Childhood lead (Pb) exposure and "greater psychopathology across the life course"

I've talked about the effects of lead (Pb) on cognition, behaviour and psychology before on this blog (see here and see here for examples). A (heavy) metal with no confirmed biological function, lead represents something that pretty much everyone should be avoiding exposure to, despite it still being used in everything from roofing materials to batteries. The findings reported by Aaron Reuben and colleagues [1] add further to the 'avoid lead' sentiments, and specifically how: "Childhood lead exposure may have long-term consequences for adult mental health and personality."

The aim of the Reuben paper was to conduct "the longest and largest psychiatric follow-up to date in a cohort of adults who were lead exposed and lead tested as children." Participants and their data came from "the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behavior in a birth cohort." This study specifically drew on data from over 500 Dunedin study members who were tested for lead exposure around age 11 years and were followed up until their late 30s. A range of psychometric measures were employed in adulthood to complement participants' blood lead test results during childhood, including "(1) repeated clinical interviews assessing psychopathology symptoms across adulthood up to 38 years of age; (2) comprehensive, dimensional measures of psychopathology that account for severity, comorbidity, and reoccurrence; and (3) a broad measure of adult personality (Big Five Personality Inventory)... that did not rely on self-report." Importantly, researchers relied on a sample where "the extent of children's exposure to lead was unrelated to their socioeconomic origins."

Results: most of the cohort (over 90%) had tested blood lead levels above the 5 μg/dL level that the US CDC currently describes as a "reference value for clinical attention." This threshold value replaced the 10 μg/dL level that used to be thought to be important. Indeed within the Reuben cohort: "The mean (SD) blood lead level was 11.08 (4.96) μg/dL."

Researchers also observed that: "After adjusting for covariates, each 5-μg/dL increase in childhood BLL was associated with a 1.34-point increase... in general psychopathology." Covariates included "family socioeconomic status, maternal IQ, and family history of mental illness." This seemingly dose-dependent relationship looked to be quite important.

Onward: "study members with higher BLLs [blood lead levels] at 11 years of age were viewed in adulthood by their informants as more neurotic..., less agreeable..., and less conscientious" than those with lower levels. Personality it seems *might* also be affected by childhood lead exposure (at least partially). These and other factors lead Reuben et al to conclude that: "the association between lead exposure and psychopathology may begin to manifest broadly well before adulthood" and "early-life lead exposure in the era of leaded gasoline experienced by individuals who are currently adults may have contributed to subtle, lifelong differences in emotion and behavior that are detectable at least up to 38 years of age."

I know there are caveats to this type of observational work - "there was only one time point of lead testing" - and even controlling for some potential covariates does not mean that the total spread of covariates has been covered in this study. Personally, I'm not overly enthused by the whole personality types bit either; particularly in light of further revelations about some of the historical proponents of such an idea (see here). But taken as part of a wider series of research on lead exposure and psychopathology, the Reuben work is in line with other results on how an environmental factor can seemingly affect both development and psychopathology. And minus any sweeping generalisations about psychopathology and crime, the so-called 'lead-crime hypothesis' under the guise of biosocial criminology for example, doesn't exactly suffer as a result of the Reuben findings...

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[1] Reuben A. et al. Association of Childhood Lead Exposure With Adult Personality Traits and Lifelong Mental Health. JAMA Psychiatry. 2019. Jan 23.

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Early lead (Pb) exposure and risk of ADHD: yet more 'nothing good comes from exposure to lead'

Lead (Pb) is a metal that has cropped up more than once on this blog (see here and see here and see here) in relation to early exposure and it's *possible* links to various childhood behaviour(s). As per part of the title of this post - 'nothing good comes from exposure to lead' - there really does seem to be very little good to say about exposure to lead (see here) given an apparent lack of any (advantageous) biological role when it comes to the human body. In short, we should be doing everything we can to ensure that exposure levels for everyone, particularly the very youngest, are kept to an absolute minimum...

The study results published by Yuelong Ji and colleagues [1] add to a pretty large peer-reviewed research literature observing a possible connection between biological lead levels "in early childhood" and risk of childhood psychopathology. They concluded that: "Elevated early childhood blood lead levels increased the risk of ADHD [attention-deficit hyperactivity disorder]."

The source material for the Ji study was the Boston Birth Cohort (a research initiative that has cropped up before on this blog) and specifically the examination of blood lead levels in conjunction with "physician-diagnosed ADHD" in some 1500 infants: "299 ADHD, 1180 neurotypical." Various other co-variates were also included in the statistical mix and sex/gender was analysed as an independent variable. And before you mention it, yes, as per my other musings on the word 'neurotypical' in the context of autism (see here), I'd prefer another term to denote not-ADHD such as er, 'not-ADHD'.

Results: approaching 1 in 10 of the cohort had elevated blood lead levels defined as a value between 5-10 µg/dL. This is quite worrying, particularly as various agencies have started to reduce the cut-offs/definition of a 'safe' level of lead in recent years (see here). For the 8.9% of the cohort with such blood lead levels, authors noted that this was "associated with a 66% increased risk of ADHD." Boys also seemed to be particularly vulnerable to the effects of elevated blood lead levels in relation to ADHD: "Among boys, the association was significantly stronger."

What else?  Well, bearing in mind the observational methodology employed in the Ji study, authors noted that the relationship between blood lead levels and ADHD also seemed to be mediated by other factors. So, the "risk of ADHD in boys was reduced by one-half if the mother had adequate high-density lipoprotein levels or low stress" where high-density lipoprotein (HDL) typically refers to the 'good type of cholesterol' (bearing in mind that biology is rarely so black-and-white) and 'low stress' refers to stress during pregnancy. In effect, whilst early lead exposure (or blood lead levels) may be important when it comes to risk of ADHD, other factors also seem to play a role; some potentially protective, others not so much (see here for example). This is something that has been noted in other studies looking at other heavy metals and neurodevelopmental outcomes (see here).

In conclusion, still nothing good comes from (early) exposure to lead...

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[1] Ji Y. et al. A Prospective Birth Cohort Study on Early Childhood Lead Levels and Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences. J Pediatr. 2018 May 8. pii: S0022-3476(18)30488-8.

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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

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

Still 'nothing good comes from exposure to lead'

Consider this short-ish entry a sort of extension of other discussions on this blog on the topic of lead (Pb) (see here). As per the blog title, the systematic review published by Maryam Daneshparvar and colleagues [1] (open-access available here) adds to the quite voluminous peer-reviewed literature indicating that lead exposure, particularly during infancy and childhood, seems to be associated with nothing but adverse outcomes in terms of development and behaviour.

Surveying the research literature "on the role of lead exposure in children with ADHD‏ [attention-deficit hyperactivity disorder] ‏symptoms" up to May 2014 - including some sources that I've not come across before e.g. IRAN Medex - the authors eventually boiled down the current research landscape to 18 articles "selected and entered into the data synthesis." It appears that some important guidance was followed when it came to study selection and interpretation and, all in all, some 12,000 participants were included in the selected research literature included for analysis.

Results: well as perhaps expected, nothing good seems to come from lead exposure. The authors reported that even at quite small concentrations in blood (blood lead levels, BLLs below 10µg/dL), lead is potentially linked to the presentation of ADHD in one form or another. In 16 of the 18 studies included in their analysis: "a significant association was found between ‎BLL and one of the types of ADHD.‎"

What's more to say on this topic? Well, as the authors note, the vast majority of the studies analysed included only one measure of BLL so one perhaps has to be a little cautious about the 'snapshot' nature of the data included. They also make some comment on how the symptoms of ADHD were a focus over and above a 'diagnosis' so that could also be considered a methodological weakness.

That all being said, and knowing what we know about 'lead being a strong poison' I'm yet again convinced that keeping kids in particular away from sources of possible lead contamination is of vital importance. I say that not just from the point of view of risk of ADHD-type behaviours or any other label (see here), but simply because nothing good comes from exposure to the stuff. When also we talk about lead exposure, we might also be inclined to note that ambient levels of the stuff might also show some interesting correlations too [2] (yes, correlation is not the same as causation).

Finally, in amongst all the doom and gloom about lead exposure and developing brains, there may also be a ray of hope...

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[1] Daneshparvar M. et al. The Role of Lead Exposure on Attention-Deficit/ Hyperactivity Disorder ‎in Children: A Systematic Review. Iran J Psychiatry. 2016 Jan;11(1):1-14.

[2] Dickerson AS. et al. Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic. Environ Monit Assess. 2016 Jul;188(7):407.

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Daneshparvar M, Mostafavi SA, Zare Jeddi M, Yunesian M, Mesdaghinia A, Mahvi AH, & Akhondzadeh S (2016). The Role of Lead Exposure on Attention-Deficit/ Hyperactivity Disorder ‎in Children: A Systematic Review. Iranian journal of psychiatry, 11 (1), 1-14 PMID: 27252763

Blood lead levels and 'autistic behaviors in school-age children'

Lead (Pb) has been in the news quite a lot recently. The Flint water crisis (see here for some background) has brought back into stark view why science has pretty conclusive labelled lead as "a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero" [1].

I've talked about lead and behaviour quite a bit on this blog (see here and see here for example). The crux of the combined peer-reviewed research looking at lead and children is that the two don't mix well. In fact, the two don't mix at all. Not at all, and we should be doing everything possible to limit childhood exposure in particular.

So far I've tended to cover research on this blog suggesting that general behavioural 'issues' have been correlated with increasing levels of lead (as measured in blood) over and above specific types of behaviour. Autism or autism-associated behaviours has been mentioned (see here) but more speculatively than anything else, and also in conjunction with findings reporting an increased biological lead load (see here) at least for some on the spectrum.

The paper by Kyoung-Nam Kim and colleagues [2] brings autism or rather autistic traits, more squarely into the frame with lead in mind as a result of their findings: "Blood lead concentrations at 7–8 years of age (geometric mean: 1.64 μg/dL), but not at 9–10 and 11–12 years of age, were associated with more autistic behaviors at 11–12 years of age."

Looking at nearly 2500 South Korean children aged 7-8 years old (South Korea eh?), researchers measured blood lead levels and 'autistic behaviours' every 2 years until children reached 11-12 years old. The Autism Spectrum Screening Questionnaire (ASSQ) and Social Responsiveness Scale (SRS) were the tools of choice for assessing autism-related signs and symptoms. The results as I've just mentioned suggested that there might be some important *correlation* between blood lead levels at 7-8 years and offspring outcomes at 11-12 years. Indeed: "Even low blood lead concentrations at 7–8 years of age are associated with more autistic behaviors at 11–12 years of age, underscoring the need for continued efforts to reduce lead exposure."

OK, one has to be a little cautious about making too much of when one variable (blood lead level) is correlated with another (autistic traits) over the course of quite a long time. Set within the idea that there may be literally thousands of factors influencing the presentation of autism or autistic traits (or some of its important comorbidity), to pin everything just on lead is perhaps taking things a little too far. That other groups in other parts of the world have not noted any significant association between lead levels and autism [diagnosed autism] is also something else to mention (see here).

But, and it is an important point to make, it would perhaps be unwise to poo-poo the Kim results outright. We know, for example, that having a diagnosis of autism does not protect someone from lead poisoning [2] and one might even suggest that the risk is higher where autism coincides with issues such as pica [3] for example (see here). That screening for lead intoxication might also be preferentially offered to those with a diagnosis of autism for example [4] is another important point to make. Screening is the first step.

As and when lead intoxication is detected alongside autism, treatment should follow recommended guidance. If intervention *might* also have other effects linked to decreasing lead levels [5], one might reasonably ask questions about how the lead might indeed play an important role for at least some on the autism spectrum or presenting with autistic traits bearing in mind the dangers of generalising (see here)...

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[1] Hou S. et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theoretical Biology & Medical Modelling. 2013;10:13.

[2] Kim K-N. et al. Low-level lead exposure and autistic behaviors in school-age children. NeuroToxicology. 2016. Feb 11.

[3] Cohen DJ. et al. Pica and elevated blood lead level in autistic and atypical children. Am J Dis Child. 1976 Jan;130(1):47-8.

[4] Shannon M. & Graef JW. Lead intoxication in children with pervasive developmental disorders. J Toxicol Clin Toxicol. 1996;34(2):177-81.

[5] Eppright TD. et al. Attention deficit hyperactivity disorder, infantile autism, and elevated blood-lead: a possible relationship. Mo Med. 1996 Mar;93(3):136-8.

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Kim, K., Kwon, H., & Hong, Y. (2016). Low-level lead exposure and autistic behaviors in school-age children NeuroToxicology DOI: 10.1016/j.neuro.2016.02.004

Nothing good comes from exposure to lead

"In this population of Mexican children, current blood lead level among children with low exposure (< 5µg/dL) was positively associated with hyperactive/impulsive behaviors, but not with inattentiveness. These results add to the existing evidence of lead-associated neurodevelopmental deficits at low levels of exposure."

That quote from the paper by Siying Huang and colleagues [1] (open-access available here) kinda says it all when it comes particularly to childhood exposure to lead (Pb) insofar as there really being no safe limit. Allied to other research in this area (see here) the message is coming through loud and clear that when it comes to this stuff: "Lead is a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero." [2]

Without pushing specific associations, I'd also suggest that where particular groups of children may be more prone to present with issues with lead (see here) (although not all [3]), science and clinical practice might be minded to think about minimising potential routes of exposure (see here) and perhaps strategies for removing any excess load [4]. Questions about whether there may be underlying biological or genetic 'issues' pertinent to the metabolism of such xenobiotics might also figure, specifically in light of where elements of autism research in particular, have already cast a spotlight (see here).

Nothing good comes from exposure to lead.

Tomorrow (30th December) I have my annual review of research on this blog so please come by and take a look. For now, I leave you with an idea for 2016... bring back Yub Nub (and original Anakin).

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[1] Huang S. et al. Childhood Blood Lead Levels and Symptoms of Attention Deficit Hyperactivity Disorder (ADHD): A Cross-Sectional Study of Mexican Children. Environ Health Perspect. 2015 Dec 8.

[2] Hou S. et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model. 2013 Feb 18;10:13.

[3] Fuentes-Albero M. et al. Lead excretion in spanish children with autism spectrum disorder. Brain Sci. 2015 Feb 16;5(1):58-68.

[4] Gracia RC. & Snodgrass WR. Lead toxicity and chelation therapy. Am J Health Syst Pharm. 2007 Jan 1;64(1):45-53.

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Huang S, Hu H, Sánchez BN, Peterson KE, Ettinger AS, Lamadrid-Figueroa H, Schnaas L, Mercado-García A, Wright RO, Basu N, Cantonwine DE, Hernández-Avila M, & Téllez-Rojo MM (2015). Childhood Blood Lead Levels and Symptoms of Attention Deficit Hyperactivity Disorder (ADHD): A Cross-Sectional Study of Mexican Children. Environmental health perspectives PMID: 26645203

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

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

Temporal trends in US autism prevalence: mainly real increase

"Diagnosed autism prevalence has risen dramatically in the U.S over the last several decades 
and continued to trend upward as of birth year 2005. The increase is mainly real and has occurred mostly since the late 1980s".

"They call me Cha Cha because I'm the
best dancer at St. Bernadette's"

That was the conclusion reached in the paper by Cynthia Nevison [1] (open-access) following her analysis of temporal trends in autism diagnosis for birth years between 1970 and 2005. Based on an analysis of datasets derived from IDEA (Individuals with Disabilities Education Act) and the CDDS (California Department of Developmental Services), the author suggested that between 75-80% "of the tracked increase in autism since 1988 is due to an actual increase in the disorder rather than to changing diagnostic criteria". The question of what environmental factors might have been driving such an increase in cases is also discussed in the Nevison paper, with the author concluding "children’s exposure to most of the top ten toxic compounds has remained flat or decreased over this same time frame". That top 10 list by the way, seems to come at least partly from the Landrigan paper talked about a couple of years back (see here).

There is quite a bit of information included in the Nevison paper which I'm reluctant to write a mega-blog entry on at this time. This includes various caveats about the use of IDEA and CDDS databases and their constraints on for example, what ASDs (autism spectrum disorders) are included in the datasets. I will however summarise some of the main findings in relation to the environmental factors probed by the author bearing in mind that autism research does not appear to be her main area of scientific interest (with all due respect).

So:

• Air pollution... something which has cropped up with ever-increasing frequency in the peer-reviewed research on autism (see here and see here for example). Nevison concludes: "there is no obvious evidence to suggest that trends in estimated vehicular emissions or directly measured air pollution are consistent with the sharp temporal increase in U.S. autism". So no smoking tailpipe (exhaust) there then as per other recent research findings [2].
• Mercury in vaccines... a topic guaranteed to furrow brows and raise blood pressure in some quarters (see here and see here for example). Nevison discusses the phaseout of thimerosal (thiomersal) from paediatric vaccines used in the US concluding that "the expansion of thimerosal exposure in the late 1980s and early 1990s coincides closely with the rise in autism around that time". But... "the temporal trends in autism and thimerosal following the childhood vaccine thimerosal phaseout are incompatible". Other sources of mercury exposure get a similarly 'unlikely' mark from Nevison.
• Organophosphate (OP) pesticide exposure... an interesting area which again has been covered previously on this blog (see here and see here). Nevison points out the declining use of such pesticides in the US following "the adoption of crops genetically modified to produce Bt toxin, which repels targeted insect pests, thus reducing the need for external insecticides". Recognising that pesticides are not to be trifled with (see here) I've always been a little confused about the mechanism(s) through which OP exposure could theoretically impact on the presentation of autism. I know people have talked about PON1 and autism [3] (some autism) but I do feel as though the primary effect of OPs - acting on acetlycholinesterase -  is something in need of a lot more research with autism in mind before anyone gets too carried away. 
• There is however a caveat to the pesticides-autism conclusion by the author following some mention of "the rapidly increasing application of glyphosate, the active ingredient in the herbicide Roundup®". She continues: "it appears that glyphosate cannot be responsible for the first autism cases in the 1930s and is unlikely to have caused the late 1980s uptick, but could be interacting in recent years with other toxins to drive up the prevalence of U.S. autism". Depending on where you look, you'll get various different messages about the pros and cons of glyphosate. I remember reading a report a few years back (see here) authored by one of the researchers involved in that 'organic food might be better for you' paper recently (see here) which painted a rather disturbing picture of the product. For balance, I'm going to also refer you to the various documents provided by Monsanto (the producer of Roundup) for their response to safety concerns. When it comes to a search of PubMed with the terms 'autism and glyphosate' the current result is zero although it has been mentioned elsewhere in the peer-reviewed domain [4]. 
• Maternal obesity... I'm being quite careful here accepting the previous discussions in this area of autism research (see here). Nevison reports that: "the time trend in obesity among U.S. women correlates well to that of autism, suggesting maternal obesity may be a direct influence or a comorbid consequence of the dietary factors contributing to autism, or both". 

One needs to bear in mind that the United States was the focus on these findings and as such the conclusions may not pertain to other parts of the globe. I probably don't need to say it but one should also bear in mind the saying 'correlation is not the same as causation' too. There are also other issues which have been discounted by Nevison as being related to the autism prevalence. Lead (Pb) is one of them; something which I personally would not be so keen to disregard given the more recent evidence on even trace amounts of this stuff not being great for the developing child (see here). This on top of what has been talked about with autism in mind (see here). 

I have a few other points to make which were perhaps not readily implied in the Nevison paper: first is the assumption that autism is some kind of universal condition. What I think many people have come to realise over the past few years is that within the significant behavioural and developmental heterogeneity grouped under the label autism, also compounded by the increased frequency of various comorbid conditions, a more plural description - the autisms - might be more pertinent. What this implies is that different weightings for concepts like genetics or environment (or epigenetics!) are likely acting across risk of different types of autism. 

Second, and related to point one, is the concept of synergy across different 'causative' factors. In the same way that autism science has started to accept that there is no one gene linked to all cases of autism, so environmental examinations can't really expect there to be one environmental factor working alone pertinent to all autism. If one is to assume that various environmental factors (see here and see here for example) may be linked to autism onset, it is more likely that combinations of factors are playing a role or possibly specific environmental factors acting on specific types of autism. Take for example the early work on air pollution and genotype being potentially associated with autism risk [5] as one example.

At the risk of being too speculative, I'm also minded to bring to your attention an emerging idea which might also be relevant: transgenerational epigenetics. The idea is that what happened in previous generations might have an influence on subsequent generations without structurally altering DNA in terms of the physical language of the genome. There has been some media interest in this concept in recent times (see here). With autism in mind, we've seen hints of this idea in the peer-reviewed research literature as per discussions on how advancing grandparental age might be linked to an increased risk of autism (see here). Jill Escher also talked about past chemical exposures potentially impacting on "vulnerable fetal germline epigenetics" (see here for her presentation). The implication being that correlating current exposure patterns with current autism diagnosis prevalence might not necessarily be the best way of looking at whether (and which) environmental factors might have a bearing on autism prevalence...

The primary message from the Nevison report is that the numbers of cases of autism do appear to be on the rise in the United States, and as per other reports from geographical neighbours (see here) the debates are not yet over about the reasons for that increase. Something another study has also talked about recently [6]...

So then, Only Love Can Break Your Heart by Saint Etienne.

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[1] Nevison CD. A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors. Environmental Health 2014, 13:73

[2] Gong T. et al. Exposure to Air Pollution From Traffic and Neurodevelopmental Disorders in Swedish Twins. Twin Res Hum Genet. 2014 Sep 17:1-10.

[3] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[4] Seneff S. et al. Is Encephalopathy a Mechanism to Renew Sulfate in Autism? Entropy 2013. 15; 372-406.

[5] 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.

[6] Dave DM. & Fernandez JM. Rising autism prevalence: real or displacing other mental disorders? Evidence from demand for auxiliary healthcare workers in California. Economic Inquiry. 2014. 25 August.

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Nevison, C. (2014). A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors Environmental Health, 13 (1) DOI: 10.1186/1476-069X-13-73