Friday, 16 March 2012

Estimating parental occupational exposures and autism

Under pressure @ Paul Whiteley
I've spent quite a bit of time ducking in and out of an analytical chemistry lab down the years. Aside from a surprising lack of bubbling test tubes - cue the media representation of a scientist complete with white lab coat and safety specs holding up a funny coloured liquid to the light whilst looking inquisitively - there are a few things that you pick up quickly while at the bench. So interesting acronyms like COSHH (Control of Substances Hazardous to Health) and MSDS (Materials Safety Data Sheet) become watchwords, all in the name of 'elf and safety.

Reading MSDS-s in particular, can give you quite a wake-up call about how even routinely used chemicals can hide some pretty damaging effects as per this example for the solvent methanol. Don't even ask me about the commonly used solvent acetonitrile, also called methyl cyanide - that's cyanide but not the sparkling variety. Even good old dihydrogen oxide - 'water' to you and me - has its own MSDS. You and fire brigades across the globe will be glad to know that it's non-flammable.

Regular readers of this blog will probably have seen a few common threads running through the various posts with particular emphasis on how our modern-day physical environment may potentially impact on various facets of human (and animal) biology and functioning. I have tried not to fall too far into the 'synthetic is bad' pothole simply because such sweeping generalisations about all the various 'chemicals' making up our environment are not supported by the available evidence base. That however does not mean that certain compounds may not be able to potentially exert an effect on health and wellbeing, either at an individual or group level, in the short- or long-term, and even impact on our future generations. Sounds suspiciously like epigenetics again to me...

With this in mind, a recent paper by McCanlies and colleagues* was always going to be of interest and the suggestion that parental occupational exposure to certain chemical compounds might be more common to parents of children with autism compared to controls. Admittedly based on quite a small participant group (N=174) derived from the CHARGE study, the authors who included Irva Hertz-Picciotto, reported that "... exposures to lacquer, varnish, and xylene occurred more often in the parents of children with ASD". With sentences like that you can see how headlines can be made. There is however some 'devil in the detail' about such statements which becomes apparent from the full-text paper:

  • Of the 174 families included in this study (based on an original cohort of 249 children), 93 families had a child with an autism spectrum condition and 81 had 'unaffected' children.
  • Both parents were quizzed via a structured telephone interview about their jobs and likely exposure to chemicals found in the workplace before, during and shortly after pregnancy. So questions relating to the place of employment, what the company did/made and respective work duties were amongst the data collected.
  • One of three industrial hygienists also independently assessed potential occupational exposures initially based on a list of 49 agents supplied by the study authors. Industrial hygienists did not have access to participant grouping (autism or control) nor access to identifiable parental responses. They were however provided with some data relating to things like job history, tasks and responsibilities. Exposure level based on the 49 agents was then estimated and coded on a 0-3 scale where 0 = none and 3 = high estimated level of exposure.
  • Results: several possible exposures were identified. The most common exposures identified by industrial hygienists in the autism group were toluene (30.4%), metals (30.4%) and nickel (30.4%). The least common exposures were carbon disulfide (1.1%) and perchlorate (1.1%). For the control group, top of the pops were metals (32.5%) and aluminium (30%).
  • Parental self-reports suggested that disinfectant exposure was most frequently cited in the autism group (42.5%) same also with control parents (37.2%) during the index (pre-pregnancy) and pregnancy time frames.
  • When it came to assigning odds ratios (OR) (based on forest plots), lacquer exposure, varnish and xylene showed the strongest differences between the autism vs. control group from the industrial hygienists results. Parent self-reported OR data suggested that solvent and asphalt exposure were the better differentiators between the groups but when adjusted, no association was significantly so. 
  • Interestingly when it came to pesticide exposure, the industrial hygienists actually suggested that a slightly greater percentage of parents in the control group were exposed to things like insecticides and herbicides than the autism group parents, although overall the numbers were quite small.

I've thought quite a bit about this study and what the results might mean. Granted it was a pilot study and all in all no significant group differences were noted between the autism and control groups, so no smoking gun for all cases. Having said that nothing rules out a possible effect from individual level exposures as perhaps showing some relationship - remembering the recent post on HPPE and cognitive functions - and as yet the cumulative impact of more than one exposure cannot be forgotten. Bear in mind also that no specific biological measures of exposure were included in this trial; so even though exposure patterns were estimated, in reality, no real evidence of effect (or not) can be truly gained from this study as it stands.

Genes and environment is a relationship also worth bearing in mind when reading such studies, as per the recent data looking at the Rett syndrome MECP2 issue combined with PBDE exposure (in mice). The genetics of autism is, er, complicated, very complicated (2193 genes, etc, etc. so far). I would perhaps be interested to see if at an individual level, there is any relationship between exposure pattern and genes. The primary question being: where do you start to look?

As discussed in previous posts, we all live in a very different 'chemical' world these days compared with only a couple of hundred years ago. Granted, quite a bit of the progress made in terms of industrialisation is as a direct result of that new synthetic chemical world and so we should be cautious about forming too many sweeping prejudices about how bad the chemical soup is that we live in (ever wondered what chemical components are present in your PC/laptop/tablet/phone that allow you to read this post?).

To quote that wise old sage Darth Vader "don't be too proud of this technological terror you've constructed..".  Wise words indeed. It could be argued that we have been playing with fire for quite a few years now in terms of not keeping up with the potential individual and importantly, cumulative effects of the compounds we have ingeniously invented. In particular what effect they may / may not have on the developing infant.

More research please.

To end, if I had to have one, this would be my favourite Fleetwood Mac song: Go your own way.

* McCanlies EC. et al. Parental Occupational Exposures and Autism Spectrum Disorder. JADD. March 2012.
DOI: 10.1007/s10803-012-1468-1


  1. I have written to Erin McCanlies about the study. I pointed out to her that the four manufactured products identified in the study (lacquer, varnish, xylene, and asphalt) all use benzene in the manufacturing process and the association was with occupational exposures. An important study was published a few months ago that examined the frequency of sperm mutations in workers at manufacturing plants in China who were exposed to benzene. The study recruited 30 workers who had worked at the manufacturing plants for more than a year and divided the workers into three groups, a low exposure group, a moderate exposure group and a high exposure group. The study included a control group of 11 unexposed workers from the same town.

    Every participant in all four groups was found to have de novo sperm mutations including 1p36 sperm mutations. The frequency of de novo 1p36 sperm mutations was lowest, but present, in the unexposed group, higher in the low exposed group, higher still in the moderate exposed group and highest in the high exposed group. The 1p36 deletion syndrome is present in 1 in 5,000 to 10,000 newborns:

    The 1p36 deletion syndrome is also associated with autism:

    This is the first study that has demonstrated a direct connection between a specific sperm mutation (1p36 deletion), a specific severe genetic syndrome (1p36 deletion syndrome) and a specific environmental pathogen (benzene).
    The CHARGE group who published the occupational exposure study also published a paper last year that found that living in close proximity (<309m) to heavily congested freeways in densely populated California urban areas was associated with increased risk for autism. Benzene, because of its high octane number, is an important component in the production of refined gasoline and diesel fuels and one has to consider the possibility that at least some of these cases might be related to sperm mutations associated with long-lasting exposure to benzene particles and other air borne environmental pathogens produced by exhaust fumes.
    The CHARGE group has been studying the environmental effect of pathogens in the womb and early in childhood development. Environmental pathogens have neurotoxic effects but the CHARGE group was not studying the genotoxic effects of environmental pathogens. They now realize that both genotoxic and neurotoxic effects should be part of their continuing studies and may modify the study design to account for this.

  2. Many thanks RAJ and very well spotted.

    Not to steal any thunder from RAJ, readers can see more about benzene (and the benzene ring) here:

    and here:

  3. Hi Paul Whiteley -

    don't be too proud of this technological terror you've constructed.


    Serendipitously, I ran into this paper:

    exactly one bookmark click before coming to questioning-answers today.

    An algorithm designed by US scientists to trawl through a plethora of drug interactions has yielded thousands of previously unknown side effects caused by taking drugs in combination.


    The team then used this method to compile a database of 1,332 drugs and possible side effects that were not listed on the labels for those drugs. The algorithm came up with an average of 329 previously unknown adverse events for each drug — far surpassing the average of 69 side effects listed on most drug labels.

    We don't get to pick and choose which functions get re-jiggered when you try to monkey with the molecular machinery of intertwined systems.

    Thanks for an assessment of this paper, it was one I'd been meaning to read, but my initial thoughts were that it was probably too scattershot to be much more than (broad) hypothesis forming.

    - pD

  4. Thanks for the comment pD.

    My Star Wars obsession leaks out yet again (just for the record, the original 3 films are still infinitely better than the last 3!)

    I had heard some rumblings about the Nature story on drug interactions and found the whole thing to be fascinating, not least because the question is now one of 'what do you tell the patient'? Someone, somewhere who writes the patient information leaflet to these medications is about to put in some serious overtime I think.

    For all the hype on the recent exposure paper, I do like it, and the continued message that the 'chemicals' (solvents, particulates, etc) around us do need a lot more investigation individually and collectively.

  5. I have discussed the C-BASS (Chines benzene and sperm study) study in greater detail with full refernces in the comments section that addresses three questions that have puzzled epidemiologists:

    1. Since autistic people seldom reproduce, why hasn't autism become extinct.

    2. Why is increased autism risk assoicated with advancing parental age

    3. What are the mechanisms underlying de novo sperm or egg mutations in the genetic syndromes and in simplex families.

    The in depth discussion is here: