Abstract: Disability originating from neurodevelopmental disorders is extremely common affecting more than 10% of children (1) (2).The most common neurodevelopmental disorders include learning disabilities, sensory deficits, developmental delays, attention deficit and hyperactivity disorder and autism, which is the most severe and costly(3) since the associated disabilities are permanent. 

The cause of autism spectrum disorder (ASD) remains elusive despite a large amount of basic and clinical research performed over the last ten years. There are reliable reasons to think that ASD is already present at birth, with many neurological changes that develop during fetal life in response to various heterogeneous factors. The role of genetic abnormalities has attracted huge amount of research effort but the final scenario does not satisfy the original expectation. 

Many twins and family studies point out the importance of inherited predisposition to the disorder even though epidemiologic research suggest the strong contribution of prenatal and early postnatal environmental factors. In fact genetic factors alone account for no more than 20-30% of all cases, whereas other 70-80% are the result of a complex interaction between environmental risk factors and inherited or de novo genetic susceptibility (4). 

As a matter of facts, the prevalence of autism is undoubtedly rising (2) and it is not clear if this increase is linked to the diagnostic improvement or to a greater susceptibility of the population to the disease. Recent studies point to an equal contribution by environmental factors, particularly environmental toxicants (5). 

A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognized causes of neurodevelopmental disorders and subclinical brain dysfunction. 

The recent discovery that heavy metals such as cadmium (Cd), arsen (As), mercury (Hg), nickel (Ni), lead (Pb) may exhibit endocrine-disrupting activity in animal experiments and that the possible mechanism acts by interfering with zinc-finger of nuclear estrogen receptor(6), justify their entrance de facto in the list of endocrine-disrupting compounds. 

Mercury 

Mercury represent the compound most studied in relation to autism risk. A recent review (7 ) found 91 studies that examined the potential relationship between mercury and ASD from 1999 to February 2016. Of these studies, the vast majority (74%) suggest that mercury is a risk factor for ASD, revealing both direct and indirect effects. The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD. 

PCBs 

As a class, Polychlorinated biphenyl ethers (PCBs) have the strongest and longest-known associations with neurological disorders. In humans, there is evidence for impaired neurodevelopment, lower IQ, and problems with attention, memory, and fine motor skills such as writing. PCBs have been designated as persistent organic pollutants and have were banned in the in almost all countries many years ago. However due to their lipophilic nature, PCBs have bio accumulated in the food chain, and levels are still measurable in blood samples today, including those from pregnant women, as well as in breast milk samples. 

In a recent population-based case-control study (8) among Southern California births, including children with ASD (N=545), intellectual deficit (ID)(N=181), and general population (GP) controls (N=418) concentrations of 11 PCB congeners have been measured in banked second trimester 

serum samples were compared between the diagnostic groups. ASD risk was elevated for a number of PCB congeners, particularly for the highest vs. lowest quartile of PCB138/158 (AOR=1.79, 95% CI 1.10, 2.71). 

With these compounds, the first evidence of their neurotoxic potential came from detection of acute adverse effects of high doses on the adult nervous system, and was followed by case reports and epidemiological evidence on developmental toxicity at successively lower doses, to which childhood populations of increasing magnitude were exposed. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain functions. 

After this discovery, many other chemical classes related to ubiquitous environmental agents were put under investigation spot giving birth to the modern environmental toxicology science. 

Until few years ago, the study of potential environmental toxicant contributions to the development of autism has been generally neglected. Today however several systematic reviews of epidemiological and clinical studies examining the role of environmental factors in ASD are available. 

Polycyclic aromatic hydrocarbons (PAHs) 

Recently, a considerable amount of research has studied whether PAHs, the main responsible of air pollution, are harmful to the brain. The most important of these studies is undoubtedly The CHARGE study. 

The American study Childhood Autism Risks from Genetics and the Environment (CHARGE) determined residential traffic exposure in a group of children with autism diagnosed between 24 and 60 months of age (N = 304) and normally developing controls matched for gender, age, and area (N = 259). Children in the highest quartile of the average concentrations of several pollutants (nitrogen oxides, PM10, PM2.5, and NO2) during the first year of life, whole pregnancy, first trimester, second trimester, and third trimester had a higher risk of autism compared to those in the lowest quartile [9]. Additionally, distance from a freeway was more likely to be smaller than or equal to 309 m (10th percentile) for cases than for controls (OR = 1.86, 95% CI: 1.04–3.45) [10]. 

Polybrominated diphenyl ethers (PBDEs) 

PBDEs are a major class of synthetic flame retardants used in large quantities since the 1970s to reduce the risk of combustion. PBDEs are ubiquitous in the environment due to their persistence and bioaccumulating properties; they are found in house dust, soil, sewage sludge, and wildlife.Measurable PBDE levels have been detected in human serum, adipose and liver tissue, placenta, cord serum, and breastmilk in populations around the world (11). 

The impact of prenatal and postnatal PBDE exposures on child behavior has been investigated by a number of epidemiologic studies reviewed recently (12). Results obtained have been conflicting. 

Some of the studies showed a positive association between serum and milk median levels of these compunds and abnormalities of children behavior and other showed no association or negative association. The final message is that prenatal and postnatal PBDE exposure adversely impacts externalizing behavior (e.g., hyperactivity and conduct problems). Additional studies are needed to determine whether PBDEs are associated with internalizing problems, adaptive skills, and social behaviors/ASD in children. 

Phtalates 

Phtalates are another chemical class defined as ubiquitous contaminants. These compounds are used as plasticizers, solvents and additives in many consumer products, i.e. vinyl flooring, wall coverings, food containers and cosmetics. In particular, DEHP [di-(2-ethylhexyl) phthalate] represents one of the most commonly used plasticizer in pharmaceutical and medical devices. 

A recent systematic review has examined published evidences on association between prenatal and/or childhood exposure to phthalate and ASD(13). The results of this systematic review have revealed the limited number of studies conducted and assessed phthalate exposure. Seven studies were regarded as relevant to the objectives of this review. Two of them did not measure phthalate exposure directly and did not result in quantitative results. Out of the five studies in which phthalate exposure was mainly measured by the examining biomarkers in biological samples, two were cohort studies (one with positive results and another one with not clear association). Among the three case control studies, two of them showed a significant relation between exposure to phthalate and ASD and the last case control study had negative results. Indeed, this case control studies showed a compromised phthalate metabolite glucuronidation pathway, as a probable explanation of mechanism of the relation between phthalate exposure and ASD. 

Bisphenol A 

Bisphenol A (BPA) is another ubiquitous agent suspected to can have adverse effects on human health. This common plasticizer is used in the manufacture of polycarbonate plastics, as an antioxidant in some plasticizers, in polyvinyl chloride (PVC) manufacture, and the Epoxy resins used to coat the inside of many food and beverage cans. While there is some recent indirect evidence linking exposure to plasticizers in general, including BPA to ASD. Just a single study has specifically addressed the possible association between BPA and autism(14). To determine whether there was a relationship between BPA exposure and ASD, urine specimens were collected from 46 children with ASD and 52 controls. Free and total BPA concentrations were determined by mass spectrometry. Total BPA was 3 times greater with the ASD group than the controls (P<0.001). 

The results suggest there is an association between BPA and ASD. 

Pesticides

Pesticides are neurotoxic by design and associations have been reported between ASD diagnoses or symptoms and organochlorine, organophosphate, and pyrethroid pesticide exposures during pregnancy. The most important study in this context is again the Charge Study a population-based case-control study of ASD, DD, and typical development (15). 

The aim of the study was to investigate if residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD). 

For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997-2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified. This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates. 

Conclusions 

The overall evidence about the pathogenetic role of EDCs exposure in autism development is compelling. Experimental animal data show numerous neurobiological changes caused by EDCs, including neuronal development, properties of synaptic organization, neurotransmitter synthesis and release, and structural organizational effects on the developing brain. In conjunction with a growing literature on behavioral effects of EDC exposures, especially during development, these studies underscore the brain as a vulnerable target of EDCs. Nevertheless it has to be admitted that 

many of the reviewed studies present significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. 

Because of the limitations of many of the reviewed studies, additional high-quality 

epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings 

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