Autism, attention deficit/hyperactivity disorder (ADHD), mental retardation, dyslexia, and other biologically based disorders of brain development affect between 400,000 and 600,000 of the 4 million children born in the United States each year. Exploration of the environmental causes of autism and other NDDs has been catalyzed by growing recognition of the exquisite sensitivity of the developing human brain to toxic chemicals.
This Editorial, written by Philip J. Landrigan, Luca Lambertini, and Linda S. Birnbaum* appeared first in Environmental Health Perspectives—the peer-reviewed, open access journal of the National Institute of Environmental Health Sciences.
The article is a verbatim version of the original and is not available for edits or additions by Encyclopedia of Earth editors or authors. Companion articles on the same topic that are editable may exist within the Encyclopedia of Earth.
A Research Strategy to Discover the Environmental
Causes of Autism and Neurodevelopmental Disabilities
Autism, attention deficit/hyperactivity disorder (ADHD), mental retardation, dyslexia, and other biologically based disorders of brain development affect between 400,000 and 600,000 of the 4 million children born in the United States each year. The Centers for Disease Control and Prevention (CDC) has reported that autism spectrum disorder (ASD) now affects 1.13% (1 of 88) of American children (CDC 2012) and ADHD affects 14% (CDC 2005; Pastor and Reuben 2008). Treatment of these disorders is difficult; the disabilities they cause can last lifelong, and they are devastating to families. In addition, these disorders place enormous economic burdens on society (Trasande and Liu 2011).
Although discovery research to identify the potentially preventable causes of neuro-develop-mental disorders (NDDs) has increased in recent years, more research is urgently needed. This research encompasses both genetic and environmental studies.
Genetic research has received particular investment and attention (Autism Genome Project Consortium et al. 2007; Buxbaum and Hof 2011; Fernandez et al. 2012; O’Roak et al. 2011; Sakurai et al. 2011) and has demonstrated that ASD and certain other NDDs have a strong hereditary component (Buxbaum and Hof 2011; Sakurai et al. 2011). Linkage studies have identified candidate autism susceptibility genes at multiple loci, most consistently on chromosomes 7q, 15q, and 16p (Autism Genome Project Consortium et al. 2007; Sakurai et al. 2011). Exome sequencing in sporadic cases of autism has detected new mutations (O’Roak et al. 2011), and copy number variant studies have identified several hundred copy number variants putatively linked to autism (Fernandez et al. 2012). The candidate genes most strongly implicated in NDD causation encode for proteins involved in synaptic architecture, neuro-transmitter synthesis (e.g., ©-amino-butyric acid serotonin), oxytocin receptors, and cation trafficking (Sakurai et al. 2011). No single anomaly predominates. Instead, autism appears to be a family of diseases with common phenotypes linked to a series of genetic anomalies, each of which is responsible for no more than 2–3% of cases. The total fraction of ASD attributable to genetic inheri-tance may be about 30–40%.
Exploration of the environmental causes of autism and other NDDs has been catalyzed by growing recognition of the exquisite sensitivity of the developing human brain to toxic chemicals (Grandjean and Landrigan 2006). This susceptibility is greatest during unique “windows of vulnerability” that open only in embryonic and fetal life and have no later counterpart (Miodovnik 2011). “Proof of the principle” that early exposures can cause autism comes from studies linking ASD to medications taken in the first trimester of pregnancy—thalidomide, misoprostol, and valproic acid—and to first-trimester rubella infection (Arndt et al. 2005; Daniels 2006).
This “proof-of-principle” evidence for environmental causation is supported further by findings from prospective birth cohort epidemio-logical studies, many of them supported by the National Institute of Environmental Health Sciences (NIEHS). These studies enroll women during pregnancy, measure prenatal exposures in real time as they occur, and then follow children longitudinally with periodic direct examinations to assess growth, development, and the presence of disease. Prospective studies are powerful engines for the discovery of etiologic associations between prenatal exposures and NDDs. They have linked autistic behaviors with prenatal exposures to the organophosphate insecticide chlorpyrifos (Eskenazi et al. 2007) and also with prenatal exposures to phthalates (Miodovnik et al. 2011). Additional prospective studies have linked loss of cognition (IQ), dyslexia, and ADHD to lead (Jusko et al. 2008), methyl-mercury (Oken et al. 2008), organophosphate insecticides (London et al. 2012), organo-chlorine insecticides (Eskenazi et al. 2008), polychlorinated biphenyls (Winneke 2011), arsenic (Wasserman et al. 2007), manganese (Khan et al. 2011), polycyclic aromatic hydrocarbons (Perera et al. 2009), bisphenol A (Braun et al. 2011), brominated flame retardants (Herbstman et al. 2010), and perfluorinated compounds (Stein and Savitz 2011).
Toxic chemicals likely cause injury to the developing human brain either through direct toxicity or inter-actions with the genome. An expert committee convened by the U.S. National Academy of Sciences (NAS) estimated that 3% of neuro-behavioral disorders are caused directly by toxic environmental exposures and that another 25% are caused by inter-actions between environmental factors, defined broadly, and inherited susceptibilities (National Research Council 2000). Epigenetic modification of gene expression by toxic chemicals that results in DNA methyla-tion, histone modification, or changes in activity levels of non-protein-coding RNA (ncRNAs) may be a mechanism of such gene–environment interaction (Grafodatskaya et al. 2010). Epigenetic “marks” have been shown to be able to influence gene expression and alter high-order DNA structure (Anway and Skinner 2006; Waterland and Jirtle 2004).
A major unanswered question is whether there are still undiscovered environ-mental causes of autism or other NDDs among the thousands of chemicals currently in wide use in the United States. In the past 50 years, > 80,000 new synthetic chemicals have been developed (Landrigan and Goldman 2011). The U.S. Environmental Protection Agency has identified 3,000 “high production volume” (HPV) chemicals that are in widest use and thus pose greatest potential for human exposure (Goldman 1998). These HPV chemicals are used today in millions of consumer products. Children and pregnant women are exposed extensively to them, and CDC surveys detect quantifiable levels of nearly 200 HPV chemicals in the bodies of virtually all Americans, including pregnant women (Woodruff et al. 2011).
The significance of early chemical exposures for children’s health is not yet fully understood. A great concern is that a large number of the chemicals in widest use have not undergone even minimal assessment of potential toxicity, and only about 20% have been screened for potential toxicity during early development (Landrigan and Goldman 2011). Unless studies specifically examine develop-mental consequences of early exposures to untested chemicals, sub-clinical dysfunction caused by these exposures can go unrecognized for years. One example is the “silent epidemic” of childhood lead poisoning: From the 1940s to the 1980s, millions of American children were exposed to excessive levels of lead from paint and gasoline, resulting in reduced average intelligence by 2–5 IQ points (Grosse et al. 2002). The late David Rall, former director of NIEHS, once observed that “If thalidomide had caused a 10-point loss of IQ instead of birth defects of the limbs, it would likely still be on the market” (Weiss 1982).
To begin formulation of a systematic strategy for discovery of potentially preventable environmental causes of autism and other NDDs, the Mount Sinai Children’s Environmental Health Center, with the support of the NIEHS and Autism Speaks, convened a workshop on “Exploring the Environmental Causes of Autism and Learning Disabilities.” This workshop produced a series of papers by leading researchers, some of which are published in this issue of Environmental Health Perspectives. It also generated a list of 10 chemicals and mixtures widely distributed in the environment that are already suspected of causing developmental neurotoxicity:
Lead (Jusko et al. 2008)
Methylmercury (Oken et al. 2008)
Polychlorinated biphenyls (Winneke 2011)
Organochlorine pesticides (Eskenazi et al. 2008)
Automotive exhaust (Volk et al. 2011)
Polycyclic aromatic hydrocarbons (Perera et al. 2009)
Brominated flame retardants (Herbstman et al. 2010)
Perfluorinated compounds (Stein and Savitz 2011).
This list is not exhaustive and will almost certainly expand in the years ahead as new science emerges. It is intended to focus research in environmental causation of NDDs on a short list of chemicals where concentrated study has high potential to generate actionable findings in the near future. Its ultimate purpose is to catalyze new evidence-based programs for prevention of disease in America’s children.
- 2006. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology 147(6): supplS43–S49. Find this article online
- 2005. The teratology of autism. Int J Dev Neurosci 23:189–199. Find this article online
- , Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, et al 2007. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328. Find this article online
- 2011. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics 128(5):873–882. Find this article online
- 2011. The emerging neuroscience of autism spectrum disorders. Brain Res 1380:1–2. Find this article online
- (Centers for Disease Control and Prevention) 2005. Mental health in the United States. Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder–United States, 2003. MMWR Morb Mortal Wkly Rep 54:842–847. Find this article online
- (Centers for Disease Control and Prevention) 2012. Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill Summ 61(3):1–19. Find this article online
- 2006. Autism and the environment. Environ Health Perspect 114:A396.. Find this article online
- 2007. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 115:792–798. Find this article online
- 2008. Pesticide toxicity and the developing brain. Basic Clin Pharmacol Toxicol 102(2):228–236. Find this article online
- 2012. Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry 71(5):392–402. Find this article online
- 1998. Chemicals and children’s environment: what we don’t know about risks. Environ Health Perspect 106: suppl 3875–880. Find this article online
- 2010. Autism spectrum disorders and epigenetics. J Am Acad Child Adolesc Psychiatry 49(8):794–809. Find this article online
- 2006. Developmental neurotoxicity of industrial chemicals: a silent pandemic. Lancet 368(9553):2167–2178. Find this article online
- 2002. Economic gains resulting from the reduction in children’s exposure to lead in the United States. Environ Health Perspect 110:563–569. Find this article online
- 2010. Prenatal exposure to PBDEs and neurodevelopment. Environ Health Perspect 118:712–719. Find this article online
- 2008. Blood lead concentrations < 10 µg/dL and child intelligence at 6 years of age. Environ Health Perspect 116:243–248. Find this article online
- 2011. Manganese exposure from drinking water and children’s classroom behavior in Bangladesh. Environ Health Perspect 119:1501–1506. Find this article online
- 2011. Children’s vulnerability to toxic chemicals: a challenge and opportunity to strengthen health and environmental policy. Health Aff 30(5):842–850. Find this article online
- London L, Beseler C, Bouchard MF, Bellinger DC, Colosio C, Grandjean P, et al. 2012. Neurotoxicology. Neurobehavioral and neurodevelopmental effects of pesticide exposures. http://dx.doi.org/10.1016/j.neuro.2012.01.004 [Online 17 January 2012].
- 2011. Environmental neurotoxicants and developing brain. Mt Sinai J Med 78(1):58–77. Find this article online
- 2011. Endocrine disruptors and childhood social impairment. Neurotoxicology 32(2):261–267. Find this article online
- 2000. Scientific Frontiers in Developmental Toxicology and Risk Assessment. Washington, DC:National Academy Press:
- 2008. Maternal fish intake during pregnancy, blood mercury levels, and child cognition at age 3 years in a US cohort. Am J Epidemiol 167(10):1171–1181. Find this article online
- 2011. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43:585–589. Find this article online
- 2008. Diagnosed attention deficit hyperactivity disorder and learning disability: United States, 2004–2006. Vital Health Stat 10 (237):1–14. Find this article online
- 2009. Prenatal airborne polycyclic aromatic hydrocarbon exposure and child IQ at age 5 years. Pediatrics. 124(2):pp. e195–e202. [Online 20 July 2009)
- 2011. Genomic architecture of autism spectrum disorders. In: Textbook of Autism Spectrum Disorders (Hollander E, Kolevzon A, Coyle JT. eds). Washington, DC:American Psychiatric Publishing: pp. 281–298.
- 2011. Serum perfluorinated compound concentration and attention deficit/hyperactivity disorder in children 5–18 years of age. Environ Health Perspect 119:1466–1471. Find this article online
- 2011. Reducing the staggering costs of environmental disease in children, estimated at $76.6 billion in 2008. Health Aff 30(5):863–870. Find this article online
- 2011. Residential proximity to freeways and autism in the CHARGE Study. Environ Health Perspect 119:873–877. Find this article online
- 2007. Water arsenic exposure and intellectual function in 6-year-old children in Araihazar, Bangladesh. Environ Health Perspect 115:285–289. Find this article online
- 2004. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20:63–68. Find this article online
- 1982. Food additives and environmental chemicals as sources of childhood behavior disorders. J Am Acad Child Psychiatry 21:144–152. Find this article online
- 2011. Developmental aspects of environmental neurotoxicology: lessons from lead and polychlorinated biphenyls. J Neurol Sci 308(1-2):9–15. Find this article online
- 2011. Environmental chemicals in pregnant women in the United States: NHANES 2003–2004. Environ Health Perspect 119:878–885. Find this article online