ALSPAC does... prenatal mercury exposure and autism or autistic traits

The ALSPAC - Avon Longitudinal Study of Parents and Children - mentioned in the title of this post is something of quite a regular feature on this blog (see here and see here for examples).

On this particular blogging occasion I'm heading into the findings reported by Jean Golding and colleagues [1] who utilised this fabulous research resource to examine whether "prenatal exposure from total maternal blood Hg [mercury] in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits." They concluded that there were "no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish."

OK, mention of the heavy metal mercury in the context of autism and/or autistic traits can be a touchy subject for some. I'm talking about the various 'discussions' that have taken place both in the lay and peer-reviewed science arenas concerned with the exposure patterns relevant to mercury in the context of autism (see here and see here). This, on the basis that mercury exists in several 'forms', and those different forms have different potential exposure routes.

Golding et al relied on some of the gold-standard analytical methods for the analysis of whole blood Hg collected in the most part "at < 18 weeks gestation": "inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS)." Variations on this method - ICP mass spectrometry - have been previously reported on in the context of mercury and autism research (see here and see here). Alongside, they looked at measured levels of mercury in relation to various behavioural and other variable groupings: "(1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000)." They however cautioned that: "Although we accounted for several important confounders which are relevant to Hg levels and autism, the possibility of unmeasured confounding cannot be ruled out." I can think of one potential confounder that was not seemingly included in their list outside of fish consumption and dental amalgams but ho-hum...

Alongside their overall 'no relationship' results, a few other details are noteworthy. First: "all correlations indicated that with increasing levels of [maternal] mercury, the signs of autism [in offspring] were slightly less, but none were statistically significant." Interesting idea - higher maternal levels of mercury during pregnancy 'correlates' with 'less' autistic traits in offspring in childhood - but to reiterate, not statistically significant. Second was that 'provided the mother ate fish' detail attached to the main findings. So: "we have shown a differential relationship between the social cognition trait and prenatal Hg exposure, such that there was a significant difference in apparently protective effects contingent upon whether the mother ate fish." The authors opine as to what it is about fish consumption that might "counteract any possible adverse cognitive and behavioral differences that may be caused by prenatal exposure to Hg" including "the beneficial components of fish such as the omega-3 fatty acids, iodine, and vitamins D and B2." This in the context that omega-3 fatty acids have some research form in relation to autism (see here) as does the sunshine vitamin/hormone that is vitamin D (see here).

One has to be slightly careful with the Golding results given the focus on prenatal exposure, and prenatal exposure at only one early point in pregnancy, as well as also not actually looking at mercury levels in the children themselves. The current results say nothing for example, about any possible direct or acquired role for mercury in relation to autism as per other findings published during the same period [2]. Neither do they offer any additional information on the idea that exposure issues to such heavy metals may be only one part of the story, and that the biological processes involved in removing such heavy metals may be somehow perturbed in relation to some autism (see here).

But... set within the idea that prenatal mercury exposure may be linked to the 'etiology' of at least some autism, the Golding findings represent pretty strong evidence suggestive of no connection.

Music to close, and could I recommend the soundtrack to Sonic 3 while you work?

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[1] Golding J. et al. Prenatal mercury exposure and features of autism: a prospective population study. Molecular Autism. 2018; 9: 30.

[2] Qin YY. et al. A comparison of blood metal levels in autism spectrum disorder and unaffected children in Shenzhen of China and factors involved in bioaccumulation of metals. Environ Sci Pollut Res Int. 2018 Apr 22.

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On baby teeth, metals and autism

So: "using novel biomarkers of early life exposure, we observed differences in uptake of multiple toxic and essential elements over the second and third trimesters and early postnatal periods in MZ [monozygotic] and DZ [dizygotic] twins discordant for ASD [autism spectrum disorder]."

That was the conclusion reached in the paper by Manish Arora and colleagues [1] (open-access). Using baby teeth as a sort of 'biologic hard drive' according to the accompanying press release (see here), researchers observed some interesting differences across twin groups with or without a diagnosis of ASD according to various pre- and post-natal periods. In particular they noted that: "In ASD cases, higher lead levels were observed over the prenatal period and first 5 months postnatally" and: "Zinc levels were lower in cases during the third trimester."

This paper has already received quite a lot of media attention (see here for example). Thankfully, many of the media outlets have focused on some of the quite important details when it comes to the study; namely that the total number of participants was quite small overall, despite being drawn from a larger research initiative: the Roots of Autism and ADHD Twin Study in Sweden (RATSS).

I am however very interested in both the methods employed during the Arora study and the results obtained. Baby teeth as a focus of autism research? I've speculated on that before (see here). The use of "Laser ablation-inductively coupled plasma mass spectrometry" is also rather good to see; being a method of choice for the determination of metals in various samples (ICP mass spectrometry) coupled to the use of laser ablation to free up the dentine surface of baby teeth for said analysis.

The results talking about levels of lead (Pb) and zinc (Zn) are also not entirely novel in relation to the autism spectrum. On this blog I've talked before about other, independent research observing a possible relationship between lead exposure and autistic traits (see here) on the basis that lead is a known neurotoxin and seemingly serves no physiological function in the body. Zinc, typically reductions in zinc levels, are also not entirely unknown to the autism spectrum either (see here); where zinc is required for quite a few important biological reactions/processes [2].

What's missing from the Arora study? Well, without trying to 'rock the boat' or anything, the focus on lead, zinc and manganese is a little limited given that other types of metals have also been discussed in the context of autism (see here). Yes, I know to mention mercury in the same sentence as autism is high on the 'hot potato' scale but peer-reviewed science is peer-reviewed science (see here). I might also have liked to see how tooth levels of those metals also correlated with blood levels of metals in the context that exposure might not be the only issue when talking about atypical metal levels and autism (see here).

Still, this is a good initial effort and should hopefully pave the way for further investigations into how metal exposure and/or inadequacies can very much impact on behaviour and development.

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[1] Arora M. et al. Fetal and postnatal metal dysregulation in autism. Nat Commun. 2017 Jun 1;8:15493.

[2] Frassinetti S. et al. The role of zinc in life: a review. J Environ Pathol Toxicol Oncol. 2006;25(3):597-610.

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Arora M, Reichenberg A, Willfors C, Austin C, Gennings C, Berggren S, Lichtenstein P, Anckarsäter H, Tammimies K, & Bölte S (2017). Fetal and postnatal metal dysregulation in autism. Nature communications, 8 PMID: 28569757

Blood heavy metal levels and autism (yet again)

"Data showed that the children with ASD [autism spectrum disorder] had significantly (p < 0.001) higher levels of mercury and arsenic and a lower level of cadmium."

And... "It is desirable to continue future research into the relationship between ASD and heavy metal exposure."

Those sentences come from the study by Huamei Li and colleagues [1] continuing a research theme regarding (generally) elevated levels of heavy metals being detected in those on the autism spectrum (see here). Yes, I know that this kind of research is not always met with great appreciation (see here) but the suggestion that the heavy metal burden seems to be quite a bit higher in the autistic population is not something that can just be ignored. More so when it might actually be treatable (with no medical or clinical advice given or intended)...

There are numerous other examples in the peer-reviewed science literature that I could give where the heavy metal burden has been found to be elevated in relation to autism. Indeed, if someone is looking for yet another systematic review and meta-analysis topic, there you go - you're welcome. Personally, I think we've reached the point where the questioning needs to move on to (a) the possible sources of those heavy metals and (b) whether 'exposure amount' is the sole reason for the elevations in relation to autism over and above issues with the biology around 'detoxifying' said metals. Answers are not likely to be simple but questioning has to continue...

To close, he was always my favourite James Bond...

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[1] Li H. et al. Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum Disorder. Biol Trace Elem Res. 2017 May 8.

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Li H, Li H, Li Y, Liu Y, & Zhao Z (2017). Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum Disorder. Biological trace element research PMID: 28480499

Autism, urinary porphyrins and mercury

I appreciate that the title of this post is probably going to result in an immediate 'click away' for some folk but for those who've endured it I'd like to talk briefly about the findings reported by Eman Khaled and colleagues [1]. Namely the observation that: "ASD [autism spectrum disorder] children in the present study had increased blood Hg [mercury] and Pb [lead] levels compared with healthy control children indicating that disordered porphyrin metabolism might interfere with the pathology associated with the autistic neurologic phenotype."

OK, language and terminology first. I don't like the use of the term 'healthy control children' set in the context of autism research it has to be said. Whilst the label of autism does indeed place someone at a significantly greater risk of various health-related complaints (see here), the connotation that someone with autism is 'unhealthy' solely as a function of their autism label is not universally borne out by the research data. Why not therefore just call controls 'control children' eh?

Next up, porphyrins in the context of autism have been covered before on this blog (see here). Although linked to processes such as heme synthesis, there have been suggestions that analysis of urinary porphyrins might also provide some important information on "renal mercury content" [2]. Mercury (Hg) has been a hot potato in the context of autism for quite a few years (see here) and discussions on this topic have sometimes turned pretty nasty (see here). The sweeping idea that all autism is 'caused' by mercury poisoning (and there are various types of the stuff) has not been supported by the peer-reviewed literature on this topic (see here) but there have been some important outliers detected (see here) potentially indicative of some role for at least some on the autism spectrum. As for lead (Pb), well let's just say that few people have anything good to say about lead exposure, particularly when it comes to childhood lead exposure (see here) and with autism in mind, the label seemingly does not guarantee lead safety (see here).

So, Khaled et al went about looking at levels of various urinary porphyrins as a function of both diagnostic status (autism, controls, siblings of autism participants) and also Hg and Pb load. They found that: "children with ASD had significantly higher levels of Hg, Pb, and the porphyrins pentacarboxyporphyrin, coproporphyrin, precoproporphyrin, uroporphyrins, and hexacarboxyporphyrin compared to healthy controls and healthy siblings of the ASD children." Again, sorry for the 'healthy' bit (these are the authors' words and not mine). They also observed that: "Mothers of ASD children showed a higher percentage of dental amalgam restorations compared to the mothers of healthy controls suggesting that high Hg levels in children with ASD may relate to the increased exposure to Hg from maternal dental amalgam during pregnancy and lactation."

This work is by no means flawless. I could go on about the preferred method of analysis - "high-performance liquid chromatography (HPLC)" - used to separate/detect urinary porphyrins (with fluorescence detection as per other research by authors on this paper [3]) as not exactly being the gold-standard for example. I might also quibble about the idea that 'dental amalgam restoration' rates are no replacement for actually measuring circulating levels of maternal mercury either (bearing in mind this would need to be done in archived samples too). There are holes in this work, of that there is no doubt.

But... it is a rather uncomfortable observation that time and time again, some children diagnosed with autism seem to be in possession of a somewhat higher than expected body burden of mercury, or at least testing positive for such a burden. Science has yet to fully understand the hows and whys of such findings for at least a group of people diagnosed with autism and what might be done to reduce any biological load and its various impacts on biological systems. Whether as Khaled and colleagues observe "a significant positive correlation between the levels of coproporphyrin and precoproporphyrin and autism severity" stands up to further independent scientific scrutiny is another question but I'm minded not to just glaze over these and other findings in the peer-reviewed literature as if they did not exist. They do exist and for those children/adults potentially registering with high levels of mercury (or other heavy metals) the onus is on treating such toxicities rather than just further adding to some growing health inequalities simply as the result of a label called 'autism'...

Oh, and adding to the 'hot potato' theme, I'll be coming to the paper by Kerns and colleagues [4] on this topic quite soon.

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[1] Khaled EM. et al. Altered urinary porphyrins and mercury exposure as biomarkers for autism severity in Egyptian children with autism spectrum disorder. Metab Brain Dis. 2016 Jul 13.

[2] Pingree SD. et al. Quantitative evaluation of urinary porphyrins as a measure of kidney mercury content and mercury body burden during prolonged methylmercury exposure in rats. Toxicol Sci. 2001 Jun;61(2):234-40.

[3] Macedoni-Lukšič M. et al. Levels of metals in the blood and specific porphyrins in the urine in children with autism spectrum disorders. Biol Trace Elem Res. 2015 Feb;163(1-2):2-10.

[4] Kern JK. et al. The relationship between mercury and autism: A comprehensive review and discussion. J Trace Elem Med Biol. 2016 Sep;37:8-24.

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Khaled EM, Meguid NA, Bjørklund G, Gouda A, Bahary MH, Hashish A, Sallam NM, Chirumbolo S, & El-Bana MA (2016). Altered urinary porphyrins and mercury exposure as biomarkers for autism severity in Egyptian children with autism spectrum disorder. Metabolic brain disease PMID: 27406246

Heavy metals, heavy conflicts and autism?

Two papers are presented for your reading delight today, both based on the often contentious issue of heavy metals and autism.

The first paper is from Farida El Baz Mohamed and colleagues [1] (open-access available here) and further substantiates the claim that for whatever reason(s) the levels of various heavy metals seem to be increased or raised in some children diagnosed with an autism spectrum disorder (ASD). The second paper by Janet Kern and colleagues [2] (open-access available here) provides results based on a systematic review of the literature on one specific heavy metal, mercury (Hg), with autism in mind and concludes that: "of the studies with public health and/or industry affiliation, 86 % reported no relationship between Hg and ASD" whilst "among studies without public health and/or industry affiliation, only 19 % find no relationship between Hg and ASD."

The Mohamed paper continues a theme that for some on the autism spectrum (remember: the autisms) there may be quite a bit more to see when it comes to the burden of heavy metals (see here). Based on hair analysis for various heavy metals - "mercury, lead, and aluminum" - researchers looked at samples from 100 children diagnosed with ASD compared with 100 age- and gender-matched controls. "Comparison between cases and controls as regards heavy metal levels shows that the mean levels of the three toxic heavy metals in hair were significantly higher among the studied ASD cases than the controls" was the primary finding. The authors further report that said heavy metal findings correlated with "maternal fish consumptions, living nearby gasoline stations, and the usage of aluminum pans" and that: "Environmental exposure to these toxic heavy metals, at key times in development, may play a causal role in autism."

I know that to talk about issues with mercury for example, can be a contentious topic with autism in mind but as uncomfortable as it might be to accept, there is some evidence of a 'connection' between elevated levels of the stuff and at least some autism (see here). The link is not, I might add, seemingly generalisable to all autism (see here) but for those children/adults presenting with elevated levels of this heavy metal, further inspection is warranted save any further health inequalities appearing when the label of autism is discussed. As to the suggestion of a connection between some autism and lead (Pb) exposure, well, again this is not the first time that this has been mentioned in the peer-reviewed literature following a more general assertion that there is nothing very good to come from when lead and children in particular meet (see here).

The paper by Kern and colleagues pours further fuel on to something of an on-going debate in some autism circles about how much factors such as conflicts of interest and research transparency may impact on autism research. Focused specifically on the issue of mercury and autism (again), the authors argue that public health or pharmaceutical industry affiliation seems to show something of a potential relationship with study outcomes when it comes to mercury and autism research. So: "over 80 % of the studies without public health or industry affiliation found evidence a relationship between Hg exposure and ASD." This contrasted with something quite a bit less when it came to studies with a public health or industry affiliation slant. Further: "The dramatic discrepancy in these results... provides evidence of biased outcomes, indicative of a conflict of interest."

The authorship group involved in the Kern paper have something of a peer-reviewed research history when it comes to this topic [3] including independent findings that hair levels of mercury might show an association with autism [4]. Their mention of mercury related compounds found in certain vaccines [5] as potentially showing a correlation with risk of autism makes for controversy in some quarters in view of the 'hot potato' that such as association has become down the years.

Appreciating that whilst the Kern findings report something of a connection between affiliations and research outcomes, I'm hard-pressed to suggest that this is hard evidence of some sort of deliberate scheme to exonerate mercury of any potential role in the very wide autism spectrum. Taking for example one paper that is cited in the Kern analysis - the paper by Barry Wright and colleagues [6] - which I've discussed before on this blog (see here) who found no overall connection between urinary mercury levels and autism, they did also call for further research in this area in light of 'outliers' being reported in their autism and their learning disability group. To quote: "further research is warranted to better understand whether a subgroup with autism or learning disabilities have mercury poisoning or excretion difficulties." In these days of plural autism (see here) one can see the logic in such a suggestion.

Music: Radiohead - Lucky.

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[1] Mohamed Fel B. et al. Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism. Behav Neurol. 2015;2015:545674.

[2] Kern JK. et al. Systematic Assessment of Research on Autism Spectrum Disorder and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research. Sci Eng Ethics. 2015 Oct 27.

[3] Geier DA. et al. Thimerosal: Clinical, epidemiologic and biochemical studies. Clinica Chimica Acta. 2015; 444: 212-220.

[4] Geier DA. et al. Hair toxic metal concentrations and autism spectrum disorder severity in young children. Int J Environ Res Public Health. 2012 Dec 6;9(12):4486-97.

[5] Geier DA. et al. A two-phase study evaluating the relationship between Thimerosal-containing vaccine administration and the risk for an autism spectrum disorder diagnosis in the United States. Translational Neurodegeneration. 2013;2:25.

[6] Wright B. et al. A Comparison of Urinary Mercury between Children with Autism Spectrum Disorders and Control Children. PLoS ONE. 2012;7(2):e29547.

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Mohamed, F., Zaky, E., El-Sayed, A., Elhossieny, R., Zahra, S., Salah Eldin, W., Youssef, W., Khaled, R., & Youssef, A. (2015). Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism Behavioural Neurology, 2015, 1-9 DOI: 10.1155/2015/545674




Kern JK, Geier DA, Deth RC, Sykes LK, Hooker BS, Love JM, Bjørklund G, Chaigneau CG, Haley BE, & Geier MR (2015). Systematic Assessment of Research on Autism Spectrum Disorder and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism Research. Science and engineering ethics PMID: 26507205

Cochrane does chelation for autism

Cochrane, in the title of this post, refers to the Cochrane Collaboration and the sterling work done throughout health care synthesising peer-reviewed evidence pertinent to the goal of evidence-based medicine.

The collaboration has recently turned its eye towards the topic of chelation with autism in mind, a topic that has been discussed previously on this blog (see here). Their conclusions based on the findings reported by Stephen James and colleagues [1] (open-access here), looking at the available evidence up to November 2014 are not entirely unexpected: "no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD [autism spectrum disorder]." Further: "Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits." A further summary of the findings can be found here.

Based on a search of the peer-reviewed literature on chelation and autism, only one study fulfilled the appropriate criteria (i.e. being randomised), that of Jim Adams and colleagues [2] (open-access here). Actually the Adams study brought about two papers (the second is here [3]) covering both medical and behavioural results following oral DMSA (dimercaptosuccinic acid) therapy in cases of autism. The Adams study reported: "Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC [Red Blood Cell] glutathione, and effective in normalizing platelet counts." Further: "Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals, and possibly helpful in reducing some of the symptoms of autism in those children."

The Cochrane review however did not share the optimism. "One trial, which had methodological issues and a relatively small sample size, is insufficient to provide robust evidence on chelation for ASD." James et al also suggested that the Adams study was judged to have "have high or uncertain risk of bias and methodological problems that limited the interpretation of outcomes presented." Even worse: "Given the deleterious effects of chelation, misinterpretation and misuse of the study of Adams et al to justify the use of chelation for ASD is unethical and potentially places children unnecessarily in harm’s way." Ouch.

"At the present time, the theory that heavy metals may cause autism or might worsen symptoms has not been established." I'd agree with this sentiment from James et al but with the proviso that there is ample peer-reviewed evidence to suggest that for at least some on the autism spectrum, the burden of heavy metals does seem to be increased (see here for example). The idea that something like lead (Pb) - a known toxicant adversely affecting child development - might be elevated in [some] cases of autism is of particular importance.

The associated comment by Adams et al on what happened to glutathione levels following DMSA use is something that I'd like to see more science resources put into. Not for one moment do I endorse the use of DMSA without appropriate medical oversight, but knowing what we know about glutathione and autism (see here) and the 'elephant in the room' sentiments, I'd be minded to suggest that there may be quite a bit more to see here particularly in light of the findings from Monin and colleagues [4] talking about glutathione deficits and "myelin maturation".

Music: The Beach Boys - Wouldn't It Be Nice. Well, yes rather.

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[1] James S. et al. Chelation for autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2015;5:CD010766.

[2] Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results. BMC Clin Pharmacol. 2009 Oct 23;9:16.

[3] Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B - behavioral results. BMC Clin Pharmacol. 2009 Oct 23;9:17.

[4] Monin A. et al. Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol Psychiatry. 2015 Jul;20(7):827-38.

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James S, Stevenson SW, Silove N, & Williams K (2015). Chelation for autism spectrum disorder (ASD). The Cochrane database of systematic reviews, 5 PMID: 26106752

Autism research in Jamaica

For the past couple of years I've been tracking some rather interesting publications coming out of data from Jamaica on the topic of autism / autism spectrum disorder (ASD) specifically looking at the possible overlap between genes and various environmental factors. I thought now would be a good time to bring this collection of papers to the blogging table and summarise their findings based on the analysis of data collected from The Jamaican Autism study. The fact that their latest research foray mentions some of the genetics of glutathione [2] with autism in mind is very interesting in light of some other findings in this area (see here). There's more on this shortly.

You're not Absolem. I'm Absolem. Stupid girl.

So:

Study 1: Maternal and paternal age are jointly associated with childhood autism in Jamaica [2].
Higher parental age - both mother and father age - seemed to be associated with a diagnosis of autism/ASD in offspring. Higher maternal age in particular, survived further statistical analysis as being a potentially important factor. This is a topic which has cropped up in autism research circles before (see here).

Study 2: Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders [3].
"Our findings do not support an association between blood mercury concentrations measured in Jamaican children 2–8 years of age and ASD case status." Such a conclusion was based on the analysis of blood mercury concentrations between ASD cases and a control group, and took into account important factors such as seafood consumption bearing in mind what is known about such a foodstuff and environmental exposures (see here).

Study 3: The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders [4].
Blood arsenic levels were the focal point of this study, and a familiar conclusion to the previous study: "Our results do not support an association between postnatal total blood arsenic measured in Jamaican children 2-8 years of age and ASD case status." Again the consumption of certain foodstuffs seemed to be important correlates related to any elevated levels of arsenic detected.

Study 4: Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder [5].
Cadmium levels this time around, and again: "we did not find any significant differences between ASD cases and typically developing (TD) controls with respect to the 75th percentile of blood cadmium concentrations." Food (yes again) seemed to be a good correlate linked to differences in blood cadmium levels.

Study 5: Blood manganese concentrations in Jamaican children with and without autism spectrum disorders [6].
Manganese, and wait for it... "Our results do not indicate a relationship between postnatal BMC [blood manganese concentrations] and ASD case status of Jamaican children ages 2–8 years."

Study 6: Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder [7].
Lead (Pb), a favourite topic of this blog, was the metal of choice when it came to analysis to see if there was any connection between the stuff and autism. Er,... "Our results do not support an association between postnatal blood lead concentration measured in Jamaican children 2–8 years of age and ASD case status."

I think you can see the trend coming out of this data examining samples of children living in Jamaica with and without autism. Perhaps just as important are the various discussions about the ways and means that participants might have been exposed to these various metals and how one needs to be aware of how food in particular, could be a significant source of exposure. This perhaps puts a new slant on previous studies which have suggested an increased body burden of certain metals to be associated with autism (see here) and the question of whether dietary sources of such metals have adequately been taken into account. Don't get me wrong, I'm still very keen to see more 'metallomics' applied to autism research (see here), perhaps just controlling for a few more potentially important confounders.

The Jamaican Autism study also provides quite a nice template for setting up further geographically distinct initiatives to compare and contrast with/against. I note for example that the recent study from Hodgson and colleagues [8] looking at autism in Oman (itself the topic of quite a few peer-reviewed publications) suggested some rather different results for their cohort: "Mercury levels were markedly elevated in the hair of autistic subjects vs. control subjects" albeit based on hair analysis not blood. With the previous caveat about confounders in operation, one wonders whether there may be more to see across different countries particular when bringing into play the potential importance of that glutathione connection which has also previously received some mention in the Jamaican autism studies [9].

And then some music. Jamaica and music, mmm... One Love.

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[1] Rahbar MH. et al. nteraction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. Research in Autism Spectrum Disorders. 2015; 12: 1-9.

[2] Rahbar MH. et al. Maternal and paternal age are jointly associated with childhood autism in Jamaica. J Autism Dev Disord. 2012 Sep;42(9):1928-38.

[3] Rahbar MH. et al. Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders. Neurotox Res. 2013 Jan;23(1):22-38.

[4] Rahbar MH. et al. The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders. Sci Total Environ. 2012 Sep 1;433:362-70.

[5] Rahbar MH. et al. Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder. Res Autism Spectr Disord. 2014 Sep 1;8(9):1134-1145.

[6] Rahbar MH. et al. Blood manganese concentrations in Jamaican children with and without autism spectrum disorders. Environ Health. 2014 Aug 23;13:69.

[7] Rahbar MH. et al. Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder. Int J Environ Res Public Health. 2014 Dec 23;12(1):83-105.

[8] Hodgson NW. et al. Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman. Exp Biol Med (Maywood). 2014 Jun;239(6):697-706.

[9] Rahbar MH. et al. Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder. Int J Environ Res Public Health. 2014 Aug 6;11(8):7874-95.

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Rahbar MH, Samms-Vaughan M, Loveland KA, Pearson DA, Bressler J, Chen Z, Ardjomand-Hessabi M, Shakespeare-Pellington S, Grove ML, Beecher C, Bloom K, & Boerwinkle E (2012). Maternal and paternal age are jointly associated with childhood autism in Jamaica. Journal of autism and developmental disorders, 42 (9), 1928-38 PMID: 22230961

Probiotics to counter heavy metal toxicity?

"In summary, this work has demonstrated the potential value of long-term probiotic-based interventions to counter mercury and arsenic exposure in vulnerable populations, particularly in pregnant women".

Sounds like an '80s man to me...

That was one of the primary conclusions reported by Jordan Bisanz and colleagues [1] (open-access) examining "at-risk populations of pregnant women and in children in Mwanza, Tanzania". The idea being that alongside the use of metal chelating medicines such as dimercaptosuccinic acid (DMSA) and ethylenediaminetetraacetic acid (EDTA) indicated for 'acute' exposure to heavy metals, there may be other ways and means of treating heavy metal exposure over longer periods and where resources may not be as plentiful. Some media about this study can be seen here.

The Bisanz paper is open-access but a few pointers might be in order:

• The study was based on the idea that certain strains of bacteria are known to have "an affinity for many toxic metals, including lead and cadmium" as documented in papers such as the one by Monachese and colleagues [2]. Further, that so-called "probiotic yogurt kitchens that service economically disadvantaged people" as a source of potentially beneficial bacteria are already working at the particular location selected by the study authors.
• So, two studies were implemented: (a) looking at school-aged children (SAC) (initial N=44) randomised to receive either a probiotic yoghurt containing "1 × 1010 CFU Lactobacillus rhamnosus GR-1 per 250 g" or "an equivalent portion of ultra-heat-treated milk as a control devoid of lactic acid bacteria" daily for 24 days; and (b) "60 pregnant women [PW] were recruited, of which 26 received a probiotic yogurt containing 1 × 1010 CFU L. rhamnosus GR-1 per 250 g and supplemented with 4.3 g of Moringa, a micronutrient-rich plant, to enhance maternal nutrition". The study entries in the US National Institutes of Health (NIH) database can be found here and here respectively. 
• Analysis of blood metal levels ("blood lead, total mercury, total arsenic, and cadmium") were undertaken at enrolment and follow-up for all participants across the two studies. Analysis of fecal samples for children in study (a) was also undertaken pre- and post-intervention to test for any differences across the yoghurt vs. milk groups. Local fish were also analysed for heavy metal content to ascertain dietary exposure alongside dietary patterns of participants.
• Results: there were quite a few... levels of heavy metals in SAC and PW studied were elevated compared to "levels present in a developed country (Canada)" somewhere in the order of over 6 times greater for lead and mercury. Children (SAC) were particularly vulnerable to an increased heavy metal burden. The authors noted: "Metal exposure from dietary fish intake likely explains why we saw elevated blood levels of mercury in both the SAC and PW groups".
• "The studies provided the first positive evidence for the use of probiotics to combat toxic heavy metal exposure in vulnerable human populations". Well, sort of, is probably the best way that I can comment on this assertion, as the authors noted: "no statistically significant differences were detected in blood metal levels in SAC receiving the probiotic or milk control, although we noted that there was a weak trend of reduced blood levels of lead and arsenic". They did find that in the control group in receipt of milk, "blood levels of mercury and arsenic increased" between the testing occasions "but remained stable in the probiotic group". So concluding that levels of certain heavy metals didn't get any worse following the use of a probiotic is probably a more accurate way of looking at things.
• Insofar as the gut bacteria analysis side of things: "Administration of the probiotic was not observed to have an effect on the gut bacterial community composition". But the authors did report that: "Elevated blood lead was associated with increases in Succinivibrionaceae and Gammaproteobacteria relative abundance levels in stool".

There are some important results to be derived from the Bisanz paper but not necessarily in the way that I think the authors hoped, bearing in mind this was a very short study limited to one specific probiotic strain. That being said, the idea that probiotics might have some kind of protective effect - "probiotic administration may be especially advocated at peak exposure times" - is an interesting one, worthy of quite a bit more investigation. 

I know discussions in certain quarters about the use of chelation therapy for certain conditions have the ability to furrow brows (see here). This despite the fact that when clinically indicated, chelation can provide some powerful results as demonstrated in the recent paper by Thurtle and colleagues [2] (open-access) on the use of oral DMSA for severe lead poisoning in Northern Nigeria. If we are to assume that certain types of bacteria might potentially be able to prevent or reduce uptake of something like heavy metals in the gastrointestinal (GI) tract from oral sources (i.e. food), I'd be minded to say that such inexpensive and potentially safer methods protecting against heavy metal poisoning, might be something to explore. And hopefully I'm talking out of turn when I mention some of the literature on lead and mercury exposure when it comes to autism (see here) as another possible avenue for more formal investigation.

Next up: probiotics and influenza anyone? (With the need for a lot more research and certainly nothing like medical or clinical advice given or intended by me on this topic).

Music then. Domino by Jessie J.

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[1] Bisanz JE. et al. Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children. mBio. 2014. 7 October.

[2] Thurtle N. et al. Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data. PLoS Medicine. 2014; 11: e1001739.

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Jordan E. Bisanz, Megan K. Enos, Joseph R. Mwanga, John Changalucha, Jeremy P. Burton, Gregory B. Gloor, & Gregor Reid (2014). Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children mBio : 10.1128/mBio.01580-14

Organic food: meta-analysed

A very quick post to direct you to the paper by Barański and colleagues [1] which is currently making a few headlines and sparking some debate (see here and see here) with their assertions: "the concentrations of a range of antioxidants such as polyphenolics were found to be substantially higher in organic crops/crop-based foods" and "the frequency of occurrence of pesticide residues was found to be four times higher in conventional crops, which also contained significantly higher concentrations of the toxic metal Cd [cadmium]".

Lead by researchers based at Nafferton Farm affiliated to Newcastle University, the literature review and meta-analysis looked at over 300 studies looking at "the composition of crops and foods". According to the BBC website, Carlo Leifert who headed the review said: "This study demonstrates that choosing food produced according to organic standards can lead to increased intake of nutritionally desirable antioxidants and reduced exposure to toxic heavy metals".

I've had the pleasure of visiting Nafferton Farm once or twice and chatting to Carlo and his team about some of the work going on. It is a lovely part of the world and some great science is being done and reported in the peer-reviewed press [2]. Appreciating that there are still some significant gaps in the science about organic vs. conventional farming methods and their impact on food in terms of yields and nutritional quality, I do think that this latest (and largest) review is something which should not be ignored...

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[1] Barański M. et al. Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. Br J Nutr. 2014 Jun 26:1-18.

[2] Stergiadis S. et al. Improving the fatty acid profile of winter milk from housed cows with contrasting feeding regimes by oilseed supplementation. Food Chem. 2014 Dec 1;164:293-300.

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Barański M, Srednicka-Tober D, Volakakis N, Seal C, Sanderson R, Stewart GB, Benbrook C, Biavati B, Markellou E, Giotis C, Gromadzka-Ostrowska J, Rembiałkowska E, Skwarło-Sońta K, Tahvonen R, Janovská D, Niggli U, Nicot P, & Leifert C (2014). Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. The British journal of nutrition, 1-18 PMID: 24968103

Toxic metal accumulation and autism?

To quote from the recent paper by Altaf Alabdali and colleagues [1] (open-access) "This study confirms earlier studies that implicate toxic metal accumulation as a consequence of impaired detoxification in autism and provides insight into the etiological mechanism of autism".

Heavy metal noise pollution @ Wikipedia 

Big words I'm sure you'll agree and certainly something that I was keen to talk about on this blog. The paper itself is open-access but a few pointers might be in order:

• A couple of familiar names are part and parcel of the authorship of this paper (Laila Al-Ayadhi & Afaf El-Ansary) who's previous research has been covered more than once on this blog (see here and see here).
• The name of the game was two fold with autism in mind: (a) measure levels of "two environmental toxicants" -  lead (Pb) and mercury (Hg), and (b) measure levels of two "enzymatic and non-enzymatic antioxidants with high activity in terminating lipid peroxidation and environmental toxicity" - an old friend glutathione, or rather glutathione-S-transferase activity (GST) and vitamin E. Authors "hypothesized that confirming the relationship between impaired detoxification mechanism and severity of ASD could enhance efforts at early prevention, diagnosis, and intervention".
• The participants groups comprised 52 boys diagnosed with an autism spectrum disorder (ASD) (mean age 7 years) and 30 age- and sex-matched "apparently healthy children" (mean age 7.2 years). The Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS) were used as measures of autism severity.
• Results: based on analysis of blood samples (red blood cells and plasma) "Mercury and Pb were significantly elevated in the autistic patients compared with the controls, with increases of 36.58% and 43.34%, respectively. GST and vitamin E levels decreased by 50.71% and 43.18% percent, respectively". So heavy metal body burden was up and detoxification compounds appeared reduced in this sample of children with autism.
• Further: "remarkably high levels of Hg and Pb were recorded in patients with severe social and cognition impairments (SRS & CARS) compared with those with mild-moderate abnormalities". Ergo, severity of symptom presentation may show more than a passing connection to heavy metal load.
• The customary ROC analysis (which seems to appear in many papers from this group) is also presented, where all "measured parameters demonstrated almost 100% sensitivity and very high specificity, which also confirmed the hypothesis that autistic patients are poor detoxifiers, unable to readily excrete toxic substances (e.g., Hg and Pb), and suggests that reduced GST activity and depleted vitamin E are two critical factors related to poor detoxification".

So there you have it. Of course there is lots more discussion in the paper probing the hows and whys of the results which readers are invited to peruse at their leisure. There are issues as with any paper: the sample size was relatively small in this particular study and confined to a particular geographical region, so one needs to be a little bit careful of extrapolating results to the wider autism spectrum population at the current time. That also the "measured form of vitamin E, α –tocopherol" for example, was analysed by HPLC solely with UV detection perhaps also opens the study up to some analytical issues given the other, more comprehensive analysis methods out there [2] realising how complex a matrix such biological fluids can be. Still, I'm not going to quibble with the Alabdali results as they stand and the requirement for further research in this area.

I've recently been hearing a lot more about lead (Pb) and things like the suggested correlation between removing lead from petrol being correlated - "correlated" - with the drop in violent crimes we seem to be witnessing these days (see here). Lead also continues to show up quite a bit on the autism research radar, and the growing consistency in findings talking about elevated levels of lead being found in cases of autism (see here) bearing in mind what we already know about lead exposure and childhood brains and development (see here). I might add that I am not in any way linking lead levels in autism and lead levels with crime in mind; the sad truth is that people with autism are far more likely to be the victim of crime rather than perpetrator (see here RIP).

Mercury and autism tends to be more of a contentious topic given the discussions about sources of mercury [3] (and see here for the other side of the coin [4]) despite there being some evidence that the biological burden may be elevated in some people on the autism spectrum [5]. I don't really want to get into the nitty-gritty of where mercury might be sourced from in this story, rather that knowing how toxic the stuff is, steps need to be taken to remove any excess burden. The implication from the Alabdali results are that further investigations might also be required on how the body deals with these pollutants too which may very well form part of a bigger picture... (yes, mitochondria).

Music to close. Controversy aside, a band called One Direction played the SoL yesterday evening. My brood have been exposing me to ever increasing doses of their music throughout the week and as a result, I think I might be developing some kind of One Direction Stockholm Syndrome.

So, here is You and I... and slowly but surely it's growing on me.

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[1] Alabdali A. et al. A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders. Behavioral and Brain Functions 2014, 10:14

[2] Nagy K. et al. Comprehensive analysis of vitamin E constituents in human plasma by liquid chromatography-mass spectrometry. Anal Chem. 2007 Sep 15;79(18):7087-96.

[3] Geier DA. et al. A two-phase study evaluating the relationship between Thimerosal-containing vaccine administration and the risk for an autism spectrum disorder diagnosis in the United States. Transl Neurodegener. 2013 Dec 19;2(1):25.

[4] Price CS. et al. Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Pediatrics. 2010 Oct;126(4):656-64.

[5] Geier DA. et al. Blood mercury levels in autism spectrum disorder: Is there a threshold level? Acta Neurobiol Exp (Wars). 2010;70(2):177-86.

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Alabdali, A., Al-Ayadhi, L., & El-Ansary, A. (2014). A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders Behavioral and Brain Functions, 10 (1) DOI: 10.1186/1744-9081-10-14

Environmental toxicants and autism reviewed

So: "The findings of this review suggest that the etiology of ASD [autism spectrum disorder] may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD".

That's the conclusion reached by a huge review paper by Dan Rossignol and colleagues* (open-access). I'm going to say no more aside from inviting readers to put half an hour aside, read and digest the significant work that has gone into this paper. Oh, and aside from including the autism research tag-team that is Rossignol and Frye (see here and see here and see here), a certain S Genuis also appears on the authorship list (see here and see here).

Toodle pip.

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* Rossignol DA. et al. Environmental toxicants and autism spectrum disorders: a systematic review. Translational Psychiatry. 2014; 4: e360; doi:10.1038/tp.2014.4

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D A Rossignol, S J Genuis, & R E Frye (2014). Environmental toxicants and autism spectrum disorders: a systematic review Translational Psychiatry DOI: 10.1038/tp.2014.4

In relation to chelation and autism

OK, just to make sure we're straight on this matter:

I am not endorsing chelation therapy for autism in this post.

Carry on Private...

I might have said it before but a few areas of the autism landscape have been, and still, are a bit of a sticking point when it comes to their discussion. Mention for example bowel issues and autism and, in at least some quarters, you can see the eyebrows raising and the eyes beginning their short rolling journey around the eye socket. This despite the fact that bowel issues are to some extent entering the mainstream autism research consciousness as witnessed for example by that recent paper from Susie Chandler and colleagues (discussed here). Dare I even mention gut bacteria and autism as per the recent write-up of Paul Patterson's [pending] work in the New Scientist? Too much?

My hand @ Miss Whiteley  

So it is with some degree of eye-rolling anticipated that I set about discussing the paper by Eleonor Blaucok-Busch and colleagues* (open-access) describing the results of their small trial based on the use of the oral chelator meso-2,3-dimercaptosuccinic acid (DMSA) in cases of autism.

I'm not altogether sure, but I wondered whether we might have already seen some part of this trial published in another paper**.

In truth I wouldn't normally be minded to talk about something like DMSA and autism given that (a) chelation - with general health in mind - is still a bit of a hot potato in many science/medical circles even despite some evidence that the 'metal-snaring' intervention might have some effects, and (b) with autism in mind, chelation is even more of a hot potato given some safety concerns and its link to heavy metals - in particular one heavy metal - onward to a suggested role in the rising numbers of cases of autism by some.

But science is science, and the manuscript by Blaucok-Busch is peer-reviewed science (the journal also indexed in PubMed). Added to the fact that some people have reported positive changes to some features associated with autism following such intervention*** alongside some recent publicity for related work by people like Jim Adams (see this previous post), this post may be timely.

The Blaucok-Busch paper is open-access but a few details might be of some use:

• I don't mean to be a stickler but the opening line of the abstract read slightly unusual to me: "the aim of this study was to provide evidence that DMSA detoxification treatments cause a reduction of the heavy metal burden in the autistic, and that this reduction lessens neurological symptoms associated with ASD". A research paper designed to provide evidence that something works? Mmm, I perhaps would have worded this differently with regards to things like hypothesis-testing over evidence-producing, but maybe that's just me.
• Anyhow, 44 children diagnosed with an ASD - most boys and most diagnosed with autism - aged between 3-9 years old were included for study. The children were all attending a child development centre in Saudi Arabia. Quite a bit of background data were available for participants and in among the various entry/exclusion criteria were the none use of regular medication including neuroleptics and antiepileptics. 
• The Childhood Autism Rating Scale (CARS) (translated into Arabic) was used to score the presence of autism-related behaviours; both before DMSA use and "six months after treatment". This actually translates as a single dose of DMSA per month (10mg/kg body weight) for a total of 6 months.
• Prior to any use of DMSA, participants were provided with a nutritional supplement including "a multi-mineral-vitamin-amino acid complex" which included zinc gluconate given once-a-day for 3 months prior to chelation.
• Baseline urine samples pre-chelation were collected and alongside (I assume first supplementation) post-DMSA administration urine samples (over 4 hours), analysis was conducted on them using everyone's favourite metal analysis technique, ICP-MS.
• Results: based on analysis for a number of metals, urine samples showed a number of differences between pre- and post-DMSA administration, most notably for increases in cadmium (p=0.006) and lead (p=0.008) excretion. Mercury also showed some difference, but only just from a statistical point of view (p=0.049). Another quote: "For this autistic group, the baseline urine concentration of all metals tested exceeded the given reference range".
• For the CARS, pre- and post-DMSA scores - bearing in mind we are talking 6-months after treatment - showed a few interesting trends in terms of items like sensory-perceptual issues and verbal and non-verbal communication, potentially indicative of positive changes to symptoms.
• The authors conclude: "Our evaluation confirmed specific metals as neuro-developmental toxins, and we observed that a reduction in toxic metals is helpful in reducing some symptoms typically associated with autism".

OK first things first. This was a simple before-and-after study based on the use of DMSA. There was no control group, no randomisation, no placebo, and everything was unblinded. This is not a great example of providing evidence for a cause-and-effect relationship.

Aside from reporting that 2-3 days prior to the DMSA challenge "no fish was eaten" and "all nutritional supplements were stopped" we know very little about what else might have happened in that intervening 6 month period between CARS assessments. Without any sample control group to compare against, we might just as well say that the changes to the CARS might be down to maturation or some other intervention put in place. Indeed I don't know whether this cohort were more or less likely to be using other interventions which might have affected results as a result of their participation in the trial; not least whether anyone went back on to the nutritional supplement after the first chelation event. There are methodological holes in this trial; of this there is no doubt.

But... [cue any eye-rolling] I am particularly interested in the pre- and post-challenge DMSA urine results detailed. Interested that even in the pre-DMSA samples, children with autism were presenting with levels of heavy metals that exceeded reference ranges. Granted, one could ask: from where the reference range is derived and whether it is truly reflective of this particular participant group in terms of age, sex, ethnicity, etc. and the myriad of other potentially influential demographic and geographic factors. I have to take the authors' word for it that it is accurate although I would like to have seen the unit of measurement when it comes to reporting metal excretion levels displayed somewhere in the paper.

Of course this is not the first time that metals like lead have for example cropped up with autism and quite a few other conditions/states in mind. Even superman had problems with lead, so went a past post on this blog. Indeed my discussion on the paper by Yasuda and colleagues quite recently (see here) and their metallomic analysis of children with autism suggested that lead, cadmium and aluminium in relation to some cases of autism were of potential importance, particularly where zinc deficiency was present. This follows similar findings previously reported (yep that Jim Adams study again) and some case studies (see here for example).

I was also interested in the variation in metal excretion following DMSA challenge. Increasing mean levels of urinary lead in the cohort follow what DMSA is supposed to do and add to the evidence already presented with autism in mind**** (open-access). But, as the authors point out, several metals were actually lower in the post challenged samples. Even the mercury results whilst showing a mean higher level showed a vastly increased standard deviation pre- and post-challenge (3.35±3.81 vs. 16.12±36.57) which probably accounts for the relatively modest p-value reported. I assume this denotes that some children were better excretors of things like mercury than others following DMSA challenge? My next question would be: why?

Evidence for the use of chelation in cases of autism is still wanting in terms of research results as per the review by Davis and colleagues*****. This trial by Blaucok-Busch is, unfortunately, unlikely to add anything significant to the existing research literature. The tragic case of Abubakar Tariq Nadama who died following intervention with a chelating agent****** (albeit a different chelating agent) still also hangs over the whole area of metal removal and autism and serves as an important but very unfortunate reminder about what can happen; also re-emphasizing the first law of any intervention: do no harm. No doubt why the NIH trial fell as it did (see here).

That's not however to say that the research door should be slammed shut, bolted, padlocked and alarmed, as several questions still remain unanswered: why for example some kids with autism present with elevations in certain heavy metals in the first place (see the paper by Levallois et al******* for one possibility) and what their relationship might or might not be to presented symptoms. One could argue that getting to the bottom of these questions is the first step, and thereafter to the question of what can or can't be done about it in a more scientifically-rigorous fashion bearing in mind safety first and the fact that not all chelating methods are the same********.

To finish, a final mention: I am not endorsing chelation therapy for autism in this post. Just in case I hadn't got my message across.

Now away from metal, how about listening to The Specials and 'Gangsters' including one of the best lines in music... "Don't call me Scarface". So, don't.... (and as it happens, thanks to a childhood prank gone wrong, I do actually have a scar on my face).

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* Blaucok-Busch E. et al. Efficacy of DMSA therapy in a sample of Arab children with autistic spectrum disorder. Maedica (Buchar). 2012; 7: 214-221.

** Amin OR. P-252 - Efficacy of oral dimercaptosuccinic acid (DMSA) therapy in a sample of arab children with autistic spectrum disorder. European Psychiatry. 2012; 27 (suppl 1).

*** Senel HG. Parents' views and experiences about complementary and alternative medicine treatments for their children with autistic spectrum disorder. J Autism Dev Disord. 2010; 40: 494-503.

**** Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results. BMC Clin Pharmacol. 2009; 9:16.

***** Davis TN. et al. Chelation treatment for autism spectrum disorders: a systematic review. Research in Autism Spectrum Disorders. 2013; 7: 49-55.

****** Baxter AJ. & Krenzelok EP. Pediatric fatality secondary to EDTA chelation. Clinical Toxicology. 2008; 46: 1083-1084.

******* Levallois P. et al. The impact of drinking water, indoor dust and paint on blood lead levels of children aged 1–5 years in Montréal (Québec, Canada). Journal of Exposure Science and Environmental Epidemiology. January 2013.

******** Cohen JP. et al. Plasma and Urine Dimercaptopropanesulfonate Concentrations after Dermal Application of Transdermal DMPS (TD-DMPS). J Med Toxicol. 2013; 9: 9-15.

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Blaucok-Busch E, Amin OR, Dessoki HH, & Rabah T. (2012). Efficacy of DMSA Therapy in a Sample of Arab Children with Autistic Spectrum Disorder. Maedica (Buchar), 7 (3), 214-221