Environmental toxicity as being associated with ASD in the exposed community

The problem with many studies concerning environmental toxicity is that they have great difficulty pointing a finger at a specific factor that is the cause. For instance you may find there to be an excess of people driving silver cars that have autistic children but this might be due to their social class and hence their diet rather than the colour of the car itself. As such specific toxins, animal models and specific sites are always useful to narrow down the toxic elements that are actually causing the damage. Also, it is difficult to nail down as to whether any toxicity is actually active on the mother of the child or the ASD child itself.

The most notable factor is that all the cases detoxified in an abnormal manner and that liver detoxification was always outside the normal range. This appeared to be as if there was an overload to the system for detoxification and hence there was not surprising to find that there was excess of specific toxins in the blood in 16 of 18 ASD patients tested.

The worry is that the overload comes from the gut in that there has been a demonstration of the absorption of compounds that would normally not be absorbed. Hence the liver’s ability to remove the toxins may be inadequate and in some way a ‘leaky gut’ syndrome could cause toxins to produce long term damage to other systems of the body. I.e. that removal of the toxin from the environment may have little effect in treatment once the ASD syndrome has been developed. Also, many compounds that are taken from the environment, such as organochlorides, mercury or non-specific ones, may be involved in the toxicity. DDT molecule

One way that the researchers have looked at toxicity excretion is through the liver’s common action of attaching the toxin to a soluble glucose-derived compound (e.g. glucaric acid) which will then allow the toxin to be excreted in the urine. They found that there was a high level of glucaric acid in the urine, and low levels in the blood. Also, sulphate may be used by the liver for the same procedure. This is no longer being absorbed from the gut easily, and its manufacture in the body has changed and this explains why there are low levels of sulphate in the blood. As a result it is as if the body’s ability of deal with toxins may well have been modified.

Diagram 1 (right) DDT, an organochloride but one of the many that are present in the environment

Diagram 2: Glucaric acid

The proportion of ASD children that have an inadequate ability to detoxify environmental or dietary factors is unsure, although it seems to be high. However, whatever cause is found for many cases of the condition, an explanation of this phenomenon must be included.

NB. It is important to understand the changes in sulphate metabolism, the leaky gut syndrome, and gut pathology.

Review

Nutritional and environmental approaches to preventing and treating autism and attention deficit hyperactivity disorder (ADHD): a review. Curtis LT, Patel K. J Altern Complement Med. 2008 Jan-Feb;14(1):79-85. Review the available literature of nutritional and environmental factors on autistic spectrum and attention deficit hyperactivity disorder (ADHD). DESIGN AND METHODS: Review of journal articles found on the PubMed database and from information from several conference proceedings. RESULTS: Many, but not all, studies link exposure to toxins such as mercury, lead, pesticides, and in utero smoking exposure to higher levels of autism and/or ADHD.

Nonspecific toxicity excess

Edelson SB, Cantor DS.. Autism: xenobiotic influences. Toxicol Ind Health. 1998 Jul-Aug;14(4):553-63. (Glucaric Acid Analysis, (2) blood analyses for identification of specific xenobiotic agents, and (3) Comprehensive Liver Detoxification Evaluation abnormal liver detoxification profiles in 20 autistic children. Notably 100% of the autistic cases were outside the normal range).

Phase II Depression (S. Edelson, DAN Conference Sept, 1997, and Toxicology and Industrial Health 14 (4): 553-563 1998.

McGovern V. Autism and agricultural pesticides. Integrating data to track trends. Environ Health Perspect. 2007 Oct;115(10):A504. However one group of pesticides did stand out: organochlorines, including the commonly used dicofol and endosulfan, were associated with ASD out to a maternal residential distance of 1,750-meter from the site of application. Dicofol and endosulfan, which are used in the production of cotton, fruit, vegetables, beans, and nuts, account for 98% of the organochlorines applied in the Central Valley region

Urinary increased sulphate (inorganic, organic), sulphite, thiocyanite (by about 50%) in autism vs control. Also d-glucaric acid was very high, which is also used as a modifier for toxins. Original source is not clear. This can be got hold of through the web site: http://www.autismone.org/uploads/2007/James%20Adams%20AO%202007%20presentation% but has partly not been published.

Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. Ashwood P, Schauer J, Pessah IN, Van de Water J. J Neuroimmunol. 2009 Mar 31;208(1-2):130-5. A common environmental contaminant, 2,2',4,4'-tetrabrominated biphenyl (BDE-47), was tested for differential effects on the immune response of peripheral blood mononuclear cells (PBMC) isolated from children with ASD (n=19) and age-matched typically developing controls (TD, n=18). PBMC were exposed in vitro to either 100 nM or 500 nM BDE-47, before challenge with bacterial lipopolysaccharide (LPS), an innate immune activator, with resultant cytokine production measured using the Luminex multiplex platform. The cytokine responses of LPS stimulated PBMC from ASD and TD subjects diverged in the presence of 100 nM BDE. For example, cells cultured from the TD group demonstrated significantly decreased levels of the cytokines IL-12p40, GM-CSF, IL-6, TNFalpha, and the chemokines MIP-1alpha and MIP-1beta following LPS stimulation of PBMC pretreated with 100 nM BDE-47 compared with samples treated with vehicle control (p<0.05). In contrast, cells cultured from subjects with ASD demonstrated an increased IL-1beta response to LPS (p=0.033) when pretreated with 100 nM BDE-47 compared with vehicle control. Preincubation with 500 nM BDE-47 significantly increased the stimulated release of the inflammatory chemokine IL-8 (p<0.04) in cells cultured from subjects with ASD but not in cells from TD controls. These data suggest that in vitro exposure of PBMC to BDE-47 affects cell cytokine production in a pediatric population. Moreover, PBMC from the ASD subjects were differentially affected when compared with the TD controls suggesting a biological basis for altered sensitivity to BDE-47 in the ASD population.

Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. Román GC. J Neurol Sci. 2007 Nov 15;262(1-2):15-26. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus-pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. They discuss a wide range of compounds and why they might perhaps be involved.

A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity. Blaylock RL. Altern Ther Health Med. 2009 Jan-Feb;15(1):60-7.

A possible central mechanism in autism spectrum disorders, part 3: the role of excitotoxin food additives and the synergistic effects of other environmental toxins. Blaylock RL. Altern Ther Health Med. 2009 Mar-Apr;15(2):56-60. foodborne excitotoxin additives can elevate blood and brain glutamate to levels known to cause neurodegeneration and in the developing brain, abnormal connectivity. Excitotoxins are also secreted by microglial activation when they are in an activated state. Recent studies, discussed in part 1 of this article, indicate that chronic microglial activation is common in the autistic brain. The interaction between excitotoxins, free radicals, lipid peroxidation products, inflammatory cytokines, and disruption of neuronal calcium homeostasis can result in brain changes suggestive of the pathological findings in cases of autism spectrum disorders. This is largely an attempt to show how it all might fit together, but it does not show good data in proof.

A hypothalamic digoxin-mediated model for autism. Kurup RK, Kurup PA. Int J Neurosci. 2003 Nov;113(11):1537-59. They did not state this as a possibility for the actual cause of autism but rather a useful model.

Common increase of GATA-3 level in PC-12 cells by three teratogens causing autism spectrum disorders. Rout UK, Clausen P. Neurosci Res. 2009 Jun;64(2):162-9. a neuron-like PC-12 cell model was used to examine the effects of valproate, alcohol and thalidomide on the binding potential of 50 different transcription factors to understand the molecular mechanism/s that may be involved in the teratogenesis caused by these agents. Cells in culture were treated with low or high concentrations of teratogens within a range that are reported in the blood of individuals. A pronounced increase in GATA transcription factor binding was observed for all three teratogens. Furthermore, Western blot analysis showed that GATA-3 level in the nuclear fractions was enhanced by each of the three teratogens.

Ockham's Razor and autism: the case for developmental neurotoxins contributing to a disease of neurodevelopment. DeSoto MC. Neurotoxicology. 2009 May;30(3):331-7. empirical support for environmental toxins as a broad class has been quietly accumulating. Recent research has shown that persons with ASD have comparatively higher levels of various toxins and are more likely to have reduced detoxifying ability, and, that rates of ASD may be higher in areas with greater pollution. This report documents that within the state with the highest rate of ASD, the rate is higher for schools near EPA Superfund sites, t (332)=3.84, p=.0001. (The authors explain the various ways in which the findings can be explained)

Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. Román GC. J Neurol Sci. 2007 Nov 15;262(1-2):15-26. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8-12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants.

Organochlorides and pesticides in the environment: association with autism

Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007 Oct;115(10):1482-9. (ASD risk increased with the poundage of organochlorine applied and decreased with distance from field sites. CONCLUSIONS: The association between residential proximity to organochlorine pesticide applications during gestation and ASD among children should be further studied.)

Goldman LR, Koduru S. Chemicals in the environment and developmental toxicity to children: a public health and policy perspective. Environ Health Perspect. 2000 Jun;108 Suppl 3:443-8. (It simply suggests priority areas for research, including a large environmental prospective study of developmental neurotoxicity. There is little specific data on individual chemicals etc. The article uses valproate, thalidomide and genetics to justify the statement)

McGovern V. Autism and agricultural pesticides. Integrating data to track trends. Environ Health Perspect. 2007 Oct;115(10):A504. (see above)

Mercury (see mercury under heavy metals)

Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas. Health Place. Health Place. 2006 Jun;12(2):203-9.

Windham GC, Zhang L, Gunier R, Croen LA, Grether JK. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco bay area. Environ Health Perspect. 2006 Sep;114(9):1438-44. Shows a potential association between amounts of airborn heavy metal and perhaps solvent pollutants.

Biomarkers of environmental toxicity and susceptibility in autism. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, Geier MR. J Neurol Sci. 2009 May 15;280(1-2):101-8. Urinary porphyrins and transsulfuration metabolites in participants diagnosed with an ASD were examined. A prospective, blinded study was undertaken to evaluate a cohort of 28 participants with an ASD diagnosis for Childhood Autism Rating Scale (CARS) scores, urinary porphyrins, and transsulfuration metabolites. They took the most ASD affected patients to be most highly mercury affected and tried to compare the aspects together of many different chemical changes with the ASD scores. Mercury intoxication-associated urinary porphyrins were significantly correlated with increasing CARS scores and GSSG levels, whereas other urinary porphyrins did not show these relationships. The urinary porphyrin and CARS score correlations observed among study participants suggest that mercury intoxication is significantly associated with autistic symptoms. The transsulfuration abnormalities observed among study participants indicate that mercury intoxication was associated with increased oxidative stress and decreased detoxification capacity.

Parental employment and associations

One of the problems with doing research into things such as this is that such a large proportion of the population do similar things as part of their post and unless there is something that sticks out (window cleaning, fishing etc) it is often difficult to find a specific factor.

Windham GC, Fessel K, Grether JK. Autism spectrum disorders in relation to parental occupation in technical fields Autism Res. 2009 Jul 15. 284 children with ASD and 659 gender-matched controls, born in 1994 in the San Francisco Bay Area. The only odds ratio that they could see that suggested an effect was with mothers of cases. Mothers of cases were somewhat more likely to work in hi-tech occupations (6.7%) than mothers of controls (4.0%, P=0.07), but little difference was observed among fathers. There was no effect seen in white collar rather than blue collar working parents.

Loss of Family Income

A very interesting phenomenon that appears be of significance. This is put here as being associated with environmental change for the child or mother.

Montes G, Halterman JS. Association of childhood autism spectrum disorders and loss of family income. Pediatrics. 2008 Apr;121(4):e821-6.

Age of Parents

Brief Report: Parental Age and the Sex Ratio in Autism. Anello A, Reichenberg A, Luo X, Schmeidler J, Hollander E, Smith CJ, Puleo CM, Kryzak LA, Silverman JM. J Autism Dev Disord. 2009 May 19. The M:F ratio of the offspring (autistic) was significantly decreased with increasing paternal age groups and remained so after also adjusting for maternal age. No significant relationship between maternal age group and the M:F ratio was observed. This study suggests that the M:F ratio is reduced with increasing paternal age consistent with de novo genetic or genomic anomalies arising more frequently as men age and then conceive children. An interesting finding and may suggest that some factor that affected mainly men was involved in causing the major excess in male autistic children (hormones? Environment? Stress?)

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