On the association between symptoms of autism spectrum disorder with environmental toxin exposure.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by behavioral observations and characterized by core impairments in speech and social interaction along with restricted and repetitive patterns of behaviors. Many children with ASD have additional behavioral impairments, including inattention, aggression, and hyperactivity. The prevalence of ASD in the US is estimated to be 1 in 68 children.1 The diagnosis of ASD was recently revised and now includes a rating of ASD severity based on the required level of support for the individual needs of the child.
A number of physiological abnormalities are implicated in ASD, including oxidative stress; immune dysregulation; inflammation; mitochondrial dysfunction; disorders of folate, cobalamin, tetrahydrobiopterin, and carnitine metabolism; gastrointestinal abnormalities; and seizures. When viewed in this light, ASD might arise from these comorbidities, as treatment of these abnormalities may improve symptoms of ASD.2
A better understanding of these comorbidities may lead to future diagnostic tests and treatments, but may also better target research toward the underlying causes of these issues. Potential causes of ASD include genetic abnormalities, but to date, only a minority of ASD cases have been shown to be caused by single gene or chromosomal abnormalities. Recent studies suggest that the etiology of ASD is most consistent with oligogenic inheritance patterns along with non-shared environmental effects. Findings from a recent systematic review indicate an association between ASD and environmental toxicants, which could potentially lead to neurotoxicity and subsequent neurological and psychiatric symptoms.3
Exposures to environmental toxicants during susceptible periods of neurodevelopment may lead to alterations in normal developmental patterns and impaired neurotransmitter function. Several environmental toxicants-including mercury, lead, arsenic, polychlorinated biphenyls, and toluene-cause neurodevelopmental disorders, such as autism, cerebral palsy, ADHD, and mental retardation.4 This may be because the developing brain is more susceptible to injury from toxicants than the adult brain.
Environmental toxicants can also have adverse effects on physiology and could account for some of the physiological abnormalities reported in individuals with ASD. For example, toxicants are known to inhibit mitochondrial function, deplete glutathione, contribute to immune dysregulation, and increase oxidative stress. Mitochondrial dysfunction, depleted glutathione, oxidative stress, and immune dysregulation have been seen in persons with ASD.5-7
A concern when evaluating adverse effects of toxicants in patients is a potential difference in the ability to detoxify and neutralize environmental toxicants, which might vary from person to person depending on genetic susceptibility. Polymorphisms in genes involved with detoxification can lead to impairments in detoxification. In many cases, the exposure to the toxicant may have occurred many years earlier, which makes the identification of the toxicant and a connection between exposure and a particular neurodevelopment disorder difficult at best.
Ongoing exposures to environmental toxicants in individuals with ASD may also be difficult to identify. For example, one study reported that children with ASD were older at the diagnosis of lead toxicity and were more likely to be re-exposed to lead.8 This may be because some children with ASD have an oral-motor stage that is longer than that of typically developing children, and they are more likely to have pica. The presentation of acute lead toxicity in children with ASD can sometimes be unusual and include flu-like symptoms, weight loss, vomiting, diarrhea, and abdominal pain. Therefore, a high index of suspicion for environmental toxicant exposure may be needed in individuals with ASD. This may include periodic screening for blood lead levels.
The following Case Vignette emphasizes the unusual presentation of toxicant exposure that can occur in a child with ASD.
A 14-year-old boy with autism presents to the Rossignol Medical Center (RMC) with depressed appetite and vomiting for 3 weeks and discolored urine. He also has profound fatigue and a 20-lb weight loss over the previous several months. He had seen his pediatrician about a week earlier. At the time, urinalysis had revealed ketones in the urine and increased glucose, protein, and bilirubin; his serum creatinine was 0.35 mg/dL, with elevated alanine aminotransferase (99 U/L) and aspartate aminotransferase (100 U/L). A complete blood cell count showed anemia with a hemoglobin level of 10.7 g/dL (no previous history).
The history taken at the RMC reveals that the boy’s symptoms started shortly after he began taking Ayurvedic herbs from India. Once he became ill, he stopped taking the herbs. Given this history, suspicion is high for possible toxin exposure because some Ayurvedic herbs contain metals. Laboratory studies once again show elevations in liver test results; a test for mononucleosis is negative. A 24-hour urine test for heavy metals reveals normal arsenic, mercury, and cadmium, but elevated lead levels. The boy is admitted to the hospital for intravenous chelation. Upon discharge, his appetite is improved and his fatigue and nausea resolved.
Association between toxicant exposure and ASD
A review of the connection between environmental toxicants and ASD showed the strongest link with exposure to air pollutants and pesticides during preconceptual, gestational, and early childhood stages.9-18 Other toxicants included phthalates, polychlorinated biphenyls, solvents, toxic waste, and heavy metals.
A number of studies examined toxicant biomarkers in ASD.18 The results were mixed for heavy metals. Only about 47% showed higher levels of heavy metals in bodily fluids or tissues of individuals with ASD. Other biomarker studies reported associations of solvents, pesticides, and phthalates with ASD. A correlation between toxicant biomarkers and ASD severity was found in several studies, which is expected if toxicants play a role in ASD; however, few trials looked at a dose response to toxicants, and more research is needed. Finally, some studies reported that polymorphisms in genes involved with detoxification (which would potentially diminish the ability to detoxify) are more common in persons with ASD than in controls, which suggests that some individuals with ASD may have impaired detoxification ability.
More recent studies have continued to implicate environmental toxicants in ASD, particularly air pollution. Individuals with a polymorphism in the MET receptor tyrosine kinase gene (specifically MET rs1858830 CC genotype) and exposure to high levels of air pollution had a higher risk of ASD than those with this polymorphism and lower exposures.19 This gene is involved with cellular migration and survival, and this polymorphism leads to lower MET protein expression in the brain and immune system.
A number of additional studies also reported a correlation between environmental toxicants and ASD severity or physiological abnormalities in children with ASD:
• Blood lead concentrations were significantly correlated with markers of oxidative stress and mitochondrial dysfunction20
• Lymphoblastoid cell lines were more sensitive to the toxic effect of mercury on mitochondrial function21
• Bisphenol-A–induced mitochondrial dysfunction and oxidative stress were observed in lymphoblasts22
• Organic pollutants were significantly correlated with ASD severity, and lead levels were significantly correlated with ASD severity and seropositivity to brain-specific autoantibodies23,24
• A significant correlation was seen between lead blood levels and changes in plasma neurotransmitters25
A small number of studies have looked at potential treatments for toxicants in ASD. One recent study reported improvements in children with ASD by using a clean room sleeping environment that incorporates high-efficiency particulate air (HEPA) filters with activated carbon to remove chemicals and fine particulate matter from the air. Improvements were seen in oxidative stress and immune-related markers as well as behavior.26 Improvements in either autism symptoms or physiological abnormalities in individuals with ASD with the use of chelation and other detoxification methods have also been demonstrated.27-29
Although a significant amount of research has shown an association between environmental toxicants and ASD, further studies are needed to confirm these findings and to identify preventive and treatment strategies. In the meantime, clinicians need to have a high index of suspicion for toxicant exposures in individuals with ASD.
Dr. Rossignol is a family practice physician, Rossignol Medical Center, Aliso Viejo. CA. Dr. Frye is Director of Autism Research, Arkansas Children’s Hospital Research Institute, Little Rock, AR, and Associate Professor, Division of Neurology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR. The authors report no conflicts of interest concerning the subject matter of this article.
1. US Department of Health and Human Services. Prevalence of autism spectrum disorder among children aged 8 years: autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR. 2014;63:1-21.
2. Frye RE, Rossignol DA. Identification and treatment of pathophysiological comorbidities of autism spectrum disorder to achieve optimal outcomes. Pediatrics. 2016;10:43-56.
3. Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry. 2014;4:e360.
4. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. 2006; 368:2167-2178.
5. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012;17:290-314.
6. Rose S, Melnyk S, Pavliv O, et al. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry. 2012;2:e134.
7. Zerbo O, Leong A, Barcellos L, et al. Immune mediated conditions in autism spectrum disorders. Brain Behav Immun. 2015;46:232-236.
8. Shannon M, Graef JW. Lead intoxication in children with pervasive developmental disorders. J Toxicol Clin Toxicol. 1996;34:177-181.
9. McCanlies EC, Fekedulegn D, Mnatsakanova A, et al. Parental occupational exposures and autism spectrum disorder. J Autism Dev Disord. 2012;42: 2323-2334.
10. Roberts EM, English PB, Grether JK, et al. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007;115:1482-1489.
11. Rauh VA, Garfinkel R, Perera FP, et al. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics. 2006;118:e1845-e1859.
12. Eskenazi B, Marks AR, Bradman A, et al. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect. 2007;115:792-798.
13. Volk HE, Hertz-Picciotto I, Delwiche L, et al. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011; 119:873-877.
14. Kalkbrenner AE, Daniels JL, Chen JC, et al. Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Epidemiol. 2010;21:631-641.
15. Becerra TA, Wilhelm M, Olsen J, et al. Ambient air pollution and autism in Los Angeles county, California. Environ Health Perspect. 2013;121:380-386.
16. Volk HE, Lurmann F, Penfold B, et al. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013;70:71-77.
17. Windham GC, Zhang L, Gunier R, et al. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Environ Health Perspect. 2006;114:1438-1444.
18. Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry. 2014;4:e360.
19. Volk HE, Kerin T, Lurmann F, et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiol. 2014;25:44-47.
20. El-Ansary A, Al-Daihan S, Al-Dbass A, Al-Ayadhi L. Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children. Clin Biochem. 2010;43:63-70.
21. Rose S, Wynne R, Frye RE, et al. Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines. J Toxicol. 2015. http://www.hindawi.com/journals/jt/2015/573701/. Accessed July 26, 2016.
22. Kaur K, Chauhan V, Gu F, Chauhan A. Bisphenol A induces oxidative stress and mitochondrial dysfunction in lymphoblasts from children with autism and unaffected siblings. Free Radic Biol Med. 2014; 76:25-33.
23. Boggess A, Faber S, Kern J, Kingston HM. Mean serum-level of common organic pollutants is predictive of behavioral severity in children with autism spectrum disorders. Scientific Reps. 2016. http://www.nature.com/articles/srep26185. Accessed July 26, 2016.
24. Mostafa GA, Bjorklund G, Urbina MA, Al-Ayadhi LY. The positive association between elevated blood lead levels and brain-specific autoantibodies in autistic children from low lead-polluted areas. Metab Brain Dis. June 2016; Epub ahead of print.
25. El-Ansary AK, Bacha AB, Ayahdi LY. Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Biochem. 2011;44:1116-1120.
26. Faber S, Zinn GM, Boggess A, et al. A cleanroom sleeping environment’s impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders. BMC. 2015;15:71.
27. Blaucok-Busch E, Amin OR, Dessoki HH, Rabah T. Efficacy of DMSA therapy in a sample of Arab children with autistic spectrum disorder. Maedica (Buchar). 2012;7:214-221.
28. Patel K, Curtis LT. A comprehensive approach to treating autism and attention-deficit hyperactivity disorder: a prepilot study. J Alt Comp Med. 2007; 13:1091-1097.
29. Eppright TD, Sanfacon JA, Horwitz EA. Attention deficit hyperactivity disorder, infantile autism, and elevated blood-lead: a possible relationship. MO Med. 1996;9:136-138.