinent to an autism and/or asthma diagnosis (see section 2 here) reveals how information about diagnosis is arrived at. I was taken by the fact that questioning about an autism spectrum disorder (ASD) diagnosis was "applicable for ages 2-17 years only" which perhaps ties into some of the issues raised in other papers when it comes to early diagnosis.

Asthma and autism is a topic not totally unfamiliar to this blog (see here). The quite recent paper from Tsai and colleagues [3] covered in a previous post (see here) detailing how asthma might be a risk factor for autism puts the Kotey findings into some potential context albeit not necessarily with the same directional association. The paper from Chen and colleagues [4] likewise also discussed in another post (see here) also implicates comorbidity (ADHD in that case) as a potential confounding variable bearing in mind the estimated rates of ADHD in cases of autism (see here).

When it comes to the hows and whys of any relationship between asthma and autism, a rather large void starts to appear outside of any link just being due to coincidence [5]. "[The] Autism-secondhand smoke interaction was insignificant" kinda suggests that tobacco smoke filled houses and cars were probably not a primary reason for any connection. Given what is known about asthma - a chronic lung condition characterised by inflammation of the airways - one might look to something like immune function as being a commonality between the conditions especially in light of recent meta-analyses with autism in mind. A couple of years back I did a sort of focus on some of the work from Kevin Becker (see here) including his paper on the hygiene hypothesis [6] (open-access here). I'm not necessarily saying that this is the primary connector, merely that the interaction between immune functions and environment might have some role to play. I might add that all the recent chatter on air pollution and autism (see here and see here and most recently here) might also be something to look at with further assiduity. Oh, and one might also think about certain medicines as perhaps being important to this relationship too (see here).

I would close with a last sentence from Kotey et al: "screening may be an efficient approach to reduce risk of morbidity due to asthma". In other words, asthma is yet another comorbidity for which a diagnosis of autism seemingly carries no protection, and the onus is on professionals to reduce any further health inequality...

So: Ben E King and Stand By Me. "Chopper! Sic'em, boy!"


[1] Kotey S. et al. Co-occurrence of Autism and Asthma in a Nationally-Representative Sample of Children in the United States. J Autism Dev Disord. 2014 Jul 6.

[2] Davies HT. et al. When can odds ratios mislead? BMJ. 1998 Mar 28;316(7136):989-91.

[3] Tsai PH. et al. Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study. Research in Autism Spectrum Disorders. 2014; 8: 381-386.

[4] Chen MH. et al. Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. J Child Psychol Psychiatry. 2013 Nov;54(11):1208-14.

[5] Mrozek-Budzyn D. et al. The frequency and risk factors of allergy and asthma in children with autism--case-control study. Przegl Epidemiol. 2013;67(4):675-9, 761-4.

[6] Becker KG. Autism, asthma, inflammation, and the hygiene hypothesis. Med Hypotheses. 2007;69(4):731-40.

---------- Kotey, S., Ertel, K., & Whitcomb, B. (2014). Co-occurrence of Autism and Asthma in a Nationally-Representative Sample of Children in the United States Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-014-2174-y

Friday, 18 July 2014

Ultrafine particulate matter air pollution, mice and autism

Reading the headline "Study links air pollution to autism, schizophrenia" in a media piece about the study by Joshua Allen and colleagues* (open-access here) made me want to delve a little more into this research. I've talked before about air pollution and autism (see here) on this blog. Although a healthy degree of scepticism is to be expected with any autism correlation, particularly when it comes to something as generalised as air pollution (or pesticide exposure) there is a growing research interest in how this aspect of the environment may have some bearing on autism risk.
Cloudy with a chance of... @ Wikipedia 

A few details about the Allen study might be useful:

  • This was a study involving mice. I'll repeat that: this was a study involving mice. It involved exposing a particular strain of mouse, modelled to represent a particular age "during early postnatal development" to "human relevant levels" of air pollution in the form of ultrafine particulates (<100 nm).
  • Mouse brains were analysed at different time periods following exposure (24 hours, 40 days and 270 days after) looking at brain morphology, neurotransmitter levels and those all important immune system chemicals involved in processes like inflammation: the cytokines.
  • Results: bearing in mind some quite detailed control of the amount of air pollution exposure mimicking ambient doses near roadways, quite a few effects were noted. There was for example, "a persistent dilation of the lateral ventricles" induced by CAPS (concentrated ambient ultrafine particles) "preferentially in male mice". I believe this is called ventriculomegaly.
  • "CAPS induces brain region- and sex-dependent alterations in cytokines and neurotransmitters in both males and females". So in male mice, "increased hippocampal glutamate" among other things was observed. In females, "CAPS reduced hippocampal GABA" and more.
  • Of the various cytokines included for analysis, an old friend ranked up there when it came to some of the results obtained: IL-6. Again, there seemed to be region and sex specific alterations to this cytokine and some of them were "unanticipated" as per the lower levels of IL-6 and other relations in certain areas. IL-6 shares some features of a pro-inflammatory and anti-inflammatory cytokine [2] although more often than not, it is the pro-inflammatory effects which get the headlines [3]. 
  • The word 'microglia' also crops up in the Allen results. "CAPS altered IBA-1 immunostaining in the anterior commissure and hippocampus only in males". IBA-1 is a protein expressed in microglia.
  • The authors conclude: "Collectively these data show a dramatic susceptibility of male mice to environmentally relevant levels of early postnatal air pollution exposure, with effects that persist into adulthood and cause permanent neuropathology characterized by ventricular enlargement, a pathology not seen in females".

Reiterating again that this was a study of mice and that mice are mice not humans, these are some intriguing data presented by Allen and colleagues. The focus on male mice slots nicely into the [seemingly] over-representation of autism in boys and men. Elevations in glutamate - hippocampal glutamate [4] in male mice - might also overlap with the growing fascination that autism and schizophrenia research have with this neurotransmitter (see here). Some light reading around the finding of "CAPS-induced ventricular enlargement" observed in males leads down some interesting paths such as a possible relationship with agenesis of the corpus callosum [5] reported to be "a major risk factor for developing autism" according to some authors [6]. In short, there are plenty of correlations seemingly heading back to conditions like autism.

But... there are a few important points to bear in mind before we get too carried away. First and foremost, nothing is reported in the Allen paper around mouse behaviour and how that may or may not have overlapped with other mouse data trying to model autism. One should always be a little cautious when one hears the words 'autistic behaviour' when it comes to a mouse and whether for example, they vocalise or not, or decide to bury their marbles in a particular way as being representative of facets of the condition. It isn't but it's some of the best animal model behaviour that we currently have including the rat models. Allen et al on this occasion reported nothing about behaviour and how it may or may not link to their physiological findings. 

Second is a question already asked by someone in/on the Twittersphere: "Air pollution was so much worse many decades ago yet autism rates staggeringly higher today, not then" (thanks Jill). This is an important point which may have lots of different answers bearing in mind your acceptance that things were worse back in olden times (see here for more news from urban China). Perhaps one of the most relevant issues at the moment was the study by Heather Volk and colleagues [7] discussed in a previous post (see here) talking about gene x environment interactions. If one assumes that genes, gene expression, are being affected by air pollution and that some people might already be more 'at risk' than others, there could be something more to do in this area of investigation.

Finally, Allen and colleagues seemed to have focused all their attention on the brain of their brave mouse participants. They don't talk about whether other organs or biological systems were affected by air pollution. I know that I'm probably going to get some rolling of the eyes for this but harking back to other mouse models of autism, I note some interest in things like the gastrointestinal (GI) tract to be an upcoming area (see here for example on the VPA mouse model). Assuming that the GI tract will also an important exposure point for air pollution [8], could there be merit in looking at this and other organs too all in the name of the gut-brain axis? Also, not forgetting lungs (see here) and skin as important exposure sites too.


[1] Allen JL. et al. Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice. Environ Health Perspect. 2014 Jun 5.

[2] Scheller J. et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2011; 1813: 878-888.

[3] Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends in Immunology. 2012; 33: 571-577.

[4] Kraguljac NV. et al. Increased Hippocampal Glutamate and Volumetric Deficits in Unmedicated Patients With Schizophrenia. JAMA Psychiatry. 2013; 70.

[5] Amato M. et al. Fetal ventriculomegaly, agenesis of the corpus callosum and chromosomal translocation--case report. J Perinat Med. 1986;14(4):271-4.

[6] Paul LK. et al. Agenesis of the corpus callosum and autism: a comprehensive comparison. Brain. 2014; April 25.

[7] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[8] Kaplan G. Air pollution and the inflammatory bowel diseases. Inflamm Bowel Dis. 2011 May;17(5):1146-8.

---------- Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Pröschel M, & Cory-Slechta DA (2014). Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice. Environmental health perspectives PMID: 24901756

Thursday, 17 July 2014

Blood lead levels and childhood behaviour

"Blood lead concentrations, even at a mean concentration of 6.4 µg/dL, were associated with increased risk of behavioral problems in Chinese preschool children, including internalizing and pervasive developmental problems". That was the conclusion of the study by Jianghong Liu and colleagues [1] looking at blood lead levels in preschoolers aged 3-5 years resident in Jiangsu province in China. Some associated media accompanying this study can be viewed here including the text: "This research focused on lower blood lead levels than most other studies and adds more evidence that there is no safe lead level".
You lead... @ Wikipedia 

Lead (Pb) is a metal which has appeared before on this blog - quite a few times in fact (see here and see here for example) - all for the wrong reasons. Outside of it's many and varied industrial uses, including helping many of us get from A to B, lead is pretty dangerous stuff if it manages to find itself into the human and animal body in any amount particularly with its neurotoxic effects [2] in mind.

For quite a few years, much of the guidance on exposure to lead had suggested that blood lead levels above 10 μg/dL "should prompt public health actions" [3] albeit not defining "a threshold for the harmful effects of lead". As per that CDC report [3] there has been an increasing realisation that even blood lead levels below 10 microg/dL may have some undesirable effects particularly on infants and young children. Indeed the revised CDC guidance now lists "5 micrograms per deciliter of lead in blood" as the point where concerns should be raised about blood lead levels and action taken.

Back to the Liu paper...

  • Looking at spot blood lead levels (BLLs) or even blood lead concentrations for over 1300 youngsters, researchers administered the "Chinese versions of the Child Behavior Checklist and Caregiver-Teacher Report Form" to parents and teachers of participants when children were aged 6 years old.
  • Results: the mean (average) BLL for participants was 6.4 µg/dL, although a range of results were reported. Incremental increases in BLLs correlated with an "increase of teacher-reported behavior scores on emotional reactivity, anxiety problems, and pervasive developmental problems". Also: "mean teacher-reported behavior scores increased with blood lead concentrations, particularly for older girls".
  • The authors conclude: "continued monitoring of blood lead concentrations, as well as clinical assessments of mental behavior during regular pediatric visits, may be warranted".

Bearing in mind this was a study looking at parent and teacher scoring of Chinese children and not more formal assessment of behavioural (or cognitive) issues, also focused on spot samples rather than multiple samples to assess BLLs, there are some important lessons to be learned from these results. Not least is the continued undesirability of contact with lead and it's potential effects on behaviour. I think back to some of the chatter on lead exposure and crime (see here) taking into account the old 'correlation is not the same as causation' mantra as one potential societal effect.

Reading through some of the other literature in this area, it's not difficult to find supporting information about the detrimental effects of lead exposure particularly in children. The paper by Hou and colleagues [4] (open-access here) pretty much sums it up: "Compared with healthy children, more children with lead poisoning had abnormal behaviors, especially social withdrawal, depression, and atypical body movements, aggressions and destruction". They conclude: "Lead is a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero".

Whilst exposure to lead through older formulations of petrol or house paint or plumbing is a declining issue in many areas of the world, I don't think we can be complacent about our situation. Roberts and colleagues [5] commented on this issue in their study (bearing in mind their use of the 10 microg/dL cutoff level). They noted: "Despite a low prevalence of children with EBLL [elevated blood lead levels], parental report suggested that approximately 29% of children had lead-based paint in their home environment". Similar analyses of other areas of lead exposure risk such as dust, soil and water suggest continued monitoring is required as per the study results from Oulhote and colleagues [6].

If there is a take-home message from this post and the Liu results it is that lead exposure can have often pronounced developmental effects on behaviour (and cognition) in infants and children and that even markers of low levels of exposure should be examined with much greater assiduity. Without trying to brush everyone with autism as lead poisoned, such results might also direct much greater research attention when findings of EBLL are noted in cases of autism (see here). Indeed, papers like the one from El-Ansary and colleagues [7] might offer much more information than they have hitherto been given credit for...


[1] Liu J. et al. Blood Lead Concentrations and Children’s Behavioral and Emotional Problems. JAMA Pediatrics. 2014. June 30.

[2] Lidsky TI. & Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain. 2003; 126: 5-19.

[3] CDC. nterpreting and managing blood lead levels < 10 microg/dL in children and reducing childhood exposures to lead: recommendations of CDC's Advisory Committee on Childhood Lead Poisoning Prevention. MMWR Recomm Rep. 2007 Nov 2;56(RR-8):1-16.

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---------- Liu, J., Liu, X., Wang, W., McCauley, L., Pinto-Martin, J., Wang, Y., Li, L., Yan, C., & Rogan, W. (2014). Blood Lead Concentrations and Children’s Behavioral and Emotional Problems JAMA Pediatrics DOI: 10.1001/jamapediatrics.2014.332