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Table 2 Systematic reviews and epidemiological studies focused on the association between chemical exposure and autism spectrum disorder

From: Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology

Study design Main findings Reference
Heavy metals
Systematic review on ASD and child exposure to heavy metals. Collectively, the studies support evidence of a positive association between exposure and ASD risk. [43]
Cohort of monozygotic and dizygotic twins discordant for ASD; tooth-matrix biomarkers to estimate pre- and post-natal exposure to metals. Higher levels of lead and lower levels of manganese in ASD. Moderate negative and positive association between respectively manganese and lead levels and ASD severity. [44]
Lead
Comparison between children with high and low concentration of lead in the blood. Association of higher lead levels with decreased IQ performance. [45]
Measurement of blood lead concentration in 172 children at several time-points. Blood lead concentration inversely and significantly associated with IQ. [46]
Pooled analysis on 1333 children from seven cohort studies. Inverse relationship between blood lead concentration and IQ score, with 6.9 IQ point decrement (CI 4.2–9.4) for an increase in blood lead levels from 2.4 to 30 μg/dL. [47]
Methylmercury
Cohort of children in Faroe Islands followed from birth to 7 years of age. Mercury exposure measured in several biological matrices. Association of exposure with language, attention, and memory dysfunctions. [48]
Cohort of children in Faroe Islands followed from birth to 7 years of age. Mercury exposure measured in several biological matrices. Prenatal methylmercury exposure is a predictor of neurobehavioral deficits. [49]
Cohort of children in Faroe Islands. Cohort members examined at 22 years of age: association between prenatal exposure and cognitive deficits. [50]
Cohort of children from New Zealand; mercury levels measured in mother’s hair. Association between high prenatal methylmercury exposure and decreased performance on psychological and scholastic tests. [51]
Cohort of mother-child pairs from Seychelles. Mercury exposure measured in mother’s hair. No relevant association found with several neurocognitive and behavioral functions in children at 9 years of age. [52]
Systematic review on methylmercury prenatal exposure and neurodevelopmental effects. Definition of a “lowest observable adverse effect hair concentration” from evidence by 48 studies on neurodevelopmental risks associated to methylmercury exposure. [53]
Air pollution
Systematic review on environmental toxicants and ASD. Evidence from exposure to air pollution during gestation or childhood overall support an association with increased ASD risk. [43]
Review on potential confounding factors in assessing association of air pollution and ASD. General consistency of findings pointing to a causal association between air pollution and ASD. [54]
Meta-analysis on 25 studies examining maternal exposure to air pollution and ASD risk. Evidence of positive association for PM2.5, weak evidence for NO2, and little evidence for PM10 and ozone. [55]
Meta-analysis on 23 studies examining developmental exposure to air pollution and ASD diagnosis. Statistically significant summary OR for 10 μg/m3 increase in PM10 (OR 1.07; CI 1.06–1.08) and PM2.5 (OR 2.32; CI 2.15–2.51). [56]
ASD prevalence and exposure to traffic-related air pollution assessed in a pregnancy cohort in Los Angeles County (California). 7603 ASD cases and 10 matched controls for each case. 12–15% relative increase in autism odds for each interquartile range (IQR) increase for ozone and PM 2.5. [57]
Cohort of 645 children with autism born in North Carolina and 334 children born in San Francisco Bay area. Compared to 14,666 randomly sampled children born in the same county and year. Exposure to PM10 assessed by geostatistical interpolation methods. Temporal patterns show an inverse correlation between PM10 concentrations in first and third trimester. OR estimated for 10 μg/m3 increase in PM10 after accounting for the correlation are 1.01 (CI 0.81–1.27) for the first trimester and 1.38 (CI 1.03–1.84) for the third trimester. [58]
Nested case-control study of participants in the Nurses’ Health Study II. PM 2.5 and PM 10–2.5 exposure predicted from a spatio-temporal model. Increased ASD risk for PM2.5 exposure, with OR per IQR increase of 1.57 (95% CI 1.22–2.03). Stronger association for exposure in the third trimester (OR 1.42; 95% CI 1.09–1.86). [59]
Case-control study from southwestern Pennsylvania: 217 ASD cases compared to two control groups (intertwined controls and controls from random selection of birth certificates). Analysis performed comparing fourth to first exposure quartile. Increased ASD risk identified for styrene and chromium; borderline effects for PAH and methylene chloride. [60]
Case-control study on 279 ASD and 245 TD children from the Childhood Autism Risks from Genetics and the Environment study in California. ASD children are more likely to live in areas with the highest quartile of traffic-related air pollution during gestation (OR 1.98; CI 1.20–3.31) and during the first year of life (OR 3.10; CI 1.76–5.57). Positive association with ASD found for nitrogen dioxide, PM2.5, PM10. [61]
Cohort of children born in Los Angeles County (California) between 1995 and 2006 from mothers that resided nearby toxic monitoring stations. Increase in ASD risk per IQR increase in average concentration for 1,3-butadiene (OR 1.59; CI 1.18–2.15), meta/para-xylene (OR 1.51; CI 1.26–1.82), lead (OR 1.49; CI 1.23–1.81), perchloroethylene (OR 1.40; CI 1.09–1.80) and formaldehyde (OR 1.34; CI 1.17–1.52). [62]
CHARGE study: examined association between ASD and proximity of residence to freeways or major roadways during pregnancy for 304 ASD and 259 TD children. Maternal residence in the third trimester (OR 2.22, CI 1.16–4.42) and at delivery (OR 1.86, CI 1.04–3.45) more likely near a freeway for ASD than TD. [63]
ESCAPE project: 8079 children from several European birth/child cohorts. No association identified for exposure to NO2 or PM with autistic traits. [64]
Children from the Nurses’ Health Study II (325 cases, 22,101 controls). Exposure to air pollutants assessed at the time and place of birth from the US EPA-modeled levels. Comparing highest versus lowest quintile, association with ASD reported for diesel, lead, manganese, mercury, and methylene chloride with OR from 1.5 to 2. A stronger association was found in boys compared to girls. [65]
Retrospective cohort study on 246,420 children born in South California. Identified a boy-specific association between PM2.5 levels and ASD risk (hazard ratio for first trimester exposure 1.18 per 6.5 μg/m3; CI 1.08–1.27). [66]
Population-based cohort of 132,256 births in Vancouver; prenatal exposure to PM2.5, NO, and NO2 estimated. Association between exposure to NO and ASD (OR for IQR increase 1.07; CI 1.01–1.13). [67]
Case-control study on 124 ASD and 1240 TD from Shanghai. Exposure to PM1, PM2.5, and PM10 estimated for the first 3 years after birth. Association with increased ASD risk for an IQR increase for PM1 (OR 1.85, 95% CI 1.09–3.17), PM2.5 (OR 1.78, 95% CI 1.14–2.75), and PM10 (OR 1.68, 95% CI 1.09–2.59). [68]
Endocrine disruptors
Review on the links between endocrine disruptors and neurodevelopment. Converging body of research from animal models, clinical observations, and human population studies implicates EDCs in an array of neurodevelopmental disorders. [69]
Review summarizing epidemiological studies on the relations of early-life exposure to bisphenol A (BPA), phthalates, triclosan, and perfluoroalkyl substance (PFAS) with childhood neurobehavioral disorders and obesity. Prenatal exposure to several EDCs is associated with adverse neurobehavior (BPA and phthalates) and excess adiposity or increased risk of obesity/overweight (PFAS). [70]
Phthalates
Prospective cohort study of primiparous women in New York between 1998 and 2002 (n = 404). Third-trimester maternal urines analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. Behavioral domains adversely associated with prenatal exposure to low molecular weight phthalates. [71]
Prospective cohort study in New York. Mono-n-butyl phthalate, monobenzyl phthalate, monoisobutyl phthalate, and four di-2-ethylhexyl phthalate metabolites measured in urine. 319 women sampled in the third trimester. Mental, motor, and behavioral development in children at 3 years of age. Prenatal exposure to Di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), and benzyl butyl phthalate (BBzP) may adversely affect child mental, motor, and behavioral development during the preschool years. [72]
Australian pregnancy cohort of 1064 women; exposure to phthalates measured in maternal urine. Oxidative stress-related genetic score calculated from a panel of SNPs. Higher exposure to phthalates was associated to ASD (OR 1.65 per SD unit increase in phthalates; CI 1.00–2.72). Multiple phthalate-SNP interactions observed. [73]
Bisphenol A
Prospective cohort study in Cincinnati (2003–2006). BPA concentrations at 16 and 26 weeks gestation (n = 389). Thyroid stimulating hormone (TSH) and free and total thyroxine (T4) and triiodothyronine (T3) at 16 weeks (n = 181). Prenatal BPA exposure may reduce TSH among newborn girls, particularly when exposure occurs later in gestation. [74]
Collaborative project called the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY–BPA) launched by three US federal agencies: the FDA, the NIH National Institute of Environmental Health Sciences, and the National Toxicology Program. Published studies indicate among the most consistent effects those of BPA on the brain, including alterations of the volume of sexually dimorphic structures and gene expression within specific brain regions. [75]
Perfluoroalkyl substances
Scientific Opinion of the European Food Safety Authority (EFSA) panel on contaminants in the food chain. Administration of PFOS to 10-day old mice has been reported to result in impaired performance in behavioral tests conducted when the mice were 2 and 4 months old. [76]
A nested case-control study in the Danish National Birth Cohort (1996–2002). 220 cases of ADHD, 220 cases of ASD, 550 controls. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. No consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children. [77]
A matched case-control study in Malmö, Sweden (1978–2005). Children with ADHD (n  =  206), controls (n  =  206). PFOS and PFOA concentrations were measured in umbilical cord serum samples. The study revealed no support for an association between fetal exposure to PFOS, PFOA, or PFNA and ADHD. [78]
Polychlorinated biphenyls
Mother-child pairs from MARBLES (California, Davis, from 2006). PCB concentrations were measured in maternal blood at each trimester. Clinical diagnosis of ASD and non-typical development compared to typically developing (TD) analyzed in 3-year-old children. This study does not provide strong supporting evidence that PCBs are risk factors for ASD or non-typical development. [79]
  1. CI 95% confidence interval, OR odds ratio, IQR interquartile range, SD standard deviation, PM2.5 particulate matter ≤ 2.5 micron, PM10 particulate matter ≤ 10 micron