"To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder"

The quote heading this post - "To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder" - reflects the aim of the study published by Ondine von Ehrenstein and colleagues [1]. Said aim was accomplished by examining data from "California’s main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics" with regards to autism diagnoses (see here) and pesticide use and exposure. The results: "Findings suggest that an offspring’s risk of autism spectrum disorder increases following prenatal exposure to ambient pesticides within 2000 m of their mother’s residence during pregnancy, compared with offspring of women from the same agricultural region without such exposure." Also: "Infant exposure could further increase risks for autism spectrum disorder with comorbid intellectual disability."

The von Ehrenstein findings also come with an accompanying editorial [2] both published in the British Medical Journal (BMJ). That editorial provides a good overview of the findings and, importantly, some of their limitations. The editorial notes for example, that: "the study included only children with a diagnosis of “autistic disorder” by the California Department of Developmental Services, based on criteria described in the Diagnostic and Statistical Manual of Mental Disorders version IV-R." It cautions that the von Ehrenstein findings might not generalise to "milder forms of autism spectrum disorder." This 'lack of generalisation to milder forms' is a real reversal of what is typically seen in the peer-reviewed autism research literature (see here).

I don't want to linger too much on the von Ehrenstein study but a few points are worth noting. The question of what specific pesticides *might* influence risk of offspring autism is a complicated one. The researchers reported that "small to moderately increased risks for the disorder in offspring with prenatal exposure to the organophosphates chlorpyrifos, diazinon, and malathion, the pyrethroids permethrin and bifenthrin, as well as to glyphosate, avermectin, and methyl bromide" were observed. They (and the editorial) talk about how further research is required to "examine the joint effects of multi-exposure mixtures to more effectively protect human health." This is important in the context of other research (see here and see here) and also to avoid any big media headlines (see here) about specific preparations 'causing' autism (which has not yet been authoritatively established). Given that various different classes of pesticides have somewhat slightly different biological actions, there is a lot of work to be done on the possible biological mechanisms/targets and any synergistic effects.

Also: "children with autism spectrum disorder and co-occurring intellectual disability were examined as a separate outcome." The fact that von Ehrenstein et al observed something like a 'stronger association' between pesticide exposure and those at the "more severe end of the autism spectrum" (the description according to one media source) is another important point requiring further study. I say this in the context that 'comorbidity' might not always be the best description for symptoms and diagnoses accompanying autism (see here).

The authors conclude that their findings - with appropriate caveats - have implications. Namely: "Exposure of pregnant women and infants to ambient pesticides with a potential neurodevelopmental toxicity mode of action should be avoided as a preventive measure against autism spectrum disorder." I don't think too many people would disagree with the sentiments of 'avoiding pesticide exposure' particularly for pregnant women and those who might also be more vulnerable to their potential effects. The questions now turn to genetics and biology and the question of why...

Music to close: Hostiles on the Hill (apparently)...

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[1] von Ehrenstein OS. et al. Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study. BMJ. 2019; 364: I962.

[2] Bakian AV. & VanDerslice JA. Pesticides and autism. BMJ. 2019; 364: I1149.

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Pesticides and autism: chapter II

I've labelled this entry a chapter II post reflecting some continued interest in how agricultural pesticide exposure might fit into autism research (see here for the chapter I post). In that previous post, I talked about various issues such as the old correlation-is-not-necessarily-causation mantra and indeed, how use of something like galantamine for cases of autism spectrum disorder (ASD) [1] might present something of a paradox for certain types of pesticides being involved in the condition, as a function of its similar acetylcholinesterase inhibitor activity (albeit reversible).

Altogether Now? @ Wikipedia 

Continuing the pesticide theme, I'm talking today about the paper by Janie Shelton and colleagues [2] (open-access) and their results strengthening "the evidence linking neurodevelopmental disorders with gestational pesticide exposures, and particularly, organophosphates". Some of the press on this study be seen here.

Based on data derived from the CHARGE study (beincharge!) authors reported that maternal residence during pregnancy close to locations undertaking "agricultural pesticide application" might elevate the risk of offspring autism; something previously discussed by some of the authors [3]. Results from CHARGE by the way, have already talked about other environmental associations with autism risk such as air pollution (see here). This initiative also recently confirmed what many people already knew in saying the gastrointestinal (GI) symptoms seem to be over-represented in cases of autism (see here).

The Shelton paper is open-access but here are a few pointers:

• With an authorship list of the great and the good associated with CHARGE, commercial pesticide use data was linked to the addresses of mothers when pregnant for groups diagnosed with autism (n=486) or developmental delay (DD) (n=168) compared with asymptomatic controls (n=316) living in California, USA. As alluded to in a post on that most undesirable of jobs - the commercial pesticide applicator - commercial pesticide use tends to be quite tightly regulated as a result of the potential for health effects when mis-used.
• Various models and algorithms built up a statistical picture of different classes of pesticides, their use and when and where they sprayed. The authors aimed to ascertain whether gestational exposure was linked to autism risk and whether there were "specific windows of vulnerability during gestation". 
• Results: bearing in mind there were quite a few estimates built into this study, a few points are worth mentioning. "Proximity to organophosphates at some time during gestation was associated with a 60% increased risk for ASD". Organophosphate (OP) pesticides were also "the most commonly applied agricultural pesticide near the home during pregnancy" and chlorpyrifos exposure in particular, during the 2nd trimester, seemed to show some association with offspring ASD risk.
• "Children of mothers residing near pyrethroid insecticide applications, just prior to conception or during 3rd trimester were at greater risk for both ASD and DD". Pyrethroids were the "second most commonly applied class of pesticides".
• A few additional points: males were slightly more likely than females to be exposed to pesticides during gestation, and the effects of multiple exposures (various different classes of pesticides) was generally "not found to be higher that the observations of the individual classes of pesticides".

Reiterating that this was a study based on estimation rather than looking at actual individual pesticide exposure during pregnancy or any biological testing for said exposure, this is an interesting study. I say that not to further condemn pesticides, which actually do quite a good job at helping to maintain our food supply and reduce our exposure to various pests. But rather that further study is indicated in this area as a result. The authors note the various strengths of their study based to a large extent on the fairly extensive data held on CHARGE participants. Likewise they note that their study did not for example, take into account "external non-agricultural sources" of pesticides such as those which many of us see sprayed around our homes, gardens and other areas of residence/work which could have affected their data. An 'underestimate' in actual exposure according to some external commentary on the study.

The question of pesticide exposure being potentially linked to autism risk carries quite a bit of the same baggage as the air pollution correlation. Yes, to some degree, we're all pretty unfit for consumption (see here) as a function of our 'chemical load' - bearing in mind the mis-representation of that word. Some people use this generality as a stick to beat such hypotheses on environment being potentially linked to conditions like autism (yes, we know the autisms are a complicated set of conditions). But as we've seen with the air pollution work, it may be the sum of the environmental risks combined with some genetic fragility which eventually provides the more important answers (see here); something which Shelton et al conclude: "Further research on gene-by-environment interactions may reveal vulnerable sub-populations". I might at this point also throw in a related post on Reelin and OPs as one area where we might begin searching.

In terms of the mechanism of effect, well if other autism research is anything to go by, it's gonna be complicated and probably not just confined to old the grey-pink matter. The obvious place to start looking would be the biological mechanisms which we rely on to metabolise things like OPs. PON1 is a good example, and as I've mentioned in other posts (see here) how PON1 has already seen some autism research action [4]. Indeed the paper by Gaita and colleagues [5] adds to the interest here and their findings of decreased serum arylesterase activity in case of autism. Paşca and colleagues [6] further suggested that a correlation (that word again) between high levels of homocysteine and low serum paraoxonase 1 arylesterase activity in cases of autism might be important. Certainly, when it comes to the 'big H' there is quite a bit of data with autism in mind (see here) but I'm not going to get ahead of myself here. I'll also direct your attention to other research talking about in-utero OP exposure being linked to shortened gestational duration [7] as an example of how effects may be peripheral as well as central. Oh and how PON1 enzyme levels might also tie into birth measurements [8].

If there is a take-home point to this post it is that the Shelton results suggestive of a link between gestational pesticide exposure and autism risk invite quite a bit more further scientific inspection of this area. I don't give clincial or medical advice on this blog but certainly the idea that pregnant women should perhaps "take special care to avoid contact with agricultural chemicals whenever possible" seems like a sensible statement to make (see here).

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[1] Ghaleiha A. et al. Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2013 Oct 15;28(7):677-685.

[2] Shelton JF. et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study. Environ Health Perspect. 2014: June 23.

[3] Shelton JF. et al. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environ Health Perspect. 2012 Jul;120(7):944-51.

[4] 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.

[5] Gaita L. et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010 Dec 30;180(2-3):105-13.

[6] Paşca SP. et al. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci. 2006 Apr 4;78(19):2244-8.

[7] Eskenazi B. et al. Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Population. Environ Health Perspect. 2004; 112(10): 1116–1124.

[8] Harley KG. et al. Association of organophosphate pesticide exposure and paraoxonase with birth outcome in Mexican-American women. PLoS One. 2011;6(8):e23923.

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Janie F. Shelton, Estella M. Geraghty, Daniel J. Tancredi, Lora D. Delwiche, Rebecca J. Schmidt, Beate Ritz, Robin L. Hansen, & Irva Hertz-Picciotto (2014). Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study Environmental Health Perspectives : 10.1289/ehp.1307044